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Sample records for related ligand-centered pseudocontact

  1. Rationalization of Anomalous Pseudocontact Shifts and Their Solvent Dependence in a Series of C3-Symmetric Lanthanide Complexes.

    Science.gov (United States)

    Vonci, Michele; Mason, Kevin; Suturina, Elizaveta A; Frawley, Andrew T; Worswick, Steven G; Kuprov, Ilya; Parker, David; McInnes, Eric J L; Chilton, Nicholas F

    2017-10-11

    Bleaney's long-standing theory of magnetic anisotropy has been employed with some success for many decades to explain paramagnetic NMR pseudocontact shifts, and has been the subject of many subsequent approximations. Here, we present a detailed experimental and theoretical investigation accounting for the anomalous solvent dependence of NMR shifts for a series of lanthanide(III) complexes, namely [LnL 1 ] (Ln = Eu, Tb, Dy, Ho, Er, Tm, and Yb; L 1 : 1,4,7-tris[(6-carboxypyridin-2-yl)methyl]-1,4,7-triazacyclononane), taking into account the effect of subtle ligand flexibility on the electronic structure. We show that the anisotropy of the room temperature magnetic susceptibility tensor, which in turn affects the sign and magnitude of the pseudocontact chemical shift, is extremely sensitive to minimal structural changes in the first coordination sphere of L 1 . We show that DFT structural optimizations do not give accurate structural models, as assessed by the experimental chemical shifts, and thus we determine a magnetostructural correlation and employ this to evaluate the accurate solution structure for each [LnL 1 ]. This approach allows us to explain the counterintuitive pseudocontact shift behavior, as well as a striking solvent dependence. These results have important consequences for the analysis and design of novel magnetic resonance shift and optical emission probes that are sensitive to the local solution environment and polarity.

  2. A partial differential equation for pseudocontact shift.

    Science.gov (United States)

    Charnock, G T P; Kuprov, Ilya

    2014-10-07

    It is demonstrated that pseudocontact shift (PCS), viewed as a scalar or a tensor field in three dimensions, obeys an elliptic partial differential equation with a source term that depends on the Hessian of the unpaired electron probability density. The equation enables straightforward PCS prediction and analysis in systems with delocalized unpaired electrons, particularly for the nuclei located in their immediate vicinity. It is also shown that the probability density of the unpaired electron may be extracted, using a regularization procedure, from PCS data.

  3. PARAssign-paramagnetic NMR assignments of protein nuclei on the basis of pseudocontact shifts

    Energy Technology Data Exchange (ETDEWEB)

    Skinner, Simon P., E-mail: skinnersp@chem.leidenuniv.nl [Leiden University, Gorlaeus Laboratories, Leiden Institute of Chemistry (Netherlands); Moshev, Mois, E-mail: mois@monomon.me [Leiden University, Leiden Institute of Advanced Computer Science (Netherlands); Hass, Mathias A. S., E-mail: hassmas@chem.leidenuniv.nl; Ubbink, Marcellus, E-mail: m.ubbink@chem.leidenuniv.nl [Leiden University, Gorlaeus Laboratories, Leiden Institute of Chemistry (Netherlands)

    2013-04-15

    The use of paramagnetic NMR data for the refinement of structures of proteins and protein complexes is widespread. However, the power of paramagnetism for protein assignment has not yet been fully exploited. PARAssign is software that uses pseudocontact shift data derived from several paramagnetic centers attached to the protein to obtain amide and methyl assignments. The ability of PARAssign to perform assignment when the positions of the paramagnetic centers are known and unknown is demonstrated. PARAssign has been tested using synthetic data for methyl assignment of a 47 kDa protein, and using both synthetic and experimental data for amide assignment of a 14 kDa protein. The complex fitting space involved in such an assignment procedure necessitates that good starting conditions are found, both regarding placement and strength of paramagnetic centers. These starting conditions are obtained through automated tensor placement and user-defined tensor parameters. The results presented herein demonstrate that PARAssign is able to successfully perform resonance assignment in large systems with a high degree of reliability. This software provides a method for obtaining the assignments of large systems, which may previously have been unassignable, by using 2D NMR spectral data and a known protein structure.

  4. Numbat: an interactive software tool for fitting Δχ-tensors to molecular coordinates using pseudocontact shifts

    International Nuclear Information System (INIS)

    Schmitz, Christophe; Stanton-Cook, Mitchell J.; Su Xuncheng; Otting, Gottfried; Huber, Thomas

    2008-01-01

    Pseudocontact shift (PCS) effects induced by a paramagnetic lanthanide bound to a protein have become increasingly popular in NMR spectroscopy as they yield a complementary set of orientational and long-range structural restraints. PCS are a manifestation of the χ-tensor anisotropy, the Δχ-tensor, which in turn can be determined from the PCS. Once the Δχ-tensor has been determined, PCS become powerful long-range restraints for the study of protein structure and protein-ligand complexes. Here we present the newly developed package Numbat (New User-friendly Method Built for Automatic Δχ-Tensor determination). With a Graphical User Interface (GUI) that allows a high degree of interactivity, Numbat is specifically designed for the computation of the complete set of Δχ-tensor parameters (including shape, location and orientation with respect to the protein) from a set of experimentally measured PCS and the protein structure coordinates. Use of the program for Linux and Windows operating systems is illustrated by building a model of the complex between the E. coli DNA polymerase III subunits ε186 and θ using PCS

  5. An NMR strategy for fragment-based ligand screening utilizing a paramagnetic lanthanide probe

    International Nuclear Information System (INIS)

    Saio, Tomohide; Ogura, Kenji; Shimizu, Kazumi; Yokochi, Masashi; Burke, Terrence R.; Inagaki, Fuyuhiko

    2011-01-01

    A nuclear magnetic resonance-based ligand screening strategy utilizing a paramagnetic lanthanide probe is presented. By fixing a paramagnetic lanthanide ion to a target protein, a pseudo-contact shift (PCS) and a paramagnetic relaxation enhancement (PRE) can be observed for both the target protein and its bound ligand. Based on PRE and PCS information, the bound ligand is then screened from the compound library and the structure of the ligand–protein complex is determined. PRE is an isotropic paramagnetic effect observed within 30 Å from the lanthanide ion, and is utilized for the ligand screening in the present study. PCS is an anisotropic paramagnetic effect providing long-range (∼40 Å) distance and angular information on the observed nuclei relative to the paramagnetic lanthanide ion, and utilized for the structure determination of the ligand–protein complex. Since a two-point anchored lanthanide-binding peptide tag is utilized for fixing the lanthanide ion to the target protein, this screening method can be generally applied to non-metal-binding proteins. The usefulness of this strategy was demonstrated in the case of the growth factor receptor-bound protein 2 (Grb2) Src homology 2 (SH2) domain and its low- and high-affinity ligands.

  6. Integral membrane protein structure determination using pseudocontact shifts

    Energy Technology Data Exchange (ETDEWEB)

    Crick, Duncan J.; Wang, Jue X. [University of Cambridge, Department of Biochemistry (United Kingdom); Graham, Bim; Swarbrick, James D. [Monash University, Monash Institute of Pharmaceutical Sciences (Australia); Mott, Helen R.; Nietlispach, Daniel, E-mail: dn206@cam.ac.uk [University of Cambridge, Department of Biochemistry (United Kingdom)

    2015-04-15

    Obtaining enough experimental restraints can be a limiting factor in the NMR structure determination of larger proteins. This is particularly the case for large assemblies such as membrane proteins that have been solubilized in a membrane-mimicking environment. Whilst in such cases extensive deuteration strategies are regularly utilised with the aim to improve the spectral quality, these schemes often limit the number of NOEs obtainable, making complementary strategies highly beneficial for successful structure elucidation. Recently, lanthanide-induced pseudocontact shifts (PCSs) have been established as a structural tool for globular proteins. Here, we demonstrate that a PCS-based approach can be successfully applied for the structure determination of integral membrane proteins. Using the 7TM α-helical microbial receptor pSRII, we show that PCS-derived restraints from lanthanide binding tags attached to four different positions of the protein facilitate the backbone structure determination when combined with a limited set of NOEs. In contrast, the same set of NOEs fails to determine the correct 3D fold. The latter situation is frequently encountered in polytopical α-helical membrane proteins and a PCS approach is thus suitable even for this particularly challenging class of membrane proteins. The ease of measuring PCSs makes this an attractive route for structure determination of large membrane proteins in general.

  7. DipoCoup: A versatile program for 3D-structure homology comparison based on residual dipolar couplings and pseudocontact shifts

    International Nuclear Information System (INIS)

    Meiler, Jens; Peti, Wolfgang; Griesinger, Christian

    2000-01-01

    A program, DipoCoup, is presented that allows to search the protein data bank for proteins which have a three dimensional fold that is at least partially homologous to a protein under investigation. The three dimensional homology search uses secondary structure alignment based on chemical shifts and dipolar couplings or pseudocontact shifts for the three dimensional orientation of secondary structure elements. Moreover, the program offers additional tools for handling and analyzing dipolar couplings

  8. Improving the Accuracy of NMR Structures of Large Proteins Using Pseudocontact Shifts as Long-Range Restraints

    Energy Technology Data Exchange (ETDEWEB)

    Gaponenko, Vadim [National Cancer Institute, Structural Biophysics Laboratory (United States); Sarma, Siddhartha P. [Indian Institute of Science, Molecular Biophysics Unit (India); Altieri, Amanda S. [National Cancer Institute, Structural Biophysics Laboratory (United States); Horita, David A. [Wake Forest University School of Medicine, Department of Biochemistry (United States); Li, Jess; Byrd, R. Andrew [National Cancer Institute, Structural Biophysics Laboratory (United States)], E-mail: rabyrd@ncifcrf.gov

    2004-03-15

    We demonstrate improved accuracy in protein structure determination for large ({>=}30 kDa), deuterated proteins (e.g. STAT4{sub NT}) via the combination of pseudocontact shifts for amide and methyl protons with the available NOEs in methyl-protonated proteins. The improved accuracy is cross validated by Q-factors determined from residual dipolar couplings measured as a result of magnetic susceptibility alignment. The paramagnet is introduced via binding to thiol-reactive EDTA, and multiple sites can be serially engineered to obtain data from alternative orientations of the paramagnetic anisotropic susceptibility tensor. The technique is advantageous for systems where the target protein has strong interactions with known alignment media.

  9. Magic Angle Spinning NMR Structure Determination of Proteins from Pseudocontact Shifts

    KAUST Repository

    Li, Jianping

    2013-06-05

    Magic angle spinning solid-state NMR is a unique technique to study atomic-resolution structure of biomacromolecules which resist crystallization or are too large to study by solution NMR techniques. However, difficulties in obtaining sufficient number of long-range distance restraints using dipolar coupling based spectra hamper the process of structure determination of proteins in solid-state NMR. In this study it is shown that high-resolution structure of proteins in solid phase can be determined without the use of traditional dipolar-dipolar coupling based distance restraints by combining the measurements of pseudocontact shifts (PCSs) with Rosetta calculations. The PCSs were generated by chelating exogenous paramagnetic metal ions to a tag 4-mercaptomethyl-dipicolinic acid, which is covalently attached to different residue sites in a 56-residue immunoglobulin-binding domain of protein G (GB1). The long-range structural restraints with metal-nucleus distance of up to ∼20 Å are quantitatively extracted from experimentally observed PCSs, and these are in good agreement with the distances back-calculated using an X-ray structure model. Moreover, we demonstrate that using several paramagnetic ions with varied paramagnetic susceptibilities as well as the introduction of paramagnetic labels at different sites can dramatically increase the number of long-range restraints and cover different regions of the protein. The structure generated from solid-state NMR PCSs restraints combined with Rosetta calculations has 0.7 Å root-mean-square deviation relative to X-ray structure. © 2013 American Chemical Society.

  10. Magic Angle Spinning NMR Structure Determination of Proteins from Pseudocontact Shifts

    KAUST Repository

    Li, Jianping; Pilla, Kala Bharath; Li, Qingfeng; Zhang, Zhengfeng; Su, Xuncheng; Huber, Thomas; Yang, Jun

    2013-01-01

    Magic angle spinning solid-state NMR is a unique technique to study atomic-resolution structure of biomacromolecules which resist crystallization or are too large to study by solution NMR techniques. However, difficulties in obtaining sufficient number of long-range distance restraints using dipolar coupling based spectra hamper the process of structure determination of proteins in solid-state NMR. In this study it is shown that high-resolution structure of proteins in solid phase can be determined without the use of traditional dipolar-dipolar coupling based distance restraints by combining the measurements of pseudocontact shifts (PCSs) with Rosetta calculations. The PCSs were generated by chelating exogenous paramagnetic metal ions to a tag 4-mercaptomethyl-dipicolinic acid, which is covalently attached to different residue sites in a 56-residue immunoglobulin-binding domain of protein G (GB1). The long-range structural restraints with metal-nucleus distance of up to ∼20 Å are quantitatively extracted from experimentally observed PCSs, and these are in good agreement with the distances back-calculated using an X-ray structure model. Moreover, we demonstrate that using several paramagnetic ions with varied paramagnetic susceptibilities as well as the introduction of paramagnetic labels at different sites can dramatically increase the number of long-range restraints and cover different regions of the protein. The structure generated from solid-state NMR PCSs restraints combined with Rosetta calculations has 0.7 Å root-mean-square deviation relative to X-ray structure. © 2013 American Chemical Society.

  11. Pulse EPR-enabled interpretation of scarce pseudocontact shifts induced by lanthanide binding tags

    Energy Technology Data Exchange (ETDEWEB)

    Abdelkader, Elwy H.; Yao, Xuejun [Australian National University, Research School of Chemistry (Australia); Feintuch, Akiva [Weizmann Institute of Science, Department of Chemical Physics (Israel); Adams, Luke A.; Aurelio, Luigi; Graham, Bim [Monash University, Monash Institute of Pharmaceutical Sciences (Australia); Goldfarb, Daniella [Weizmann Institute of Science, Department of Chemical Physics (Israel); Otting, Gottfried, E-mail: gottfried.otting@anu.edu.au [Australian National University, Research School of Chemistry (Australia)

    2016-01-15

    Pseudocontact shifts (PCS) induced by tags loaded with paramagnetic lanthanide ions provide powerful long-range structure information, provided the location of the metal ion relative to the target protein is known. Usually, the metal position is determined by fitting the magnetic susceptibility anisotropy (Δχ) tensor to the 3D structure of the protein in an 8-parameter fit, which requires a large set of PCSs to be reliable. In an alternative approach, we used multiple Gd{sup 3+}-Gd{sup 3+} distances measured by double electron–electron resonance (DEER) experiments to define the metal position, allowing Δχ-tensor determinations from more robust 5-parameter fits that can be performed with a relatively sparse set of PCSs. Using this approach with the 32 kDa E. coli aspartate/glutamate binding protein (DEBP), we demonstrate a structural transition between substrate-bound and substrate-free DEBP, supported by PCSs generated by C3-Tm{sup 3+} and C3-Tb{sup 3+} tags attached to a genetically encoded p-azidophenylalanine residue. The significance of small PCSs was magnified by considering the difference between the chemical shifts measured with Tb{sup 3+} and Tm{sup 3+} rather than involving a diamagnetic reference. The integrative sparse data approach developed in this work makes poorly soluble proteins of limited stability amenable to structural studies in solution, without having to rely on cysteine mutations for tag attachment.

  12. The coordination chemistry of the neutral tris-2-pyridyl silicon ligand [PhSi(6-Me-2-py)3].

    Science.gov (United States)

    Plajer, Alex J; Colebatch, Annie L; Enders, Markus; García-Romero, Álvaro; Bond, Andrew D; García-Rodríguez, Raúl; Wright, Dominic S

    2018-05-22

    Difficulties in the preparation of neutral ligands of the type [RSi(2-py)3] (where 2-py is an unfunctionalised 2-pyridyl ring unit) have thwarted efforts to expand the coordination chemistry of ligands of this type. However, simply switching the pyridyl substituents to 6-methyl-pyridyl groups (6-Me-2-py) in the current paper has allowed smooth, high-yielding access to the [PhSi(6-Me-2-py)3] ligand (1), and the first exploration of its coordination chemistry with transition metals. The synthesis, single-crystal X-ray structures and solution dynamics of the new complexes [{PhSi(6-Me-2-py)3}CuCH3CN][PF6], [{PhSi(6-Me-2-py)3}CuCH3CN][CuCl2], [{PhSi(6-Me-2-py)3}FeCl2], [{PhSi(6-Me-2-py)3}Mo(CO)3] and [{PhSi(6-Me-2-py)3}CoCl2] are reported. The paramagnetic Fe2+ and Co2+ complexes show strongly shifted NMR resonances for the coordinated pyridyl units due to large Fermi-contact shifts. However, magnetic anisotropy also leads to considerable pseudo-contact shifts so that both contributions have to be included in the paramagnetic NMR analysis.

  13. Implicit ligand theory for relative binding free energies

    Science.gov (United States)

    Nguyen, Trung Hai; Minh, David D. L.

    2018-03-01

    Implicit ligand theory enables noncovalent binding free energies to be calculated based on an exponential average of the binding potential of mean force (BPMF)—the binding free energy between a flexible ligand and rigid receptor—over a precomputed ensemble of receptor configurations. In the original formalism, receptor configurations were drawn from or reweighted to the apo ensemble. Here we show that BPMFs averaged over a holo ensemble yield binding free energies relative to the reference ligand that specifies the ensemble. When using receptor snapshots from an alchemical simulation with a single ligand, the new statistical estimator outperforms the original.

  14. Three-Dimensional Protein Fold Determination from Backbone Amide Pseudocontact Shifts Generated by Lanthanide Tags at Multiple Sites

    KAUST Repository

    Yagi, Hiromasa

    2013-06-01

    Site-specific attachment of paramagnetic lanthanide ions to a protein generates pseudocontact shifts (PCS) in the nuclear magnetic resonance (NMR) spectra of the protein that are easily measured as changes in chemical shifts. By labeling the protein with lanthanide tags at four different sites, PCSs are observed for most amide protons and accurate information is obtained about their coordinates in three-dimensional space. The approach is demonstrated with the chaperone ERp29, for which large differences have been reported between X-ray and NMR structures of the C-terminal domain, ERp29-C. The results unambiguously show that the structure of rat ERp29-C in solution is similar to the crystal structure of human ERp29-C. PCSs of backbone amides were the only structural restraints required. Because these can be measured for more dilute protein solutions than other NMR restraints, the approach greatly widens the range of proteins amenable to structural studies in solution. © 2013 Elsevier Ltd. All rights reserved.

  15. Sequence-specific assignment of methyl groups from the neuronal SNARE complex using lanthanide-induced pseudocontact shifts

    International Nuclear Information System (INIS)

    Pan, Yun-Zu; Quade, Bradley; Brewer, Kyle D.; Szabo, Monika; Swarbrick, James D.; Graham, Bim; Rizo, Josep

    2016-01-01

    Neurotransmitter release depends critically on the neuronal SNARE complex formed by syntaxin-1, SNAP-25 and synaptobrevin, as well as on other proteins such as Munc18-1, Munc13-1 and synaptotagmin-1. Although three-dimensional structures are available for these components, it is still unclear how they are assembled between the synaptic vesicle and plasma membranes to trigger fast, Ca 2+ -dependent membrane fusion. Methyl TROSY NMR experiments provide a powerful tool to study complexes between these proteins, but assignment of the methyl groups of the SNARE complex is hindered by its limited solubility. Here we report the assignment of the isoleucine, leucine, methionine and valine methyl groups of the four SNARE motifs of syntaxin-1, SNAP-25 and synaptobrevin within the SNARE complex based solely on measurements of lanthanide-induced pseudocontact shifts. Our results illustrate the power of this approach to assign protein resonances without the need of triple resonance experiments and provide an invaluable tool for future structural studies of how the SNARE complex binds to other components of the release machinery.

  16. Sequence-specific assignment of methyl groups from the neuronal SNARE complex using lanthanide-induced pseudocontact shifts

    Energy Technology Data Exchange (ETDEWEB)

    Pan, Yun-Zu; Quade, Bradley; Brewer, Kyle D. [University of Texas Southwestern Medical Center, Department of Biophysics (United States); Szabo, Monika; Swarbrick, James D.; Graham, Bim [Monash Institute of Pharmaceutical Sciences, Monash University (Australia); Rizo, Josep, E-mail: Jose.Rizo-Rey@UTSouthwestern.edu [University of Texas Southwestern Medical Center, Department of Biophysics (United States)

    2016-12-15

    Neurotransmitter release depends critically on the neuronal SNARE complex formed by syntaxin-1, SNAP-25 and synaptobrevin, as well as on other proteins such as Munc18-1, Munc13-1 and synaptotagmin-1. Although three-dimensional structures are available for these components, it is still unclear how they are assembled between the synaptic vesicle and plasma membranes to trigger fast, Ca{sup 2+}-dependent membrane fusion. Methyl TROSY NMR experiments provide a powerful tool to study complexes between these proteins, but assignment of the methyl groups of the SNARE complex is hindered by its limited solubility. Here we report the assignment of the isoleucine, leucine, methionine and valine methyl groups of the four SNARE motifs of syntaxin-1, SNAP-25 and synaptobrevin within the SNARE complex based solely on measurements of lanthanide-induced pseudocontact shifts. Our results illustrate the power of this approach to assign protein resonances without the need of triple resonance experiments and provide an invaluable tool for future structural studies of how the SNARE complex binds to other components of the release machinery.

  17. Two novel mixed-ligand complexes containing organosulfonate ligands.

    Science.gov (United States)

    Li, Mingtian; Huang, Jun; Zhou, Xuan; Fang, Hua; Ding, Liyun

    2008-07-01

    The structures reported herein, viz. bis(4-aminonaphthalene-1-sulfonato-kappaO)bis(4,5-diazafluoren-9-one-kappa(2)N,N')copper(II), [Cu(C(10)H(8)NO(3)S)(2)(C(11)H(6)N(2)O)(2)], (I), and poly[[[diaquacadmium(II)]-bis(mu-4-aminonaphthalene-1-sulfonato)-kappa(2)O:N;kappa(2)N:O] dihydrate], {[Cd(C(10)H(8)NO(3)S)(2)(H(2)O)(2)].2H(2)O}(n), (II), are rare examples of sulfonate-containing complexes where the anion does not fulfill a passive charge-balancing role, but takes an active part in coordination as a monodentate and/or bridging ligand. Monomeric complex (I) possesses a crystallographic inversion center at the Cu(II) atom, and the asymmetric unit contains one-half of a Cu atom, one complete 4-aminonaphthalene-1-sulfonate (ans) ligand and one 4,5-diazafluoren-9-one (DAFO) ligand. The Cu(II) atom has an elongated distorted octahedral coordination geometry formed by two O atoms from two monodentate ans ligands and by four N atoms from two DAFO molecules. Complex (II) is polymeric and its crystal structure is built up by one-dimensional chains and solvent water molecules. Here also the cation (a Cd(II) atom) lies on a crystallographic inversion center and adopts a slightly distorted octahedral geometry. Each ans anion serves as a bridging ligand linking two Cd(II) atoms into one-dimensional infinite chains along the [010] direction, with each Cd(II) center coordinated by four ans ligands via O and N atoms and by two aqua ligands. In both structures, there are significant pi-pi stacking interactions between adjacent ligands and hydrogen bonds contribute to the formation of two- and three-dimensional networks.

  18. Ligand-Enabled γ-C–H Olefination and Carbonylation: Construction of β-Quaternary Carbon Centers

    Science.gov (United States)

    2015-01-01

    Monoselective γ-C–H olefination and carbonylation of aliphatic acids has been accomplished by using a combination of a quinoline-based ligand and a weakly coordinating amide directing group. The reaction provides a new route for constructing richly functionalized all-carbon quaternary carbon centers at the β-position of aliphatic acids. PMID:24666182

  19. Symptom clusters in cancer patients and their relation to EGFR ligand modulation of the circadian axis.

    Science.gov (United States)

    Rich, Tyvin A

    2007-04-01

    Recent studies in chronobiology and the neurosciences have led to rapid growth in our understanding of the molecular biology of the human timekeeping apparatus and the neuroanatomic sites involved in signaling between the "master clock" in the hypothalamus and other parts of the brain. The circadian axis comprises a central clock mechanism and a downstream network of hypothalamic relay stations that modulate arousal, feeding, and sleeping behavior. Communication between the clock and these hypothalamic signaling centers is mediated, in part, by diffusible substances that include ligands of the epidermal growth factor receptor (EGFR). Preclinical studies reveal that EGFR ligands such as transforming growth factor-alpha (TGF-alpha) inhibit hypothalamic signaling of rhythmic behavior; clinical observations show that elevated levels of TGF-alpha are associated with fatigue, flattened circadian rhythms, and loss of appetite in patients with metastatic colorectal cancer. These data support the hypothesis that a symptom cluster of fatigue, appetite loss, and sleep disruption commonly seen in cancer patients may be related to EGFR ligands, released either by the cancer itself or by the host in response to the stress of cancer, and suggest that further examination of their role in the production of symptom clustering is warranted.

  20. Comparative analysis of electron-density and electron-localization function for dinuclear manganese complexes with bridging boron- and carbon-centered ligands.

    Science.gov (United States)

    Götz, Kathrin; Kaupp, Martin; Braunschweig, Holger; Stalke, Dietmar

    2009-01-01

    Bonding in borylene-, carbene-, and vinylidene-bridged dinuclear manganese complexes [MnCp(CO)(2)](2)X (X = B-tBu, B = NMe(2), CH(2), C=CH(2)) has been compared by analyses based on quantum theory of atoms in molecules (QTAIM), on the electron-localization function (ELF), and by natural-population analyses. All of the density functional theory based analyses agree on the absence of a significant direct Mn-Mn bond in these complexes and confirm a dominance of delocalized bonding via the bridging ligand. Interestingly, however, the topology of both charge density and ELF related to the Mn-bridge-Mn bonding depend qualitatively on the chosen density functional (except for the methylene-bridged complex, which exhibits only one three-center-bonding attractor both in -nabla(2)rho and in ELF). While gradient-corrected functionals provide a picture with localized two-center X-Mn bonding, increasing exact-exchange admixture in hybrid functionals concentrates charge below the bridging atom and suggests a three-center bonding situation. For example, the bridging boron ligands may be described either as substituted boranes (e.g., at BLYP or BP86 levels) or as true bridging borylenes (e.g., at BHLYP level). This dependence on the theoretical level appears to derive from a bifurcation between two different bonding situations and is discussed in terms of charge transfer between X and Mn, and in the context of self-interaction errors exhibited by popular functionals.

  1. Relative Lyapunov Center Bifurcations

    DEFF Research Database (Denmark)

    Wulff, Claudia; Schilder, Frank

    2014-01-01

    Relative equilibria (REs) and relative periodic orbits (RPOs) are ubiquitous in symmetric Hamiltonian systems and occur, for example, in celestial mechanics, molecular dynamics, and rigid body motion. REs are equilibria, and RPOs are periodic orbits of the symmetry reduced system. Relative Lyapunov...... center bifurcations are bifurcations of RPOs from REs corresponding to Lyapunov center bifurcations of the symmetry reduced dynamics. In this paper we first prove a relative Lyapunov center theorem by combining recent results on the persistence of RPOs in Hamiltonian systems with a symmetric Lyapunov...... center theorem of Montaldi, Roberts, and Stewart. We then develop numerical methods for the detection of relative Lyapunov center bifurcations along branches of RPOs and for their computation. We apply our methods to Lagrangian REs of the N-body problem....

  2. An encodable lanthanide binding tag with reduced size and flexibility for measuring residual dipolar couplings and pseudocontact shifts in large proteins

    Energy Technology Data Exchange (ETDEWEB)

    Barb, Adam W., E-mail: abarb@iastate.edu; Subedi, Ganesh P. [Iowa State University, Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology (United States)

    2016-01-15

    Metal ions serve important roles in structural biology applications from long-range perturbations seen in magnetic resonance experiments to electron-dense signatures in X-ray crystallography data; however, the metal ion must be secured in a molecular framework to achieve the maximum benefit. Polypeptide-based lanthanide-binding tags (LBTs) represent one option that can be directly encoded within a recombinant protein expression construct. However, LBTs often exhibit significant mobility relative to the target molecule. Here we report the characterization of improved LBTs sequences for insertion into a protein loop. These LBTs were inserted to connect two parallel alpha helices of an immunoglobulin G (IgG)-binding Z domain platform. Variants A and B bound Tb{sup 3+} with high affinity (0.70 and 0.13 μM, respectively) and displayed restricted LBT motion. Compared to the parent construct, the metal-bound A experienced a 2.5-fold reduction in tag motion as measured by magnetic field-induced residual dipolar couplings and was further studied in a 72.2 kDa complex with the human IgG1 fragment crystallizable (IgG1 Fc) glycoprotein. The appearance of both pseudo-contact shifts (−0.221 to 0.081 ppm) and residual dipolar couplings (−7.6 to 14.3 Hz) of IgG1 Fc resonances in the IgG1 Fc:(variant A:Tb{sup 3+}){sub 2} complex indicated structural restriction of the LBT with respect to the Fc. These studies highlight the applicability of improved LBT sequences with reduced mobility to probe the structure of macromolecular systems.

  3. An encodable lanthanide binding tag with reduced size and flexibility for measuring residual dipolar couplings and pseudocontact shifts in large proteins

    International Nuclear Information System (INIS)

    Barb, Adam W.; Subedi, Ganesh P.

    2016-01-01

    Metal ions serve important roles in structural biology applications from long-range perturbations seen in magnetic resonance experiments to electron-dense signatures in X-ray crystallography data; however, the metal ion must be secured in a molecular framework to achieve the maximum benefit. Polypeptide-based lanthanide-binding tags (LBTs) represent one option that can be directly encoded within a recombinant protein expression construct. However, LBTs often exhibit significant mobility relative to the target molecule. Here we report the characterization of improved LBTs sequences for insertion into a protein loop. These LBTs were inserted to connect two parallel alpha helices of an immunoglobulin G (IgG)-binding Z domain platform. Variants A and B bound Tb 3+ with high affinity (0.70 and 0.13 μM, respectively) and displayed restricted LBT motion. Compared to the parent construct, the metal-bound A experienced a 2.5-fold reduction in tag motion as measured by magnetic field-induced residual dipolar couplings and was further studied in a 72.2 kDa complex with the human IgG1 fragment crystallizable (IgG1 Fc) glycoprotein. The appearance of both pseudo-contact shifts (−0.221 to 0.081 ppm) and residual dipolar couplings (−7.6 to 14.3 Hz) of IgG1 Fc resonances in the IgG1 Fc:(variant A:Tb 3+ ) 2 complex indicated structural restriction of the LBT with respect to the Fc. These studies highlight the applicability of improved LBT sequences with reduced mobility to probe the structure of macromolecular systems

  4. Synthesis, characterization, and reactivity of ruthenium hydride complexes of N-centered triphosphine ligands.

    Science.gov (United States)

    Phanopoulos, Andreas; Brown, Neil J; White, Andrew J P; Long, Nicholas J; Miller, Philip W

    2014-04-07

    The reactivity of the novel tridentate phosphine ligand N(CH2PCyp2)3 (N-triphos(Cyp), 2; Cyp = cyclopentyl) with various ruthenium complexes was investigated and compared that of to the less sterically bulky and less electron donating phenyl derivative N(CH2PPh2)3 (N-triphos(Ph), 1). One of these complexes was subsequently investigated for reactivity toward levulinic acid, a potentially important biorenewable feedstock. Reaction of ligands 1 and 2 with the precursors [Ru(COD)(methylallyl)2] (COD = 1,5-cycloocatadiene) and [RuH2(PPh3)4] gave the tridentate coordination complexes [Ru(tmm){N(CH2PR2)3-κ(3)P}] (R = Ph (3), Cyp (4); tmm = trimethylenemethane) and [RuH2(PPh3){N(CH2PR2)3-κ(3)P}] (R = Ph (5), Cyp (6)), respectively. Ligands 1 and 2 displayed different reactivities with [Ru3(CO)12]. Ligand 1 gave the tridentate dicarbonyl complex [Ru(CO)2{N(CH2PPh2)3-κ(3)P}] (7), while 2 gave the bidentate, tricarbonyl [Ru(CO)3{N(CH2PCyp2)3-κ(2)P}] (8). This was attributed to the greater electron-donating characteristics of 2, requiring further stabilization on coordination to the electron-rich Ru(0) center by more CO ligands. Complex 7 was activated via oxidation using AgOTf and O2, giving the Ru(II) complexes [Ru(CO)2(OTf){N(CH2PPh2)3-κ(3)P}](OTf) (9) and [Ru(CO3)(CO){N(CH2PPh2)3-κ(3)P}] (11), respectively. Hydrogenation of these complexes under hydrogen pressures of 3-15 bar gave the monohydride and dihydride complexes [RuH(CO)2{N(CH2PPh2)3-κ(3)P}] (10) and [RuH2(CO){N(CH2PPh2)3-κ(3)P}] (12), respectively. Complex 12 was found to be unreactive toward levulinic acid (LA) unless activated by reaction with NH4PF6 in acetonitrile, forming [RuH(CO)(MeCN){N(CH2PPh2)3-κ(3)P}](PF6) (13), which reacted cleanly with LA to form [Ru(CO){N(CH2PPh2)3-κ(3)P}{CH3CO(CH2)2CO2H-κ(2)O}](PF6) (14). Complexes 3, 5, 7, 8, 11, and 12 were characterized by single-crystal X-ray crystallography.

  5. Variations of structures and solid-state conductivity of isomeric silver(I) coordination polymers having linear and V-shaped thiophene-centered ditriazole ligands

    International Nuclear Information System (INIS)

    Hu, Bin; Geng, Jiao; Zhang, Lie; Huang, Wei

    2014-01-01

    A pair of new linear and V-shaped acceptor–donor–acceptor (A−D−A) thiophene-centered ditriazole structural isomers, i.e., 2,5-di(1H-1,2,4-triazol-1-yl)thiophene (L 1 ) and 3,4-di(1H-1,2,4-triazol-1-yl)thiophene (L 2 ), has been synthesized and characterized. They are used as μ 2 -bridging ligands to prepare a pair of silver(I) coordination polymers formulated as [Ag(L 1 )(NO 3 )] n (1) and [Ag(L 2 )(NO 3 )] n (2), which are also structural isomers at the supramolecular level. X-ray single-crystal diffraction analyses for 1 and 2 reveal that they exhibit the same one-dimensional (1D) coordination polymers but different structural architectures because of the distinguishable shape and configuration of isomeric ligands (L 1 and L 2 ) and the alterations of the coordination numbers. More interestingly, compared with the free ligands, 1D silver(I) polymeric isomers 1 and 2 show significant enhancement of solid-state conductivity to different extents (1.42×10 4 and 2.17×10 3 times), where 6.96 times' enhancement of solid-state conductivity from 1 to 2 has been observed. The formation of Ag–N coordinative bonds and the configurational discrepancy of L 1 and L 2 are believed to play important roles in facilitating the electron transport between molecules, which can also be supported by Density Function Theory calculations of their band gaps. - Graphical abstract: A pair of linear and V-shaped isomeric thiophene-centered ditriazole ligands (L 1 ) and L 2 are used to prepare a pair of silver(I) polymeric isomers (1 and 2), where significant enhancement of solid-state conductivity to different extents are observed originating from the distinguishable shape and configuration of isomeric ligands. - Highlights: • A pair of linear and V-shaped thiophene-centered ditriazole structural isomers is prepared. • They are used as µ 2 -bridging ligands to prepare a pair of silver(I) polymeric isomers. • Significant enhancement of solid-state conductivity is observed

  6. Analysis of TNF-related apoptosis-inducing ligand and receptors and implications in thymus biology and myasthenia gravis.

    Science.gov (United States)

    Kanatli, Irem; Akkaya, Bahar; Uysal, Hilmi; Kahraman, Sevim; Sanlioglu, Ahter Dilsad

    2017-02-01

    Myasthenia Gravis is an autoantibody-mediated, neuromuscular junction disease, and is usually associated with thymic abnormalities presented as thymic tumors (~10%) or hyperplastic thymus (~65%). The exact role of thymus in Myasthenia Gravis development is not clear, yet many patients benefit from thymectomy. The apoptotic ligand TNF-Related Apoptosis-Inducing Ligand is thought to be involved in the regulation of thymocyte counts, although conflicting results are reported. We investigated differential expression profiles of TNF-Related Apoptosis-Inducing Ligand and its transmembrane receptors, Nuclear Factor-kB activation status, and apoptotic cell counts in healthy thymic tissue and pathological thymus from Myasthenia Gravis patients. All tissues expressed TNF-Related Apoptosis-Inducing Ligand and its receptors, with hyperplastic tissue having the highest expression levels of death receptors DR4 and DR5. No detectable Nuclear Factor-kB activation, at least via the canonical Protein Kinase A-mediated p65 Ser276 phosphorylation, was evident in any of the tissues studied. Apoptotic cell counts were higher in MG-associated tissue compared to the normal thymus. Possible use of the TNF-Related Apoptosis-Inducing Ligand within the concept of an apoptotic ligand-mediated medical thymectomy in thymoma- or thymic hyperplasia-associated Myasthenia Gravis is also discussed. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. A protocol for the refinement of NMR structures using simultaneously pseudocontact shift restraints from multiple lanthanide ions

    Energy Technology Data Exchange (ETDEWEB)

    Sala, Davide; Giachetti, Andrea; Luchinat, Claudio, E-mail: luchinat@cerm.unifi.it; Rosato, Antonio, E-mail: rosato@cerm.unifi.it [University of Florence, Magnetic Resonance Center (CERM) (Italy)

    2016-11-15

    The binding of paramagnetic metal ions to proteins produces a number of different effects on the NMR spectra of the system. In particular, when the magnetic susceptibility of the metal ion is anisotropic, pseudocontact shifts (PCSs) arise and can be easily measured. They constitute very useful restraints for the solution structure determination of metal-binding proteins. In this context, there has been great interest in the use of lanthanide(III) ions to induce PCSs in diamagnetic proteins, e.g. through the replacement native calcium(II) ions. By preparing multiple samples in each of which a different ion of the lanthanide series is introduced, it is possible to obtain multiple independent PCS datasets that can be used synergistically to generate protein structure ensembles (typically called bundles). For typical NMR-based determination of protein structure, it is necessary to perform an energetic refinement of such initial bundles to obtain final structures whose geometric quality is suitable for deposition in the PDB. This can be conveniently done by using restrained molecular dynamics simulations (rMD) in explicit solvent. However, there are no available protocols for rMD using multiple PCS datasets as part of the restraints. In this work, we extended the PCS module of the AMBER MD package to handle multiple datasets and tuned a previously developed protocol for NMR structure refinement to achieve consistent convergence with PCS restraints. Test calculations with real experimental data show that this new implementation delivers the expected improvement of protein geometry, resulting in final structures that are of suitable quality for deposition. Furthermore, we observe that also initial structures generated only with traditional restraints can be successfully refined using traditional and PCS restraints simultaneously.

  8. A diketiminate-bound diiron complex with a bridging carbonate ligand

    Science.gov (United States)

    Sadique, Azwana R.; Brennessel, William W.; Holland, Patrick L.

    2009-01-01

    Reduction of carbon dioxide by a diiron(I) complex gives μ-carbonato-κ3 O:O′,O′′-bis­{[2,2,6,6-tetra­methyl-3,5-bis­(2,4,6-triisopropyl­phenyl)heptane-2,5-diiminate(1−)-κ2 N,N′]iron(II)} toluene disolvate, [Fe2(C41H65N)2(CO3)]·2C7H8, a diiron(II) species with a bridging carbonate ligand. The asymmetric unit contains one diiron complex and two cocrystallized toluene solvent mol­ecules that are distributed over three sites, one with atoms in general positions and two in crystallographic sites. Both FeII atoms are η2-coordinated to diketiminate ligands, but η1- and η2-coordinated to the bridging carbonate ligand. Thus, one FeII center is three-coordinate and the other is four-coordinate. The bridging carbonate ligand is nearly perpendicular to the iron–diketiminate plane of the four-coordinate FeII center and parallel to the plane of the three-coordinate FeII center. PMID:19407402

  9. Lanthanide(III) complexes with tridentate Schiff base ligand ...

    African Journals Online (AJOL)

    The X-ray study reveals isotopic Nd/Sm binuclear structures were each metal ion is nine-coordinated in the same fashion. Both metal centers have distorted tricapped trigonal prism geometry, with the Schiff base acting as tridentate ligand. The DPPH· radical scavenging effects of the Schiff base ligand and its Ln(III) ...

  10. Redox-​Active Ligand-​Induced Homolytic Bond Activation

    NARCIS (Netherlands)

    Broere, D.L.J.; Metz, L.L.; de Bruin, B.; Reek, J.N.H.; Siegler, M.A.; van der Vlugt, J.I.

    2015-01-01

    Coordination of the novel redox-​active phosphine-​appended aminophenol pincer ligand (PNOH2) to PdII generates a paramagnetic complex with a persistent ligand-​centered radical. The complex undergoes fully reversible single-​electron oxidn. and redn. Homolytic bond activation of diphenyldisulfide

  11. Iron and Zinc Complexes of Bulky Bis-Imidazole Ligands : Enzyme Mimicry and Ligand-Centered Redox Activity

    NARCIS (Netherlands)

    Folkertsma, E.

    2016-01-01

    The research described in this thesis is directed to the development of cheap and non-toxic iron-based homogeneous catalysts, using enzyme models and redox non-innocent ligands. Inspired by nature, the first approach focuses on the synthesis of structural models of the active site of non-heme iron

  12. related apoptosis-inducing ligand in transplastomic tobacco

    African Journals Online (AJOL)

    -inducing ligand (sTRAIL) can, as the whole length TRAIL protein, bind with its receptors and specifically induce the apoptosis of cancer cells; therefore, it has been developed as a potential therapeutic agent for various cancer treatments.

  13. Controlling Nanocrystal Superlattice Symmetry and Shape-Anisotropic Interactions through Variable Ligand Surface Coverage

    KAUST Repository

    Choi, Joshua J.; Bealing, Clive R.; Bian, Kaifu; Hughes, Kevin J.; Zhang, Wenyu; Smilgies, Detlef-M.; Hennig, Richard G.; Engstrom, James R.; Hanrath, Tobias

    2011-01-01

    The assembly of colloidal nanocrystals (NCs) into superstructures with long-range translational and orientational order is sensitive to the molecular interactions between ligands bound to the NC surface. We illustrate how ligand coverage on colloidal PbS NCs can be exploited as a tunable parameter to direct the self-assembly of superlattices with predefined symmetry. We show that PbS NCs with dense ligand coverage assemble into face-centered cubic (fcc) superlattices whereas NCs with sparse ligand coverage assemble into body-centered cubic (bcc) superlattices which also exhibit orientational ordering of NCs in their lattice sites. Surface chemistry characterization combined with density functional theory calculations suggest that the loss of ligands occurs preferentially on {100} than on reconstructed {111} NC facets. The resulting anisotropic ligand distribution amplifies the role of NC shape in the assembly and leads to the formation of superlattices with translational and orientational order. © 2011 American Chemical Society.

  14. Controlling Nanocrystal Superlattice Symmetry and Shape-Anisotropic Interactions through Variable Ligand Surface Coverage

    KAUST Repository

    Choi, Joshua J.

    2011-03-09

    The assembly of colloidal nanocrystals (NCs) into superstructures with long-range translational and orientational order is sensitive to the molecular interactions between ligands bound to the NC surface. We illustrate how ligand coverage on colloidal PbS NCs can be exploited as a tunable parameter to direct the self-assembly of superlattices with predefined symmetry. We show that PbS NCs with dense ligand coverage assemble into face-centered cubic (fcc) superlattices whereas NCs with sparse ligand coverage assemble into body-centered cubic (bcc) superlattices which also exhibit orientational ordering of NCs in their lattice sites. Surface chemistry characterization combined with density functional theory calculations suggest that the loss of ligands occurs preferentially on {100} than on reconstructed {111} NC facets. The resulting anisotropic ligand distribution amplifies the role of NC shape in the assembly and leads to the formation of superlattices with translational and orientational order. © 2011 American Chemical Society.

  15. Role of ligand-ligand vs. core-core interactions in gold nanoclusters.

    Science.gov (United States)

    Milowska, Karolina Z; Stolarczyk, Jacek K

    2016-05-14

    The controlled assembly of ligand-coated gold nanoclusters (NCs) into larger structures paves the way for new applications ranging from electronics to nanomedicine. Here, we demonstrate through rigorous density functional theory (DFT) calculations employing novel functionals accounting for van der Waals forces that the ligand-ligand interactions determine whether stable assemblies can be formed. The study of NCs with different core sizes, symmetry forms, ligand lengths, mutual crystal orientations, and in the presence of a solvent suggests that core-to-core van der Waals interactions play a lesser role in the assembly. The dominant interactions originate from combination of steric effects, augmented by ligand bundling on NC facets, and related to them changes in electronic properties induced by neighbouring NCs. We also show that, in contrast to standard colloidal theory approach, DFT correctly reproduces the surprising experimental trends in the strength of the inter-particle interaction observed when varying the length of the ligands. The results underpin the importance of understanding NC interactions in designing gold NCs for a specific function.

  16. Zn and Fe complexes containing a redox active macrocyclic biquinazoline ligand.

    Science.gov (United States)

    Banerjee, Priyabrata; Company, Anna; Weyhermüller, Thomas; Bill, Eckhard; Hess, Corinna R

    2009-04-06

    A series of iron and zinc complexes has been synthesized, coordinated by the macrocyclic biquinazoline ligand, 2-4:6-8-bis(3,3,4,4-tetramethyldihydropyrrolo)-10-15-(2,2'-biquinazolino)-[15]-1,3,5,8,10,14-hexaene-1,3,7,9,11,14-N(6) (Mabiq). The Mabiq ligand consists of a bipyrimidine moiety and two dihydropyrrole units. The electronic structures of the metal-Mabiq complexes have been characterized using spectroscopic and density-functional theory (DFT) computational methods. The parent zinc complex exhibits a ligand-centered reduction to generate the metal-coordinated Mabiq radical dianion, establishing the redox non-innocence of this ligand. Iron-Mabiq complexes have been isolated in three oxidation states. This redox series includes low-spin ferric and low-spin ferrous species, as well as an intermediate-spin Fe(II) compound. In the latter complex, the iron ion is antiferromagnetically coupled to a Mabiq-centered pi-radical. The results demonstrate the rich redox chemistry and electronic properties of metal complexes coordinated by the Mabiq ligand.

  17. The chemistry of separations ligand degradation by organic radical cations

    International Nuclear Information System (INIS)

    Mezyk, S.P.; Horne, G.P.; Mincher, B.J.; Zalupski, P.R.; Cook, A.R.; Wishart, J.F.

    2016-01-01

    Solvent based extractions of used nuclear fuel use designer ligands in an organic phase extracting ligand complexed metal ions from an acidic aqueous phase. These extractions will be performed in highly radioactive environments, and the radiation chemistry of all these complexing agents and their diluents will play a major role in determining extraction efficiency, separation factors, and solvent-recycle longevity. Although there has been considerable effort in investigating ligand damage occurring in acidic water radiolysis conditions, only minimal fundamental kinetic and mechanistic data has been reported for the degradation of extraction ligands in the organic phase. Extraction solvent phases typically use normal alkanes such as dodecane, TPH, and kerosene as diluents. The radiolysis of such diluents produce a mixture of radical cations (R"."+), carbon-centered radicals (R".), solvated electrons, and molecular products such as hydrogen. Typically, the radical species will preferentially react with the dissolved oxygen present to produce relatively inert peroxyl radicals. This isolates the alkane radical cation species, R"."+ as the major radiolytically-induced organic species that can react with, and degrade, extraction agents in this phase. Here we report on our recent studies of organic radical cation reactions with 2 ligands: CMPO and TODGA. Elucidating these parameters, and combining them with the known acidic aqueous phase chemistry, will allow a full, fundamental, understanding of the impact of radiation on solvent extraction based separation processes to be achieved. (authors)

  18. How to deal with multiple binding poses in alchemical relative protein-ligand binding free energy calculations.

    Science.gov (United States)

    Kaus, Joseph W; Harder, Edward; Lin, Teng; Abel, Robert; McCammon, J Andrew; Wang, Lingle

    2015-06-09

    Recent advances in improved force fields and sampling methods have made it possible for the accurate calculation of protein–ligand binding free energies. Alchemical free energy perturbation (FEP) using an explicit solvent model is one of the most rigorous methods to calculate relative binding free energies. However, for cases where there are high energy barriers separating the relevant conformations that are important for ligand binding, the calculated free energy may depend on the initial conformation used in the simulation due to the lack of complete sampling of all the important regions in phase space. This is particularly true for ligands with multiple possible binding modes separated by high energy barriers, making it difficult to sample all relevant binding modes even with modern enhanced sampling methods. In this paper, we apply a previously developed method that provides a corrected binding free energy for ligands with multiple binding modes by combining the free energy results from multiple alchemical FEP calculations starting from all enumerated poses, and the results are compared with Glide docking and MM-GBSA calculations. From these calculations, the dominant ligand binding mode can also be predicted. We apply this method to a series of ligands that bind to c-Jun N-terminal kinase-1 (JNK1) and obtain improved free energy results. The dominant ligand binding modes predicted by this method agree with the available crystallography, while both Glide docking and MM-GBSA calculations incorrectly predict the binding modes for some ligands. The method also helps separate the force field error from the ligand sampling error, such that deviations in the predicted binding free energy from the experimental values likely indicate possible inaccuracies in the force field. An error in the force field for a subset of the ligands studied was identified using this method, and improved free energy results were obtained by correcting the partial charges assigned to the

  19. How To Deal with Multiple Binding Poses in Alchemical Relative Protein–Ligand Binding Free Energy Calculations

    Science.gov (United States)

    2016-01-01

    Recent advances in improved force fields and sampling methods have made it possible for the accurate calculation of protein–ligand binding free energies. Alchemical free energy perturbation (FEP) using an explicit solvent model is one of the most rigorous methods to calculate relative binding free energies. However, for cases where there are high energy barriers separating the relevant conformations that are important for ligand binding, the calculated free energy may depend on the initial conformation used in the simulation due to the lack of complete sampling of all the important regions in phase space. This is particularly true for ligands with multiple possible binding modes separated by high energy barriers, making it difficult to sample all relevant binding modes even with modern enhanced sampling methods. In this paper, we apply a previously developed method that provides a corrected binding free energy for ligands with multiple binding modes by combining the free energy results from multiple alchemical FEP calculations starting from all enumerated poses, and the results are compared with Glide docking and MM-GBSA calculations. From these calculations, the dominant ligand binding mode can also be predicted. We apply this method to a series of ligands that bind to c-Jun N-terminal kinase-1 (JNK1) and obtain improved free energy results. The dominant ligand binding modes predicted by this method agree with the available crystallography, while both Glide docking and MM-GBSA calculations incorrectly predict the binding modes for some ligands. The method also helps separate the force field error from the ligand sampling error, such that deviations in the predicted binding free energy from the experimental values likely indicate possible inaccuracies in the force field. An error in the force field for a subset of the ligands studied was identified using this method, and improved free energy results were obtained by correcting the partial charges assigned to the

  20. Further Insight into the Lability of MeCN Ligands of Cytotoxic Cycloruthenated Compounds: Evidence for the Antisymbiotic Effect Trans to the Carbon Atom at the Ru Center.

    Science.gov (United States)

    Barbosa, Ana Soraya Lima; Werlé, Christophe; Colunga, Claudia Olivia Oliva; Rodríguez, Cecilia Franco; Toscano, Ruben Alfredo; Le Lagadec, Ronan; Pfeffer, Michel

    2015-08-03

    The two MeCN ligands in [Ru(2-C6H4-2'-Py-κC,N)(Phen, trans-C)(MeCN)2]PF6 (1), both trans to a sp(2) hybridized N atom, cannot be substituted by any other ligand. In contrast, the isomerized derivative [Ru(2-C6H4-2'-Py-κC,N)(Phen, cis-C)(MeCN)2]PF6 (2), in which one MeCN ligand is now trans to the C atom of the phenyl ring orthometalated to Ru, leads to fast and quantitative substitution reactions with several monodentate ligands. With PPh3, 2 affords [Ru(2-C6H4-2'-Py-κC,N)(Phen, cis-C)(PPh3)(MeCN)]PF6 (3), in which PPh3 is trans to the C σ bound to Ru. Compound 3 is not kinetically stable, because, under thermodynamic control, it leads to 4, in which the PPh3 is trans to a N atom of the Phen ligand. Dimethylsulfoxide (DMSO) can also substitute a MeCN ligand in 2, leading to 5, in which DMSO is coordinated to Ru via its S atom trans to the N atom of the Phen ligand, the isomer under thermodynamic control being the only compound observed. We also found evidence for the fast to very fast substitution of MeCN in 2 by water or a chloride anion by studying the electronic spectra of 2 in the presence of water or NBu4Cl, respectively. An isomerization related to that observed between 3 and 4 is also found for the known monophosphine derivative [Ru(2-C6H4-2'-Py-κC,N)(PPh3, trans-C)(MeCN)3]PF6 (10), in which the PPh3 is located trans to the C of the cyclometalated 2-phenylpyridine, since, upon treatment by refluxing MeCN, it leads to its isomer 11, [Ru(2-C6H4-2'-Py-κC,N)(PPh3, cis-C)(MeCN)3]PF6. Further substitutions are also observed on 11, whereby N^N chelates (N^N = 2,2'-bipyridine and phenanthroline) substitute two MeCN ligands, affording [Ru(2-C6H4-2'-Py-κC,N)(PPh3, cis-C)(N^N)(MeCN)]PF6 (12a and 12b). Altogether, the behavior of the obtained complexes by ligand substitution reactions can be rationalized by an antisymbiotic effect on the Ru center, trans to the C atom of the cyclometalated unit, leading to compounds having the least nucleophilic ligand trans to C

  1. Relative stability constants of the uranyl tropolonate system with neutral ligands in benzene

    Energy Technology Data Exchange (ETDEWEB)

    Degetto, S; Baracco, L; Marangoni, G [Consiglio Nazionale delle Ricerche, Padua (Italy). Lab. di Chimica e Tecnologia dei Radioelementi; Celon, E

    1976-01-01

    The relative formation constants K*sub(L) of some uranyl tropolonate adducts with neutral ligands L (L = cyclopentanone, pyridine, dimethyl sulphoxide, 4-chloropyridine N-oxide, 4-methylpyridine N-oxide, triphenylphosphine oxide, and triphenylarsine oxide) of general formula (U0/sub 2/(trop)/sub 2/L) (Htrop = tropolone) have been determined spectrophotometrically by studying the equilibria ((UO/sub 2/(trop)/sub 2/)/sub 2/) + 2L = 2 (UO/sub 2/(trop)/sub 2/L) in the benzene at 25/sup 0/C. The K*sub(L) sequence obtained can be used as a quantitative scale of donor ability of the various neutral ligands toward the common substrate. Other attempted qualitative correlations based on i.r., /sup 1/H n.m.r., and thermal measurements are compared and discussed.

  2. Modulators of Response to Tumor Necrosis-Related Apoptosis-Inducing Ligand (TRAIL) Therapy in Ovarian Cancer

    National Research Council Canada - National Science Library

    Behbakht, Kian

    2008-01-01

    .... More effective therapies are urgently needed. One of the most promising therapies in development for ovarian cancer is the use of either the Tumor Necrosis Factor-related Apoptosis Inducing Ligand (TRAIL...

  3. A new class of PN3-pincer ligands for metal–ligand cooperative catalysis

    KAUST Repository

    Li, Huaifeng

    2014-12-01

    Work on a new class of PN3-pincer ligands for metal-ligand cooperative catalysis is reviewed. While the field of the pyridine-based PN3-transition metal pincer complexes is still relatively young, many important applications of these complexes have already emerged. In several cases, the PN3-pincer complexes for metal-ligand cooperative catalysis result in significantly improved or unprecedented activities. The synthesis and coordination chemistry of PN3-pincer ligands are briefly summarized first to cover the synthetic routes for their preparation, followed by a focus review on their applications in catalysis. A specific emphasis is placed on the later section about the role of PN3-pincer ligands\\' dearomatization-rearomatization steps during the catalytic cycles. The mechanistic insights from density functional theory (DFT) calculations are also discussed.

  4. A new class of PN3-pincer ligands for metal–ligand cooperative catalysis

    KAUST Repository

    Li, Huaifeng; Zheng, Bin; Huang, Kuo-Wei

    2014-01-01

    Work on a new class of PN3-pincer ligands for metal-ligand cooperative catalysis is reviewed. While the field of the pyridine-based PN3-transition metal pincer complexes is still relatively young, many important applications of these complexes have already emerged. In several cases, the PN3-pincer complexes for metal-ligand cooperative catalysis result in significantly improved or unprecedented activities. The synthesis and coordination chemistry of PN3-pincer ligands are briefly summarized first to cover the synthetic routes for their preparation, followed by a focus review on their applications in catalysis. A specific emphasis is placed on the later section about the role of PN3-pincer ligands' dearomatization-rearomatization steps during the catalytic cycles. The mechanistic insights from density functional theory (DFT) calculations are also discussed.

  5. Interaction of calreticulin with CD40 ligand, TRAIL and Fas ligand

    DEFF Research Database (Denmark)

    Duus, K; Pagh, R T; Holmskov, U

    2007-01-01

    is utilized by many other functionally diverse molecules and in this work the interaction of calreticulin with C1q and structurally similar molecules was investigated. In addition to C1q and MBL, CD40 ligand (CD40L), tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas ligand (FasL) were...... found to bind calreticulin strongly. A low level or no binding was observed for adiponectin, tumour necrosis factor-alpha (TNF-alpha), CD30L, surfactant protein-A and -D and collagen VIII. The interaction with calreticulin required a conformational change in CD40L, TRAIL and FasL and showed the same...

  6. The chemistry of separations ligand degradation by organic radical cations

    Energy Technology Data Exchange (ETDEWEB)

    Mezyk, S.P.; Horne, G.P. [California State University at Long Beach, Long Beach, CA 90840 (United States); Mincher, B.J.; Zalupski, P.R. [Idaho National Laboratory, Idaho Falls, ID 83415 (United States); Cook, A.R.; Wishart, J.F. [Chemistry Department, Brookhaven National Laboratory, New York, 11973 (United States)

    2016-07-01

    Solvent based extractions of used nuclear fuel use designer ligands in an organic phase extracting ligand complexed metal ions from an acidic aqueous phase. These extractions will be performed in highly radioactive environments, and the radiation chemistry of all these complexing agents and their diluents will play a major role in determining extraction efficiency, separation factors, and solvent-recycle longevity. Although there has been considerable effort in investigating ligand damage occurring in acidic water radiolysis conditions, only minimal fundamental kinetic and mechanistic data has been reported for the degradation of extraction ligands in the organic phase. Extraction solvent phases typically use normal alkanes such as dodecane, TPH, and kerosene as diluents. The radiolysis of such diluents produce a mixture of radical cations (R{sup .+}), carbon-centered radicals (R{sup .}), solvated electrons, and molecular products such as hydrogen. Typically, the radical species will preferentially react with the dissolved oxygen present to produce relatively inert peroxyl radicals. This isolates the alkane radical cation species, R{sup .+} as the major radiolytically-induced organic species that can react with, and degrade, extraction agents in this phase. Here we report on our recent studies of organic radical cation reactions with 2 ligands: CMPO and TODGA. Elucidating these parameters, and combining them with the known acidic aqueous phase chemistry, will allow a full, fundamental, understanding of the impact of radiation on solvent extraction based separation processes to be achieved. (authors)

  7. Immobilisation of ligands by radio-derivatized polymers; Immobilisering av ligander med radioderiverte polymerer

    Energy Technology Data Exchange (ETDEWEB)

    Varga, J.M.; Fritsch, P.

    1995-01-30

    The invention relates to radio-derivatized polymers and a method of producing them by contacting non-polymerizable conjugands with radiolysable polymers in the presence of irradiation. The resulting radio-derivatized polymers can be further linked with ligand of organic or inorganic nature to immobilize such ligands. 2 figs., 5 tabs.

  8. Breaking symmetry in the structure determination of (large) symmetric protein dimers

    Energy Technology Data Exchange (ETDEWEB)

    Gaponenko, Vadim; Altieri, Amanda S.; Li, Jess; Byrd, R. Andrew [National Cancer Institute, Structural Biophysics Laboratory (United States)], E-mail: rabyrd@ncifcrf.gov

    2002-10-15

    We demonstrate a novel methodology to disrupt the symmetry in the NMR spectra of homodimers. A paramagnetic probe is introduced sub-stoichiometrically to create an asymmetric system with the paramagnetic probe residing on only one monomer within the dimer. This creates sufficient magnetic anisotropy for resolution of symmetry-related overlapped resonances and, consequently, detection of pseudocontact shifts and residual dipolar couplings specific to each monomeric component. These pseudocontact shifts can be readily incorporated into existing structure refinement calculations and enable determination of monomer orientation within the dimeric protein. This methodology can be widely used for solution structure determination of symmetric dimers.

  9. Insights into an original pocket-ligand pair classification: a promising tool for ligand profile prediction.

    Directory of Open Access Journals (Sweden)

    Stéphanie Pérot

    Full Text Available Pockets are today at the cornerstones of modern drug discovery projects and at the crossroad of several research fields, from structural biology to mathematical modeling. Being able to predict if a small molecule could bind to one or more protein targets or if a protein could bind to some given ligands is very useful for drug discovery endeavors, anticipation of binding to off- and anti-targets. To date, several studies explore such questions from chemogenomic approach to reverse docking methods. Most of these studies have been performed either from the viewpoint of ligands or targets. However it seems valuable to use information from both ligands and target binding pockets. Hence, we present a multivariate approach relating ligand properties with protein pocket properties from the analysis of known ligand-protein interactions. We explored and optimized the pocket-ligand pair space by combining pocket and ligand descriptors using Principal Component Analysis and developed a classification engine on this paired space, revealing five main clusters of pocket-ligand pairs sharing specific and similar structural or physico-chemical properties. These pocket-ligand pair clusters highlight correspondences between pocket and ligand topological and physico-chemical properties and capture relevant information with respect to protein-ligand interactions. Based on these pocket-ligand correspondences, a protocol of prediction of clusters sharing similarity in terms of recognition characteristics is developed for a given pocket-ligand complex and gives high performances. It is then extended to cluster prediction for a given pocket in order to acquire knowledge about its expected ligand profile or to cluster prediction for a given ligand in order to acquire knowledge about its expected pocket profile. This prediction approach shows promising results and could contribute to predict some ligand properties critical for binding to a given pocket, and conversely

  10. Insights into an original pocket-ligand pair classification: a promising tool for ligand profile prediction.

    Science.gov (United States)

    Pérot, Stéphanie; Regad, Leslie; Reynès, Christelle; Spérandio, Olivier; Miteva, Maria A; Villoutreix, Bruno O; Camproux, Anne-Claude

    2013-01-01

    Pockets are today at the cornerstones of modern drug discovery projects and at the crossroad of several research fields, from structural biology to mathematical modeling. Being able to predict if a small molecule could bind to one or more protein targets or if a protein could bind to some given ligands is very useful for drug discovery endeavors, anticipation of binding to off- and anti-targets. To date, several studies explore such questions from chemogenomic approach to reverse docking methods. Most of these studies have been performed either from the viewpoint of ligands or targets. However it seems valuable to use information from both ligands and target binding pockets. Hence, we present a multivariate approach relating ligand properties with protein pocket properties from the analysis of known ligand-protein interactions. We explored and optimized the pocket-ligand pair space by combining pocket and ligand descriptors using Principal Component Analysis and developed a classification engine on this paired space, revealing five main clusters of pocket-ligand pairs sharing specific and similar structural or physico-chemical properties. These pocket-ligand pair clusters highlight correspondences between pocket and ligand topological and physico-chemical properties and capture relevant information with respect to protein-ligand interactions. Based on these pocket-ligand correspondences, a protocol of prediction of clusters sharing similarity in terms of recognition characteristics is developed for a given pocket-ligand complex and gives high performances. It is then extended to cluster prediction for a given pocket in order to acquire knowledge about its expected ligand profile or to cluster prediction for a given ligand in order to acquire knowledge about its expected pocket profile. This prediction approach shows promising results and could contribute to predict some ligand properties critical for binding to a given pocket, and conversely, some key pocket

  11. Lack of evidence of CD40 ligand involvement in transfusion-related acute lung injury

    NARCIS (Netherlands)

    Tuinman, P. R.; Gerards, M. C.; Jongsma, G.; Vlaar, A. P.; Boon, L.; Juffermans, N. P.

    2011-01-01

    Activated platelets have been implicated in playing a major role in transfusion-related acute lung injury (TRALI), as platelets can trigger neutrophils, resulting in vascular damage. We hypothesized that binding of platelet CD40 ligand (CD40L) to endothelial CD40 is essential in the onset of TRALI.

  12. Coordination of different ligands to copper(II) and cobalt(III) metal centers enhances Zika virus and dengue virus loads in both arthropod cells and human keratinocytes.

    Science.gov (United States)

    Dutta, Shovan; Celestine, Michael J; Khanal, Supreet; Huddleston, Alexis; Simms, Colin; Arca, Jessa Faye; Mitra, Amlan; Heller, Loree; Kraj, Piotr J; Ledizet, Michel; Anderson, John F; Neelakanta, Girish; Holder, Alvin A; Sultana, Hameeda

    2018-01-01

    Trace elements such as copper and cobalt have been associated with virus-host interactions. However, studies to show the effect of conjugation of copper(II) or cobalt(III) metal centers to thiosemicarbazone ligand(s) derived from either food additives or mosquito repellent such as 2-acetylethiazole or citral, respectively, on Zika virus (ZIKV) or dengue virus (serotype 2; DENV2) infections have not been explored. In this study, we show that four compounds comprising of thiosemicarbazone ligand derived from 2-acetylethiazole viz., (E)-N-ethyl-2-[1-(thiazol-2-yl)ethylidene]hydrazinecarbothioamide (acetylethTSC) (compound 1), a copper(II) complex with acetylethTSC as a ligand (compound 2), a thiosemicarbazone ligand-derived from citral (compound 3) and a cobalt(III) complex with a citral-thiosemicarbazone ligand (compound 4) increased DENV2 and ZIKV replication in both mosquito C6/36 cells and human keratinocytes (HaCaT cells). Treatment of both cell lines with compounds 2 or 4 showed increased dengue viral titers at all three tested doses. Enhanced dengue viral plaque formation was also noted at the tested dose of 100μM, suggesting higher production of infectious viral particles. Treatment with the compounds 2 or 4 enhanced ZIKV and DENV2 RNA levels in HeLa cell line and primary cultures of mouse bone marrow derived dendritic cells. Also, pre- or post treatments with conjugated compounds 2 or 4 showed higher loads of ZIKV or DENV2 envelope (E) protein in HaCaT cells. No changes in loads of E-protein were found in ZIKV-infected C6/36 cells, when compounds were treated after infection. In addition, we tested bis(1,10-phenanthroline)copper(II) chloride ([Cu(phen) 2 ]Cl 2 , (compound 5) and tris(1,10-phenanthroline)cobalt(III) chloride ([Co(phen) 3 ]Cl 3 , (compound 6) that also showed enhanced DENV2 loads. Also, we found that copper(II) chloride dehydrate (CuCl 2 ·2H 2 O) or cobalt(II) chloride hexahydrate (CoCl 2 ·6H 2 O) alone had no effects as "free" cations

  13. NeoPHOX – a structurally tunable ligand system for asymmetric catalysis

    Directory of Open Access Journals (Sweden)

    Jaroslav Padevět

    2016-06-01

    Full Text Available A synthesis of new NeoPHOX ligands derived from serine or threonine has been developed. The central intermediate is a NeoPHOX derivative bearing a methoxycarbonyl group at the stereogenic center next to the oxazoline N atom. The addition of methylmagnesium chloride leads to a tertiary alcohol, which can be acylated or silylated to produce NeoPHOX ligands with different sterical demand. The new NeoPHOX ligands were tested in the iridium-catalyzed asymmetric hydrogenation and palladium-catalyzed allylic substitution. In both reactions high enantioselectivities were achieved, that were comparable to the enantioselectivities obtained with the up to now best NeoPHOX ligand derived from expensive tert-leucine.

  14. Ligand and Metal Based Multielectron Redox Chemistry of Cobalt Supported by Tetradentate Schiff Bases.

    Science.gov (United States)

    Andrez, Julie; Guidal, Valentin; Scopelliti, Rosario; Pécaut, Jacques; Gambarelli, Serge; Mazzanti, Marinella

    2017-06-28

    We have investigated the influence of bound cations on the reduction of cobalt complexes of redox active ligands and explored the reactivity of reduced species with CO 2 . The one electron reduction of [Co II ( R salophen)] with alkali metals (M = Li, Na, K) leads to either ligand-centered or metal-centered reduction depending on the alkali ion. It affords either the [Co I ( R salophen)K] complexes or the [Co II 2 (bis-salophen)M 2 ] (M = Li, Na) dimers that are present in solution in equilibrium with the respective [Co I (salophen)M] complexes. The two electron reduction of [Co II ( OMe salophen)] results in both ligand centered and metal centered reduction affording the Co(I)-Co(II)-Co(I) [Co 3 (tris- OMe salophen)Na 6 (THF) 6 ], 6 complex supported by a bridging deca-anionic tris- OMe salophen 10- ligand where three OMe salophen units are connected by two C-C bonds. Removal of the Na ion from 6 leads to a redistribution of the electrons affording the complex [(Co( OMe salophen)) 2 Na][Na(cryptand)] 3 , 7. The EPR spectrum of 7 suggests the presence of a Co(I) bound to a radical anionic ligand. Dissolution of 7 in pyridine leads to the isolation of [Co I 2 (bis- OMe salophen)Na 2 Py 4 ][Na(cryptand)] 2 , 8. Complex 6 reacts with ambient CO 2 leading to multiple CO 2 reduction products. The product of CO 2 addition to the OMe salophen ligand, [Co( OMe salophen-CO 2 )Na] 2 [Na(cryptand)] 2 , 9, was isolated but CO 3 2- formation in 53% yield was also detected. Thus, the electrons stored in the reversible C-C bonds may be used for the transformation of carbon dioxide.

  15. Process of Fragment-Based Lead Discovery—A Perspective from NMR

    Directory of Open Access Journals (Sweden)

    Rongsheng Ma

    2016-07-01

    Full Text Available Fragment-based lead discovery (FBLD has proven fruitful during the past two decades for a variety of targets, even challenging protein–protein interaction (PPI systems. Nuclear magnetic resonance (NMR spectroscopy plays a vital role, from initial fragment-based screening to lead generation, because of its power to probe the intrinsically weak interactions between targets and low-molecular-weight fragments. Here, we review the NMR FBLD process from initial library construction to lead generation. We describe technical aspects regarding fragment library design, ligand- and protein-observed screening, and protein–ligand structure model generation. For weak binders, the initial hit-to-lead evolution can be guided by structural information retrieved from NMR spectroscopy, including chemical shift perturbation, transferred pseudocontact shifts, and paramagnetic relaxation enhancement. This perspective examines structure-guided optimization from weak fragment screening hits to potent leads for challenging PPI targets.

  16. Manipulating charge transfer excited state relaxation and spin crossover in iron coordination complexes with ligand substitution

    DEFF Research Database (Denmark)

    Zhang, Wenkai; Kjær, Kasper Skov; Alonso-Mori, Roberto

    2017-01-01

    iron complexes with four cyanide (CN-;) ligands and one 2,2′-bipyridine (bpy) ligand. This enables MLCT excited state and metal-centered excited state energies to be manipulated with partial independence and provides a path to suppressing spin crossover. We have combined X-ray Free-Electron Laser (XFEL...... state lifetime of iron based complexes due to spin crossover-the extremely fast intersystem crossing and internal conversion to high spin metal-centered excited states. We revitalize a 30 year old synthetic strategy for extending the MLCT excited state lifetimes of iron complexes by making mixed ligand...

  17. Effect of Ligand Field Tuning on the SMM Behavior for Three Related Alkoxide-Bridged Dysprosium Dimers.

    Science.gov (United States)

    Peng, Yan; Mereacre, Valeriu; Baniodeh, Amer; Lan, Yanhua; Schlageter, Martin; Kostakis, George E; Powell, Annie K

    2016-01-04

    The synthesis and characterization of three Dy2 compounds, [Dy2(HL1)2(NO3)4] (1), [Dy2(L2)2(NO3)4] (2), and [Dy2(HL3)2(NO3)4] (3), formed using related tripodal ligands with a central tertiary amine bearing picolyl and alkoxy arms, 2-[(2-hydroxy-ethyl)-pyridin-2-ylmethylamino]-ethanol (H2L1), 2-(bis-pyridin-2-ylmethylamino)-ethanol (HL2), and 2-(bis-pyridin-2-ylmethylamino)-propane-1,3-diol (H2L3), are reported. The compounds are rare examples of alkoxide-bridged {Dy2} complexes and display capped square antiprism coordination geometry around each Dy(III) ion. Changes in the ligand field environment around the Dy(III) ions brought about through variations in the ligand donors can be gauged from the magnetic properties, with compounds 1 and 2 showing antiparallel coupling between the Dy(III) ions and 3 showing parallel coupling. Furthermore, slow relaxation of the magnetization typical of SMM behavior could be observed for compounds 2 and 3, suggesting that small variations in the ligand field can have a significant influence on the slow relaxation processes responsible for SMM behavior of Dy(III)-based systems.

  18. Protonation of Ferrous Dinitrogen Complexes Containing a Diphosphine Ligand with a Pendant Amine

    Energy Technology Data Exchange (ETDEWEB)

    Heiden, Zachariah M.; Chen, Shentan; Mock, Michael T.; Dougherty, William G.; Kassel, W. S.; Rousseau, Roger J.; Bullock, R. Morris

    2013-04-01

    The addition of protons to pendant amine containing ferrous dinitrogen complexes, of the type [FeX(N2)(PEtNMePEt)(dmpm)]+ (X = H, Cl, or Br; PEtNMePEt = Et2PCH2N(Me)CH2PEt2 and dmpm = Me2PCH2PMe2), was found to protonate at the pendant amine as opposed to the dinitrogen ligand. This protonation increased the νN2 of the complex by about 25 cm-1, shifting the Fe(II/I) couple 330 mV to a more positive potential. A similar shift was observed in the case of [FeX(CO)(PEtNMePEt)(dmpm)]+ (X = H, Cl, or Br). Computational analysis verified these experimental results and showed the coordination of N2 to Fe(II) centers increases the basicity of N2 (vs. free N2) by 13 and 20 pKa units for the trans halides and hydrides, respectively. Although the iron center was found to increase the basicity of the bound N2 ligand, coordinated N2 is not sufficiently basic to be protonated. In the case of ferrous dinitrogen complexes containing a basic pendant methylamine, the amine site was determined to be the most basic site by 30 pKa units compared to protonation at the N2 ligand. To increase the basicity of the N2 ligand in order to promote proton transfer from the pendant amine to the N2 ligand, chemical reduction of these ferrous dinitrogen complexes was performed and found to result in oxidative addition of the methylene C-H bond of the PEtNMePEt ligand to Fe, preventing isolation of a reduced Fe(0) N2 complex. This work was supported as part of the Center for Molecular Electrocatalysis, an Energy Frontier Research Center funded by the U.S. Department of Energy Office of Science, Office of Basic Energy Sciences.

  19. Expanding the Library of Uranyl Amide Derivatives: New Complexes Featuring the tert-Butyldimethylsilylamide Ligand.

    Science.gov (United States)

    Pattenaude, Scott A; Coughlin, Ezra J; Collins, Tyler S; Zeller, Matthias; Bart, Suzanne C

    2018-04-16

    New uranyl derivatives featuring the amide ligand, -N(SiHMe 2 ) t Bu, were synthesized and characterized by X-ray crystallography, multinuclear NMR spectroscopy, and absorption spectroscopies. Steric properties of these complexes were also quantified using the computational program Solid-G. The increased basicity of the free ligand -N(SiHMe 2 ) t Bu was demonstrated by direct comparison to -N(SiMe 3 ) 2 , a popular supporting ligand for uranyl. Substitutional lability on a uranyl center was also demonstrated by exchange with the -N(SiMe 3 ) 2 ligand. The increased basicity of this ligand and diverse characterization handles discussed here will make these compounds useful synthons for future reactivity.

  20. Ligand identification using electron-density map correlations

    International Nuclear Information System (INIS)

    Terwilliger, Thomas C.; Adams, Paul D.; Moriarty, Nigel W.; Cohn, Judith D.

    2007-01-01

    An automated ligand-fitting procedure is applied to (F o − F c )exp(iϕ c ) difference density for 200 commonly found ligands from macromolecular structures in the Protein Data Bank to identify ligands from density maps. A procedure for the identification of ligands bound in crystal structures of macromolecules is described. Two characteristics of the density corresponding to a ligand are used in the identification procedure. One is the correlation of the ligand density with each of a set of test ligands after optimization of the fit of that ligand to the density. The other is the correlation of a fingerprint of the density with the fingerprint of model density for each possible ligand. The fingerprints consist of an ordered list of correlations of each the test ligands with the density. The two characteristics are scored using a Z-score approach in which the correlations are normalized to the mean and standard deviation of correlations found for a variety of mismatched ligand-density pairs, so that the Z scores are related to the probability of observing a particular value of the correlation by chance. The procedure was tested with a set of 200 of the most commonly found ligands in the Protein Data Bank, collectively representing 57% of all ligands in the Protein Data Bank. Using a combination of these two characteristics of ligand density, ranked lists of ligand identifications were made for representative (F o − F c )exp(iϕ c ) difference density from entries in the Protein Data Bank. In 48% of the 200 cases, the correct ligand was at the top of the ranked list of ligands. This approach may be useful in identification of unknown ligands in new macromolecular structures as well as in the identification of which ligands in a mixture have bound to a macromolecule

  1. Tunable paramagnetic relaxation enhancements by [Gd(DPA)3]3- for protein structure analysis

    International Nuclear Information System (INIS)

    Yagi, Hiromasa; Loscha, Karin V.; Su, Xun-Cheng; Stanton-Cook, Mitchell; Huber, Thomas; Otting, Gottfried

    2010-01-01

    Paramagnetic relaxation enhancements (PRE) present a powerful source of structural information in nuclear magnetic resonance (NMR) studies of proteins and protein-ligand complexes. In contrast to conventional PRE reagents that are covalently attached to the protein, the complex between gadolinium and three dipicolinic acid (DPA) molecules, [Gd(DPA) 3 ] 3- , can bind to proteins in a non-covalent yet site-specific manner. This offers straightforward access to PREs that can be scaled by using different ratios of [Gd(DPA) 3 ] 3- to protein, allowing quantitative distance measurements for nuclear spins within about 15 A of the Gd 3+ ion. Such data accurately define the metal position relative to the protein, greatly enhancing the interpretation of pseudocontact shifts induced by [Ln(DPA) 3 ] 3- complexes of paramagnetic lanthanide (Ln 3+ ) ions other than gadolinium. As an example we studied the quaternary structure of the homodimeric GCN4 leucine zipper.

  2. Ligand Exchange Kinetics of Environmentally Relevant Metals

    Energy Technology Data Exchange (ETDEWEB)

    Panasci, Adele Frances [Univ. of California, Davis, CA (United States)

    2014-07-15

    The interactions of ground water with minerals and contaminants are of broad interest for geochemists but are not well understood. Experiments on the molecular scale can determine reaction parameters (i.e. rates of ligand exchange, activation entropy, activation entropy, and activation volume) that can be used in computations to gain insight into reactions that occur in natural groundwaters. Experiments to determine the rate of isotopic ligand exchange for three environmentally relevant metals, rhodium (Rh), iron (Fe), and neptunium (Np), are described. Many environmental transformations of metals (e.g. reduction) in soil occur at trivalent centers, Fe(III) in particular. Contaminant ions absorb to mineral surfaces via ligand exchange, and the reversal of this reaction can be dangerous, releasing contaminants into the environment. Ferric iron is difficult to study spectroscopically because most of its complexes are paramagnetic and are generally reactive toward ligand exchange; therefore, Rh(III), which is diamagnetic and less reactive, was used to study substitution reactions that are analogous to those that occur on mineral oxide surfaces. Studies on both Np(V) and Np(VI) are important in their own right, as 237Np is a radioactive transuranic element with a half-life of 2 million years.

  3. Evidence that tumor necrosis factor-related apoptosis inducing ligand (TRAIL) inhibits angiogenesis by inducing vascular endothelial cell apoptosis

    International Nuclear Information System (INIS)

    Chen, Pei-Lin; Easton, Alexander S.

    2010-01-01

    Tumor necrosis factor (TNF) and its related ligands TNF-related apoptosis inducing ligand (TRAIL) and Fas ligand (FasL) play roles in the regulation of vascular responses, but their effect on the formation of new blood vessels (angiogenesis) is unclear. Therefore, we have examined the effects of these ligands on angiogenesis modeled with primary cultures of human umbilical vein endothelial cells (HUVEC). To examine angiogenesis in the context of the central nervous system, we have also modeled cerebral angiogenesis with the human brain endothelial cell line hCMEC/D3. Parameters studied were bromodeoxyuridine (BrdU) incorporation and cell number (MTT) assay (to assess endothelial proliferation), scratch assay (migration) and networks on Matrigel (tube formation). In our hands, neither TRAIL nor FasL (1, 10, and 100 ng/ml) had an effect on parameters of angiogenesis in the HUVEC model. In hCMEC/D3 cells by contrast, TRAIL inhibited all parameters (10-100 ng/ml, 24 h). This was due to apoptosis, since its action was blocked by the pan-caspase inhibitor zVADfmk (5 x 10 -5 mol/l) and TRAIL increased caspase-3 activity 1 h after application. However FasL (100 ng/ml) increased BrdU uptake without other effects. We conclude that TRAIL has different effects on in vitro angiogenesis depending on which model is used, but that FasL is generally ineffective when applied in vitro. The data suggest that TRAIL primarily influences angiogenesis by the induction of vascular endothelial apoptosis, leading to vessel regression.

  4. Transfer of the human NKG2D ligands UL16 binding proteins (ULBP) 1-3 is related to lytic granule release and leads to ligand retransfer and killing of ULBP-recipient natural killer cells.

    Science.gov (United States)

    López-Cobo, Sheila; Romera-Cárdenas, Gema; García-Cuesta, Eva M; Reyburn, Hugh T; Valés-Gómez, Mar

    2015-09-01

    After immune interactions, membrane fragments can be transferred between cells. This fast transfer of molecules is transient and shows selectivity for certain proteins; however, the constraints underlying acquisition of a protein are unknown. To characterize the mechanism and functional consequences of this process in natural killer (NK) cells, we have compared the transfer of different NKG2D ligands. We show that human NKG2D ligands can be acquired by NK cells with different efficiencies. The main findings are that NKG2D ligand transfer is related to immune activation and receptor-ligand interaction and that NK cells acquire these proteins during interactions with target cells that lead to degranulation. Our results further demonstrate that NK cells that have acquired NKG2D ligands can stimulate activation of autologous NK cells. Surprisingly, NK cells can also re-transfer the acquired molecule to autologous effector cells during this immune recognition that leads to their death. These data demonstrate that transfer of molecules occurs as a consequence of immune recognition and imply that this process might play a role in homeostatic tuning-down of the immune response or be used as marker of interaction. © 2015 John Wiley & Sons Ltd.

  5. Towards ligand docking including explicit interface water molecules.

    Directory of Open Access Journals (Sweden)

    Gordon Lemmon

    Full Text Available Small molecule docking predicts the interaction of a small molecule ligand with a protein at atomic-detail accuracy including position and conformation the ligand but also conformational changes of the protein upon ligand binding. While successful in the majority of cases, docking algorithms including RosettaLigand fail in some cases to predict the correct protein/ligand complex structure. In this study we show that simultaneous docking of explicit interface water molecules greatly improves Rosetta's ability to distinguish correct from incorrect ligand poses. This result holds true for both protein-centric water docking wherein waters are located relative to the protein binding site and ligand-centric water docking wherein waters move with the ligand during docking. Protein-centric docking is used to model 99 HIV-1 protease/protease inhibitor structures. We find protease inhibitor placement improving at a ratio of 9:1 when one critical interface water molecule is included in the docking simulation. Ligand-centric docking is applied to 341 structures from the CSAR benchmark of diverse protein/ligand complexes [1]. Across this diverse dataset we see up to 56% recovery of failed docking studies, when waters are included in the docking simulation.

  6. Integration of a semi-rigid proline ligand and 4,4'-bipyridine in the synthesis of homochiral metal-organic frameworks with helices.

    Science.gov (United States)

    Xu, Zhong-Xuan; Kang, Yao; Han, Min-Le; Li, Dong-Sheng; Zhang, Jian

    2015-06-28

    A pair of 3-D homochiral metal-organic frameworks (HMOFs) based on a mixed semi-rigid 5-(2-carboxypyrrolidine-1-carbonyl)isophthalate (PIA) ligand and rigid 4,4'-bipyridine (bipy), [Co3((R)-PIA)2(bipy)3]·6H2O (1-D) and [Co3((S)-PIA)2(bipy)3]·6H2O (1-L) are synthesized and structurally characterized. They are enantiomers and exhibit three-dimensional open frameworks. In each structure, the PIA ligands link the Co centers into homochiral frameworks with large open channels that are occupied by the bipy ligands. Interesting helical chains built from the connectivity between PIA ligands and Co centers are presented. Antiferromagnetic coupling is observed in 1-D. These results demonstrated that the mixed ligand approach is successful for the construction of HMOFs.

  7. A Macrocyclic Agouti-Related Protein/[Nle4, DPhe7]α-Melanocyte Stimulating Hormone Chimeric Scaffold Produces Sub-nanomolar Melanocortin Receptor Ligands

    OpenAIRE

    Ericson, Mark D.; Freeman, Katie T.; Schnell, Sathya M.; Haskell-Luevano, Carrie

    2017-01-01

    The melanocortin system consists of five receptor subtypes, endogenous agonists, and naturally occurring antagonists. These receptors and ligands have been implicated in numerous biological pathways including processes linked to obesity and food intake. Herein, a truncation structure-activity relationship study of chimeric agouti-related protein (AGRP)/[Nle4, DPhe7]α-Melanocyte Stimulating Hormone (NDP-MSH) ligands is reported. The tetrapeptide His-DPhe-Arg-Trp or tripeptide DPhe-Arg-Trp repl...

  8. Construction of three metal-organic frameworks based on multifunctional T-shaped tripodal ligands, H3PyImDC

    KAUST Repository

    Jing, Xuemin

    2010-08-04

    Three novel metal-organic frameworks (MOFs), |(C3H 7NO)2(H2O)|[Zn3(C10H 5N3O4)3(C3H 7NO)2] (1), |(H2O)5(H 3O)(NO3)|[Nd2(C10H5N 3O4)3(H2O)4] (2), and |(H2O)2|[Nd3(C10H5N 3O4)3(C10H4N 3O4)] (3), based on the T-shaped tripodal ligands 2-(pyridine-4-yl)-1H-4,5-imidazoledicarboxylic acid and 2-(pyridine-3-yl)-1H-4, 5-imidazoledicarboxylic acid (H3PyImDC), have been constructed under solvo-/hydrothermal conditions. The diverse coordination modes of H 3PyImDC ligands have afforded the assembly of three novel compounds. In compound 1, two oxygen atoms and three nitrogen atoms of the H 3PyImDC ligand, a T-shaped linker, coordinate to two zinc centers to form a novel bbm net with two distinct channels along the [100] and [001] directions. In compound 2, H3PyImDC ligands coordinate to neodymium centers to form a ladder-like chain which then interacts with a water molecules chain via hydrogen-bondings to construct a 3D supermolecular structure. In compound 3, H3PyImDC ligands, a T-shaped linker, coordinate to neodymium centers to form a (3,6)-connected net with an ant topology. In compounds 1-3, the two H3PyImDC ligands exhibit different coordination modes with zinc and neodymium centers, which afforded the expected structural diversity. Additionally, all three compounds exhibit strong fluorescence emissions in the solid state at room temperature. © 2010 American Chemical Society.

  9. Immobilisation of ligands by radio-derivatized polymers

    International Nuclear Information System (INIS)

    Varga, J.M.; Fritsch, P.

    1995-01-01

    The invention relates to radio-derivatized polymers and a method of producing them by contacting non-polymerizable conjugands with radiolysable polymers in the presence of irradiation. The resulting radio-derivatized polymers can be further linked with ligand of organic or inorganic nature to immobilize such ligands. 2 figs., 5 tabs

  10. Ligand-bridged dinuclear cyclometalated Ir(III) complexes: from metallamacrocycles to discrete dimers.

    Science.gov (United States)

    Chandrasekhar, Vadapalli; Hajra, Tanima; Bera, Jitendra K; Rahaman, S M Wahidur; Satumtira, Nisa; Elbjeirami, Oussama; Omary, Mohammad A

    2012-02-06

    Metallamacrocycles 1, 2, and 3 of the general formula [{Ir(ppy)(2)}(2)(μ-BL)(2)](OTf)(2) (ppyH = 2-phenyl pyridine; BL = 1,2-bis(4-pyridyl)ethane (bpa) (1), 1,3-bis(4-pyridyl)propane (bpp) (2), and trans-1,2-bis(4-pyridyl)ethylene (bpe) (3)) have been synthesized by the reaction of [{(ppy)(2)Ir}(2)(μ-Cl)(2)], first with AgOTf to effect dechlorination and later with various bridging ligands. Open-frame dimers [{Ir(ppy)(2)}(2)(μ-BL)](OTf)(2) were obtained in a similar manner by utilizing N,N'-bis(2-pyridyl)methylene-hydrazine (abp) and N,N'-(bis(2-pyridyl)formylidene)ethane-1,2-diamine (bpfd) (for compounds 4 and 5, respectively) as bridging ligands. Molecular structures of 1, 3, 4, and 5 were established by X-ray crystallography. Cyclic voltammetry experiments reveal weakly interacting "Ir(ppy)(2)" units bridged by ethylene-linked bpe ligand in 3; on the contrary the metal centers are electronically isolated in 1 and 2 where the bridging ligands are based on ethane and propane linkers. The dimer 4 exhibits two accessible reversible reduction couples separated by 570 mV indicating the stability of the one-electron reduced species located on the diimine-based bridge abp. The "Ir(ppy)(2)" units in compound 5 are noninteracting as the electronic conduit is truncated by the ethane spacer in the bpfd bridge. The dinuclear compounds 1-5 show ligand centered (LC) transitions involving ppy ligands and mixed metal to ligand/ligand to ligand charge transfer (MLCT/LLCT) transitions involving both the cyclometalating ppy and bridging ligands (BL) in the UV-vis spectra. For the conjugated bridge bpe in compound 3 and abp in compound 4, the lowest-energy charge-transfer absorptions are red-shifted with enhanced intensity. In accordance with their similar electronic structures, compounds 1 and 2 exhibit identical emissions. The presence of vibronic structures in these compounds indicates a predominantly (3)LC excited states. On the contrary, broad and unstructured

  11. Tumor necrosis factor related apoptosis inducing ligand triggers apoptosis in dividing but not in differentiating human epidermal keratinocytes

    NARCIS (Netherlands)

    Jansen, Bastiaan J. H.; van Ruissen, Fred; Cerneus, Stefanie; Cloin, Wendy; Bergers, Mieke; van Erp, Piet E. J.; Schalkwijk, Joost

    2003-01-01

    Using serial analysis of gene expression we have previously identified the expression of several pro-apoptotic and anti-apoptotic genes in cultured human primary epidermal keratinocytes, including tumor necrosis factor related apoptosis inducing ligand (TRAIL). TRAIL is a potent inducer of apoptosis

  12. Calculating the mean time to capture for tethered ligands and its effect on the chemical equilibrium of bound ligand pairs.

    Science.gov (United States)

    Shen, Lu; Decker, Caitlin G; Maynard, Heather D; Levine, Alex J

    2016-09-01

    We present here the calculation of the mean time to capture of a tethered ligand to the receptor. This calculation is then used to determine the shift in the partitioning between (1) free, (2) singly bound, and (3) doubly bound ligands in chemical equilibrium as a function of the length of the tether. These calculations are used in the research article Fibroblast Growth Factor 2 Dimer with Superagonist in vitro Activity Improves Granulation Tissue Formation During Wound Healing (Decker et al., in press [1]) to explain quantitatively how changes in polymeric linker length in the ligand dimers modifies the efficacy of these molecules relative to that of free ligands.

  13. Crystallization of bi-functional ligand protein complexes.

    Science.gov (United States)

    Antoni, Claudia; Vera, Laura; Devel, Laurent; Catalani, Maria Pia; Czarny, Bertrand; Cassar-Lajeunesse, Evelyn; Nuti, Elisa; Rossello, Armando; Dive, Vincent; Stura, Enrico Adriano

    2013-06-01

    Homodimerization is important in signal transduction and can play a crucial role in many other biological systems. To obtaining structural information for the design of molecules able to control the signalization pathways, the proteins involved will have to be crystallized in complex with ligands that induce dimerization. Bi-functional drugs have been generated by linking two ligands together chemically and the relative crystallizability of complexes with mono-functional and bi-functional ligands has been evaluated. There are problems associated with crystallization with such ligands, but overall, the advantages appear to be greater than the drawbacks. The study involves two matrix metalloproteinases, MMP-12 and MMP-9. Using flexible and rigid linkers we show that it is possible to control the crystal packing and that by changing the ligand-enzyme stoichiometric ratio, one can toggle between having one bi-functional ligand binding to two enzymes and having the same ligand bound to each enzyme. The nature of linker and its point of attachment on the ligand can be varied to aid crystallization, and such variations can also provide valuable structural information about the interactions made by the linker with the protein. We report here the crystallization and structure determination of seven ligand-dimerized complexes. These results suggest that the use of bi-functional drugs can be extended beyond the realm of protein dimerization to include all drug design projects. Copyright © 2013 Elsevier Inc. All rights reserved.

  14. AutoSite: an automated approach for pseudo-ligands prediction—from ligand-binding sites identification to predicting key ligand atoms

    Science.gov (United States)

    Ravindranath, Pradeep Anand; Sanner, Michel F.

    2016-01-01

    Motivation: The identification of ligand-binding sites from a protein structure facilitates computational drug design and optimization, and protein function assignment. We introduce AutoSite: an efficient software tool for identifying ligand-binding sites and predicting pseudo ligand corresponding to each binding site identified. Binding sites are reported as clusters of 3D points called fills in which every point is labelled as hydrophobic or as hydrogen bond donor or acceptor. From these fills AutoSite derives feature points: a set of putative positions of hydrophobic-, and hydrogen-bond forming ligand atoms. Results: We show that AutoSite identifies ligand-binding sites with higher accuracy than other leading methods, and produces fills that better matches the ligand shape and properties, than the fills obtained with a software program with similar capabilities, AutoLigand. In addition, we demonstrate that for the Astex Diverse Set, the feature points identify 79% of hydrophobic ligand atoms, and 81% and 62% of the hydrogen acceptor and donor hydrogen ligand atoms interacting with the receptor, and predict 81.2% of water molecules mediating interactions between ligand and receptor. Finally, we illustrate potential uses of the predicted feature points in the context of lead optimization in drug discovery projects. Availability and Implementation: http://adfr.scripps.edu/AutoDockFR/autosite.html Contact: sanner@scripps.edu Supplementary information: Supplementary data are available at Bioinformatics online. PMID:27354702

  15. Determining the magnitude and direction of photoinduced ligand field switching in photochromic metal-organic complexes: molybdenum-tetracarbonyl spirooxazine complexes.

    Science.gov (United States)

    Paquette, Michelle M; Patrick, Brian O; Frank, Natia L

    2011-07-06

    The ability to optically switch or tune the intrinsic properties of transition metals (e.g., redox potentials, emission/absorption energies, and spin states) with photochromic metal-ligand complexes is an important strategy for developing "smart" materials. We have described a methodology for using metal-carbonyl complexes as spectroscopic probes of ligand field changes associated with light-induced isomerization of photochromic ligands. Changes in ligand field between the ring-closed spirooxazine (SO) and ring-opened photomerocyanine (PMC) forms of photochromic azahomoadamantyl and indolyl phenanthroline-spirooxazine ligands are demonstrated through FT-IR, (13)C NMR, and computational studies of their molybdenum-tetracarbonyl complexes. The frontier molecular orbitals (MOs) of the SO and PMC forms differ considerably in both electron density distributions and energies. Of the multiple π* MOs in the SO and PMC forms of the ligands, the LUMO+1, a pseudo-b(1)-symmetry phenanthroline-based MO, mixes primarily with the Mo(CO)(4) fragment and provides the major pathway for Mo(d)→phen(π*) backbonding. The LUMO+1 is found to be 0.2-0.3 eV lower in energy in the SO form relative to the PMC form, suggesting that the SO form is a better π-acceptor. Light-induced isomerization of the photochromic ligands was therefore found to lead to changes in the energies of their frontier MOs, which in turn leads to changes in π-acceptor ability and ligand field strength. Ligand field changes associated with photoisomerizable ligands allow tuning of excited-state and ground-state energies that dictate energy/electron transfer, optical/electrical properties, and spin states of a metal center upon photoisomerization, positioning photochromic ligand-metal complexes as promising targets for smart materials.

  16. Investigation of Uranyl Nitrate Ion Pairs Complexed with Amide Ligands using Electrospray Ionization Ion Trap Mass Spectrometry and Density Functional Theory

    International Nuclear Information System (INIS)

    Groenewold, Gary S.; Dinescu, Adriana; Benson, Michael T.; Gresham, Garold L.; van Stipdonk, Michael J.

    2011-01-01

    Ion populations formed from electrospray of uranyl nitrate solutions containing different amides vary depending on ligand nucleophilicity and steric crowding at the metal center. The most abundant species were ion pair complexes having the general formula (UO2(NO3)(amide)n=2,3)+, and complexes containing the amide conjugate base, reduced uranyl UO2+, and a 2+ charge were also formed. The formamide experiment produced the greatest diversity of species that stems from weaker amide binding leading to dissociation and subsequent solvent coordination or metal reduction. Experiments using methyl formamide, dimethyl formamide, acetamide, and methyl acetamide produced ion pair and doubly charged complexes that were more abundant, and less abundant complexes containing solvent or reduced uranyl. This pattern is reversed in the dimethylacetamide experiment, which displayed reduced doubly charged complexes and augmented reduced uranyl complexes. DFT investigations of the tris-amide ion pair complexes showed that inter-ligand repulsion distorts the amide ligands out of the uranyl equatorial plane, and that complex stabilities do not increase with increasing amide nucleophilicity. Elimination of an amide ligand largely relieves the interligand repulsion, and the remaining amide ligands become closely aligned with the equatorial plane in the structures of the bis-amide ligands. The studies show that the phenomenological distribution of coordination complexes in a metal-ligand electrospray experiment is a function of both ligand nucleophilicity and interligand repulsion, and that the latter factor begins exerting influence even in the case of relatively small ligands like the substituted methyl-formamide and methyl-acetamide ligands.

  17. Induction and regulation of tumor necrosis factor-related apoptosis-inducing ligand/Apo-2 ligand-mediated apoptosis in renal cell carcinoma.

    Science.gov (United States)

    Griffith, Thomas S; Fialkov, Jonathan M; Scott, David L; Azuhata, Takeo; Williams, Richard D; Wall, Nathan R; Altieri, Dario C; Sandler, Anthony D

    2002-06-01

    The lack of effective therapy for disseminated renal cell carcinoma (RCC) has stimulated the search for novel treatments including immunotherapeutic strategies. However, poor therapeutic responses and marked toxicity associated with immunological agents has limited their use. The tumor necrosis factor family member tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/Apo-2 ligand induces apoptosis in a variety of tumor cell types, while having little cytotoxic activity against normal cells. In this study the activation and regulation of TRAIL-induced apoptosis and TRAIL receptor expression in human RCC cell lines and pathologic specimens was examined. TRAIL induced caspase-mediated apoptotic death of RCC cells with variable sensitivities among the cell lines tested. Compared with TRAIL-sensitive RCC cell lines (A-498, ACHN, and 769-P), the TRAIL-resistant RCC cell line (786-O) expressed lesser amounts of the death-inducing TRAIL receptors, and greater amounts of survivin, an inhibitor of apoptosis. Incubation of 786-O with actinomycin D increased the expression of the death-inducing TRAIL receptors and, concomitantly, decreased the intracellular levels of survivin, resulting in TRAIL-induced apoptotic death. The link between survivin and TRAIL regulation was confirmed when an increase in TRAIL resistance was observed after overexpression of survivin in the TRAIL-sensitive, survivin-negative RCC line A-498. These findings, along with our observation that TRAIL receptors are expressed in RCC tumor tissue, suggest that TRAIL may be useful as a therapeutic agent for RCC and that survivin may partially regulate TRAIL-induced cell death.

  18. LASSO-ligand activity by surface similarity order: a new tool for ligand based virtual screening.

    Science.gov (United States)

    Reid, Darryl; Sadjad, Bashir S; Zsoldos, Zsolt; Simon, Aniko

    2008-01-01

    Virtual Ligand Screening (VLS) has become an integral part of the drug discovery process for many pharmaceutical companies. Ligand similarity searches provide a very powerful method of screening large databases of ligands to identify possible hits. If these hits belong to new chemotypes the method is deemed even more successful. eHiTS LASSO uses a new interacting surface point types (ISPT) molecular descriptor that is generated from the 3D structure of the ligand, but unlike most 3D descriptors it is conformation independent. Combined with a neural network machine learning technique, LASSO screens molecular databases at an ultra fast speed of 1 million structures in under 1 min on a standard PC. The results obtained from eHiTS LASSO trained on relatively small training sets of just 2, 4 or 8 actives are presented using the diverse directory of useful decoys (DUD) dataset. It is shown that over a wide range of receptor families, eHiTS LASSO is consistently able to enrich screened databases and provides scaffold hopping ability.

  19. LASSO—ligand activity by surface similarity order: a new tool for ligand based virtual screening

    Science.gov (United States)

    Reid, Darryl; Sadjad, Bashir S.; Zsoldos, Zsolt; Simon, Aniko

    2008-06-01

    Virtual Ligand Screening (VLS) has become an integral part of the drug discovery process for many pharmaceutical companies. Ligand similarity searches provide a very powerful method of screening large databases of ligands to identify possible hits. If these hits belong to new chemotypes the method is deemed even more successful. eHiTS LASSO uses a new interacting surface point types (ISPT) molecular descriptor that is generated from the 3D structure of the ligand, but unlike most 3D descriptors it is conformation independent. Combined with a neural network machine learning technique, LASSO screens molecular databases at an ultra fast speed of 1 million structures in under 1 min on a standard PC. The results obtained from eHiTS LASSO trained on relatively small training sets of just 2, 4 or 8 actives are presented using the diverse directory of useful decoys (DUD) dataset. It is shown that over a wide range of receptor families, eHiTS LASSO is consistently able to enrich screened databases and provides scaffold hopping ability.

  20. Alkali Metal Ion Complexes with Phosphates, Nucleotides, Amino Acids, and Related Ligands of Biological Relevance. Their Properties in Solution.

    Science.gov (United States)

    Crea, Francesco; De Stefano, Concetta; Foti, Claudia; Lando, Gabriele; Milea, Demetrio; Sammartano, Silvio

    2016-01-01

    Alkali metal ions play very important roles in all biological systems, some of them are essential for life. Their concentration depends on several physiological factors and is very variable. For example, sodium concentrations in human fluids vary from quite low (e.g., 8.2 mmol dm(-3) in mature maternal milk) to high values (0.14 mol dm(-3) in blood plasma). While many data on the concentration of Na(+) and K(+) in various fluids are available, the information on other alkali metal cations is scarce. Since many vital functions depend on the network of interactions occurring in various biofluids, this chapter reviews their complex formation with phosphates, nucleotides, amino acids, and related ligands of biological relevance. Literature data on this topic are quite rare if compared to other cations. Generally, the stability of alkali metal ion complexes of organic and inorganic ligands is rather low (usually log K  Na(+) > K(+) > Rb(+) > Cs(+). For example, for citrate it is: log K ML = 0.88, 0.80, 0.48, 0.38, and 0.13 at 25 °C and infinite dilution. Some considerations are made on the main aspects related to the difficulties in the determination of weak complexes. The importance of the alkali metal ion complexes was also studied in the light of modelling natural fluids and in the use of these cations as probes for different processes. Some empirical relationships are proposed for the dependence of the stability constants of Na(+) complexes on the ligand charge, as well as for correlations among log K values of NaL, KL or LiL species (L = generic ligand).

  1. Ligand Depot: a data warehouse for ligands bound to macromolecules.

    Science.gov (United States)

    Feng, Zukang; Chen, Li; Maddula, Himabindu; Akcan, Ozgur; Oughtred, Rose; Berman, Helen M; Westbrook, John

    2004-09-01

    Ligand Depot is an integrated data resource for finding information about small molecules bound to proteins and nucleic acids. The initial release (version 1.0, November, 2003) focuses on providing chemical and structural information for small molecules found as part of the structures deposited in the Protein Data Bank. Ligand Depot accepts keyword-based queries and also provides a graphical interface for performing chemical substructure searches. A wide variety of web resources that contain information on small molecules may also be accessed through Ligand Depot. Ligand Depot is available at http://ligand-depot.rutgers.edu/. Version 1.0 supports multiple operating systems including Windows, Unix, Linux and the Macintosh operating system. The current drawing tool works in Internet Explorer, Netscape and Mozilla on Windows, Unix and Linux.

  2. Radiation induced ligand loss from cobalt complexes

    International Nuclear Information System (INIS)

    Funston, A. M.; McFadyen, W.D.; Tregloan, P.A.

    2000-01-01

    Full text: Due to the rapid nature of ligand dissociation from cobalt(II) complexes the study of the rate of ligand dissociation necessitates the use of a technique such as pulse radiolysis. This allows the rapid reduction of the corresponding cobalt(III) complex by a reducing radical, such as the aquated electron, to form the cobalt(II) complex. However, to date, no systematic study of either the mechanism of reduction or the influence of the electronic structure on the rate of ligand dissociation has been carried out. In order to understand these processes more fully the mechanism of reduction of a range of related cobalt(III) complexes by the aquated electron and the subsequent rate of ligand dissociation from the resulting cobalt(II) complexes is being investigated. It has been found that a number of processes are observed following the initial rapid reaction of the cobalt(III) complex with the aquated electron. Ultimately ligand loss is observed. Depending upon the complex, the initial processes observed may include the formation of coordinated radicals and electron transfer within the complex. For complexes containing aromatic ligands such as 2,2'-bipyridine, 1,10-phenanthroline and dipyrido[3,2-a:2',3'-c]phenazine the formation of a coordinated radical is observed as the initial reduction step. The kinetics of ligand dissociation of these complexes has been determined. The loss of monodentate ligands is fast and has been indistinguishable from the reduction processes when aromatic ligands are also present in the complex. However, for diamine chelates and diimine chelates spectra of the transient species can be resolved

  3. Mixed-ligand Pt(II) dithione-dithiolato complexes: influence of the dicyanobenzodithiolato ligand on the second-order NLO properties.

    Science.gov (United States)

    Espa, Davide; Pilia, Luca; Marchiò, Luciano; Artizzu, Flavia; Serpe, Angela; Mercuri, Maria Laura; Simão, Dulce; Almeida, Manuel; Pizzotti, Maddalena; Tessore, Francesca; Deplano, Paola

    2012-03-28

    The mixed-ligand dithiolene complex [Pt(Bz(2)pipdt)(dcbdt)] (1) bearing the two ligands Bz(2)pipdt = 1,4-dibenzyl-piperazine-3,2-dithione and dcbdt = dicyanobenzodithiolato, has been synthesized, characterized and studied to evaluate its second-order optical nonlinearity. The dithione/dithiolato character of the two ligands gives rise to an asymmetric distribution of the charge in the molecule. This is reflected by structural data showing that in the C(2)S(2)PtS(2)C(2) dithiolene core the four sulfur atoms define a square-planar coordination environment of the metal where the Pt-S bond distances involving the two ligands are similar, while the C-S bond distances in the C(2)S(2) units exhibit a significant difference in Bz(2)pipdt (dithione) and dcbdt (dithiolato). 1 shows a moderately strong absorption peak in the visible region, which can be related to a HOMO-LUMO transition, where the dcbdt ligand (dithiolato) contributes mostly to the HOMO, and the Bz(2)pipdt one (dithione) mostly to the LUMO. Thus this transition has ligand-to-ligand charge transfer (CT) character with some contribution of the metal and undergoes negative solvatochromism and molecular quadratic optical nonlinearity (μβ(0) = -1296 × 10(-48) esu), which was determined by the EFISH (electric-field-induced second-harmonic generation) technique and compared with the values of similar complexes on varying the dithiolato ligand (mnt = maleonitriledithiolato, dmit = 2-thioxo-1,3-dithiole-4,5-dithiolato). Theoretical calculations help to elucidate the role of the dithiolato ligands in affecting the molecular quadratic optical nonlinearity of these complexes.

  4. Structural and Electrochemical Consequences of [Cp*] Ligand Protonation.

    Science.gov (United States)

    Peng, Yun; Ramos-Garcés, Mario V; Lionetti, Davide; Blakemore, James D

    2017-09-05

    There are few examples of the isolation of analogous metal complexes bearing [η 5 -Cp*] and [η 4 -Cp*H] (Cp* = pentamethylcyclopentadienyl) complexes within the same metal/ligand framework, despite the relevance of such structures to catalytic applications. Recently, protonation of Cp*Rh(bpy) (bpy = 2,2'-bipyridyl) has been shown to yield a complex bearing the uncommon [η 4 -Cp*H] ligand, rather than generating a [Rh III -H] complex. We now report the purification and isolation of this protonated species, as well as characterization of analogous complexes of 1,10-phenanthroline (phen). Specifically, reaction of Cp*Rh(bpy) or Cp*Rh(phen) with 1 equiv of Et 3 NH + Br - affords rhodium compounds bearing endo-η 4 -pentamethylcyclopentadiene (η 4 -Cp*H) as a ligand. NMR spectroscopy and single-crystal X-ray diffraction studies confirm protonation of the Cp* ligand, rather than formation of metal hydride complexes. Analysis of new structural data and electronic spectra suggests that phen is significantly reduced in Cp*Rh(phen), similar to the case of Cp*Rh(bpy). Backbonding interactions with olefinic motifs are activated by formation of [η 4 -Cp*H]; protonation of [Cp*] stabilizes the low-valent metal center and results in loss of reduced character on the diimine ligands. In accord with these changes in electronic structure, electrochemical studies reveal a distinct manifold of redox processes that are accessible in the [Cp*H] complexes in comparison with their [Cp*] analogues; these processes suggest new applications in catalysis for the complexes bearing endo-η 4 -Cp*H.

  5. Synthesis, crystal structures, and luminescent properties of Cd(II) coordination polymers assembled from semi-rigid multi-dentate N-containing ligand

    Energy Technology Data Exchange (ETDEWEB)

    Yuan, Gang; Shao, Kui-Zhan; Chen, Lei; Liu, Xin-Xin [Institute of Functional Material Chemistry, Faculty of Chemistry, Northeast Normal University, Changchun 130024, Jilin (China); Su, Zhong-Min, E-mail: zmsu@nenu.edu.cn [Institute of Functional Material Chemistry, Faculty of Chemistry, Northeast Normal University, Changchun 130024, Jilin (China); Ma, Jian-Fang [Institute of Functional Material Chemistry, Faculty of Chemistry, Northeast Normal University, Changchun 130024, Jilin (China)

    2012-12-15

    Three new polymers, [Cd(L){sub 2}(H{sub 2}O){sub 2}]{sub n} (1), [Cd{sub 3}(L){sub 2}({mu}{sub 3}-OH){sub 2}({mu}{sub 2}-Cl){sub 2}(H{sub 2}O){sub 2}]{sub n} (2), {l_brace}[Cd{sub 2}(L){sub 2}(nic){sub 2}(H{sub 2}O){sub 2}]{center_dot}H{sub 2}O{r_brace}{sub n} (3) (HL=5-(4-((1H-1,2,4-triazol-1-yl)methyl)phenyl)-1H-tetrazole, Hnic=nicotinic acid) have been prepared and structurally characterized. Compounds 1 and 2 display 2D monomolecular layers built by the inter-linking single helical chains and L{sup -} ligands connecting chain-like [Cd({mu}{sub 3}-OH)({mu}{sub 2}-Cl)]{sub n} secondary building units, respectively. Compound 3 is constructed from the mixed ligands and possesses a (3,4)-connected framework with (4{center_dot}8{sup 2})(4{center_dot}8{sup 2}{center_dot}10{sup 3}) topology. Moreover, the fluorescent properties of HL ligand and compounds 1-3 are also been investigated. - Graphical abstract: Three new coordination polymers based on the semi-rigid multidentate N-donor ligand have been successfully synthesized by hydrothermal reaction. Complexes 1 and 2 exhibit the 2D layers formed by inter-linking single helices and L{sup -} anions bridging 1D chain-like SBUs, respectively. Complex 3 is buit by L{sup -} and assistant nic{sup -} ligands connecting metal centers and possesses a (3,4)-connected framework with (4 Multiplication-Sign 8{sup 2})(4 Multiplication-Sign 8{sup 2} Multiplication-Sign 10{sup 3}) topology. Moreover, these complexes display fluorescent properties indicating that they may have potential applications as optical materials. Highlights: Black-Right-Pointing-Pointer Three Cd-compounds were prepared from semi-rigid HL ligand with different N-containing groups. Black-Right-Pointing-Pointer They exhibit diverse structures from 2D monomolecular layer to 3D covalent framework. Black-Right-Pointing-Pointer The HL ligands displayed various coordination modes under different reaction conditions. Black-Right-Pointing-Pointer These compounds exhibit

  6. [A relational database to store Poison Centers calls].

    Science.gov (United States)

    Barelli, Alessandro; Biondi, Immacolata; Tafani, Chiara; Pellegrini, Aristide; Soave, Maurizio; Gaspari, Rita; Annetta, Maria Giuseppina

    2006-01-01

    Italian Poison Centers answer to approximately 100,000 calls per year. Potentially, this activity is a huge source of data for toxicovigilance and for syndromic surveillance. During the last decade, surveillance systems for early detection of outbreaks have drawn the attention of public health institutions due to the threat of terrorism and high-profile disease outbreaks. Poisoning surveillance needs the ongoing, systematic collection, analysis, interpretation, and dissemination of harmonised data about poisonings from all Poison Centers for use in public health action to reduce morbidity and mortality and to improve health. The entity-relationship model for a Poison Center relational database is extremely complex and not studied in detail. For this reason, not harmonised data collection happens among Italian Poison Centers. Entities are recognizable concepts, either concrete or abstract, such as patients and poisons, or events which have relevance to the database, such as calls. Connectivity and cardinality of relationships are complex as well. A one-to-many relationship exist between calls and patients: for one instance of entity calls, there are zero, one, or many instances of entity patients. At the same time, a one-to-many relationship exist between patients and poisons: for one instance of entity patients, there are zero, one, or many instances of entity poisons. This paper shows a relational model for a poison center database which allows the harmonised data collection of poison centers calls.

  7. Stable and rigid DTPA-like paramagnetic tags suitable for in vitro and in situ protein NMR analysis.

    Science.gov (United States)

    Chen, Jia-Liang; Zhao, Yu; Gong, Yan-Jun; Pan, Bin-Bin; Wang, Xiao; Su, Xun-Cheng

    2018-02-01

    Organic synthesis of a ligand with high binding affinities for paramagnetic lanthanide ions is an effective way of generating paramagnetic effects on proteins. These paramagnetic effects manifested in high-resolution NMR spectroscopy are valuable dynamic and structural restraints of proteins and protein-ligand complexes. A paramagnetic tag generally contains a metal chelating moiety and a reactive group for protein modification. Herein we report two new DTPA-like tags, 4PS-PyDTTA and 4PS-6M-PyDTTA that can be site-specifically attached to a protein with a stable thioether bond. Both protein-tag adducts form stable lanthanide complexes, of which the binding affinities and paramagnetic tensors are tunable with respect to the 6-methyl group in pyridine. Paramagnetic relaxation enhancement (PRE) effects of Gd(III) complex on protein-tag adducts were evaluated in comparison with pseudocontact shift (PCS), and the results indicated that both 4PS-PyDTTA and 4PS-6M-PyDTTA tags are rigid and present high-quality PREs that are crucially important in elucidation of the dynamics and interactions of proteins and protein-ligand complexes. We also show that these two tags are suitable for in-situ protein NMR analysis.

  8. Highly Fluorescent Group 13 Metal Complexes with Cyclic, Aromatic Hydroxamic Acid Ligands

    Energy Technology Data Exchange (ETDEWEB)

    Seitz, Michael; Moore, Evan G.; Raymond, Kenneth N.

    2008-02-11

    The neutral complexes of two ligands based on the 1-oxo-2-hydroxy-isoquinoline (1,2-HOIQO) motif with group 13 metals (Al, Ga, In) show bright blue-violet luminescence in organic solvents. The corresponding transition can be attributed to ligand-centered singlet emission, characterized by a small Stokes shifts of only a few nm combined with lifetimes in the range between 1-3 ns. The fluorescence efficiency is high, with quantum yields of up to 37% in benzene solution. The crystal structure of one of the indium(III) complexes (trigonal space group R-3, a = b = 13.0384(15) {angstrom}, c = 32.870(8) {angstrom}, ? = {beta} = 90{sup o}, {gamma} = 120{sup o}, V = 4839.3(14) {angstrom}{sup 3}, Z = 6) shows a six-coordinate geometry around the indium center which is close to trigonal-prismatic, with a twist angle between the two trigonal faces of 20.7{sup o}. Time-dependent density functional theory (TD-DFT) calculations (Al and Ga: B3LYP/6-31G(d)); In: B3LYP/LANL2DZ of the fac and mer isomers with one of the two ligands indicate that there is no clear preference for either one of the isomeric forms of the metal complexes. In addition, the metal centers do not have a significant influence on the electronic structure, and as a consequence, on the predominant intraligand optical transitions.

  9. Impact of protein and ligand impurities on ITC-derived protein-ligand thermodynamics.

    Science.gov (United States)

    Grüner, Stefan; Neeb, Manuel; Barandun, Luzi Jakob; Sielaff, Frank; Hohn, Christoph; Kojima, Shun; Steinmetzer, Torsten; Diederich, François; Klebe, Gerhard

    2014-09-01

    The thermodynamic characterization of protein-ligand interactions by isothermal titration calorimetry (ITC) is a powerful tool in drug design, giving valuable insight into the interaction driving forces. ITC is thought to require protein and ligand solutions of high quality, meaning both the absence of contaminants as well as accurately determined concentrations. Ligands synthesized to deviating purity and protein of different pureness were titrated by ITC. Data curation was attempted also considering information from analytical techniques to correct stoichiometry. We used trypsin and tRNA-guanine transglycosylase (TGT), together with high affinity ligands to investigate the effect of errors in protein concentration as well as the impact of ligand impurities on the apparent thermodynamics. We found that errors in protein concentration did not change the thermodynamic properties obtained significantly. However, most ligand impurities led to pronounced changes in binding enthalpy. If protein binding of the respective impurity is not expected, the actual ligand concentration was corrected for and the thus revised data compared to thermodynamic properties obtained with the respective pure ligand. Even in these cases, we observed differences in binding enthalpy of about 4kJ⋅mol(-1), which is considered significant. Our results indicate that ligand purity is the critical parameter to monitor if accurate thermodynamic data of a protein-ligand complex are to be recorded. Furthermore, artificially changing fitting parameters to obtain a sound interaction stoichiometry in the presence of uncharacterized ligand impurities may lead to thermodynamic parameters significantly deviating from the accurate thermodynamic signature. Copyright © 2014 Elsevier B.V. All rights reserved.

  10. Ligand cluster-based protein network and ePlatton, a multi-target ligand finder.

    Science.gov (United States)

    Du, Yu; Shi, Tieliu

    2016-01-01

    Small molecules are information carriers that make cells aware of external changes and couple internal metabolic and signalling pathway systems with each other. In some specific physiological status, natural or artificial molecules are used to interact with selective biological targets to activate or inhibit their functions to achieve expected biological and physiological output. Millions of years of evolution have optimized biological processes and pathways and now the endocrine and immune system cannot work properly without some key small molecules. In the past thousands of years, the human race has managed to find many medicines against diseases by trail-and-error experience. In the recent decades, with the deepening understanding of life and the progress of molecular biology, researchers spare no effort to design molecules targeting one or two key enzymes and receptors related to corresponding diseases. But recent studies in pharmacogenomics have shown that polypharmacology may be necessary for the effects of drugs, which challenge the paradigm, 'one drug, one target, one disease'. Nowadays, cheminformatics and structural biology can help us reasonably take advantage of the polypharmacology to design next-generation promiscuous drugs and drug combination therapies. 234,591 protein-ligand interactions were extracted from ChEMBL. By the 2D structure similarity, 13,769 ligand emerged from 156,151 distinct ligands which were recognized by 1477 proteins. Ligand cluster- and sequence-based protein networks (LCBN, SBN) were constructed, compared and analysed. For assisting compound designing, exploring polypharmacology and finding possible drug combination, we integrated the pathway, disease, drug adverse reaction and the relationship of targets and ligand clusters into the web platform, ePlatton, which is available at http://www.megabionet.org/eplatton. Although there were some disagreements between the LCBN and SBN, communities in both networks were largely the same

  11. Synthesis and characterization of an iron complex bearing a cyclic tetra-N-heterocyclic carbene ligand: An artifical heme analogue?

    KAUST Repository

    Anneser, Markus R.

    2015-04-20

    An iron(II) complex with a cyclic tetradentate ligand containing four N-heterocyclic carbenes was synthesized and characterized by means of NMR and IR spectroscopies, as well as by single-crystal X-ray structure analysis. The iron center exhibits an octahedral coordination geometry with two acetonitrile ligands in axial positions, showing structural analogies with porphyrine-ligated iron complexes. The acetonitrile ligands can readily be substituted by other ligands, for instance, dimethyl sulfoxide, carbon monoxide, and nitric oxide. Cyclic voltammetry was used to examine the electronic properties of the synthesized compounds. © 2015 American Chemical Society.

  12. Synthesis of mixed-ligand cobalt complexes and their applications in high cis-1,4-selective butadiene polymerization

    KAUST Repository

    Liu, Wen; Pan, Weijing; Wang, Peng; Li, Wei; Mu, Jingshan; Weng, Gengsheng; Jia, Xiaoyu; Gong, Dirong; Huang, Kuo-Wei

    2015-01-01

    Incomplete oxidation of (N-di-tert-butylphosphino)-6-(2-methyl-2’H-benzoimidazole)-2-aminepyridine dichlorocobalt (PN3CoCl2) in DMF results in a unique co-crystal I formed with three parts including DMF, unit A and unit B complex with Co1 and Co2, respectively, (PN3 ligand in unit A: (N-di-tert-butylphosphino)-6-(2’-methyl-2’H-benzoimidazole)-2-aminepyridine, and O=PN3 ligand in unit B: (N-di-tert-butylphosphinoxide)-6-(2’-methyl-2’H-benzoimidazole)-2-aminepyridine) with 1:1:1 molar ratio. Co1 and Co2 complexes both display a five-coordinated distorted-square-pyramidal geometry around the metal center. The Co1 center is coordinated with PN3 ligand via two N atoms from pyridine, benzoimidazole moiety as well as one P atom, and the Co2 center is coordinated with the oxidized ligandO=PN3 via two N atoms from pyridine, benzoimidazole moiety as well as one O atom from DMF molecule, while the oxidized phosphine moiety (O=P) being excluded from the coordination sphere. Activated with AlEt2Cl, the co-crystallized complexes I are able to actively convert butadiene to polybutadiene, affording cis-1,4 polybutadiene with cis-1,4 unit up to 95.5-97.8% and number average molecular weight of cal. 105g/mol. The high cis-1,4 selectivity and monomodal GPC curve of resultant polymer imply that the identical active species generated from two distinctive cobalt centers.

  13. Synthesis of mixed-ligand cobalt complexes and their applications in high cis-1,4-selective butadiene polymerization

    KAUST Repository

    Liu, Wen

    2015-08-03

    Incomplete oxidation of (N-di-tert-butylphosphino)-6-(2-methyl-2’H-benzoimidazole)-2-aminepyridine dichlorocobalt (PN3CoCl2) in DMF results in a unique co-crystal I formed with three parts including DMF, unit A and unit B complex with Co1 and Co2, respectively, (PN3 ligand in unit A: (N-di-tert-butylphosphino)-6-(2’-methyl-2’H-benzoimidazole)-2-aminepyridine, and O=PN3 ligand in unit B: (N-di-tert-butylphosphinoxide)-6-(2’-methyl-2’H-benzoimidazole)-2-aminepyridine) with 1:1:1 molar ratio. Co1 and Co2 complexes both display a five-coordinated distorted-square-pyramidal geometry around the metal center. The Co1 center is coordinated with PN3 ligand via two N atoms from pyridine, benzoimidazole moiety as well as one P atom, and the Co2 center is coordinated with the oxidized ligandO=PN3 via two N atoms from pyridine, benzoimidazole moiety as well as one O atom from DMF molecule, while the oxidized phosphine moiety (O=P) being excluded from the coordination sphere. Activated with AlEt2Cl, the co-crystallized complexes I are able to actively convert butadiene to polybutadiene, affording cis-1,4 polybutadiene with cis-1,4 unit up to 95.5-97.8% and number average molecular weight of cal. 105g/mol. The high cis-1,4 selectivity and monomodal GPC curve of resultant polymer imply that the identical active species generated from two distinctive cobalt centers.

  14. Receptor-ligand binding sites and virtual screening.

    Science.gov (United States)

    Hattotuwagama, Channa K; Davies, Matthew N; Flower, Darren R

    2006-01-01

    Within the pharmaceutical industry, the ultimate source of continuing profitability is the unremitting process of drug discovery. To be profitable, drugs must be marketable: legally novel, safe and relatively free of side effects, efficacious, and ideally inexpensive to produce. While drug discovery was once typified by a haphazard and empirical process, it is now increasingly driven by both knowledge of the receptor-mediated basis of disease and how drug molecules interact with receptors and the wider physiome. Medicinal chemistry postulates that to understand a congeneric ligand series, or set thereof, is to understand the nature and requirements of a ligand binding site. Likewise, structural molecular biology posits that to understand a binding site is to understand the nature of ligands bound therein. Reality sits somewhere between these extremes, yet subsumes them both. Complementary to rules of ligand design, arising through decades of medicinal chemistry, structural biology and computational chemistry are able to elucidate the nature of binding site-ligand interactions, facilitating, at both pragmatic and conceptual levels, the drug discovery process.

  15. Ligands in PSI structures

    International Nuclear Information System (INIS)

    Kumar, Abhinav; Chiu, Hsiu-Ju; Axelrod, Herbert L.; Morse, Andrew; Elsliger, Marc-André; Wilson, Ian A.; Deacon, Ashley

    2010-01-01

    A survey of the types and frequency of ligands that are bound to PSI structures is analyzed as well as their utility in functional annotation of previously uncharacterized proteins. Approximately 65% of PSI structures report some type of ligand(s) that is bound in the crystal structure. Here, a description is given of how such ligands are handled and analyzed at the JCSG and a survey of the types, variety and frequency of ligands that are observed in the PSI structures is also compiled and analyzed, including illustrations of how these bound ligands have provided functional clues for annotation of proteins with little or no previous experimental characterization. Furthermore, a web server was developed as a tool to mine and analyze the PSI structures for bound ligands and other identifying features

  16. Nickel speciation and complexation kinetics in freshwater by ligand exchange and DPCSV

    NARCIS (Netherlands)

    Han Bin Xue,; Jansen, S.; Prasch, A.; Sigg, L.

    2001-01-01

    A technique of ligand exchange with DMG (dimethylglyoxime) and DPCSV was applied to determine Ni speciation in lake, river, and groundwater samples. The working conditions related to ligand-exchange equilibrium were optimized, and the ligand-exchange kinetics were examined. The observed

  17. Microassay for measurement of binding of radiolabelled ligands to cell surface molecules

    International Nuclear Information System (INIS)

    Woof, J.M.; Burton, D.R.

    1988-01-01

    An improved technique for measuring the binding of radiolabelled ligands to cell surface molecules has been developed by modification of a procedure using centrifugation through a water-immiscible oil to separate free and cell-bound ligand. It maximises the percentage of ligand bound since cell-bound and free ligand can be separated easily and reproducibly even when very small reaction volumes are used. This permits low levels of ligand radiolabelling and relatively low numbers of cells to be used

  18. Ligand photo-isomerization triggers conformational changes in iGluR2 ligand binding domain.

    Directory of Open Access Journals (Sweden)

    Tino Wolter

    Full Text Available Neurological glutamate receptors bind a variety of artificial ligands, both agonistic and antagonistic, in addition to glutamate. Studying their small molecule binding properties increases our understanding of the central nervous system and a variety of associated pathologies. The large, oligomeric multidomain membrane protein contains a large and flexible ligand binding domains which undergoes large conformational changes upon binding different ligands. A recent application of glutamate receptors is their activation or inhibition via photo-switchable ligands, making them key systems in the emerging field of optochemical genetics. In this work, we present a theoretical study on the binding mode and complex stability of a novel photo-switchable ligand, ATA-3, which reversibly binds to glutamate receptors ligand binding domains (LBDs. We propose two possible binding modes for this ligand based on flexible ligand docking calculations and show one of them to be analogues to the binding mode of a similar ligand, 2-BnTetAMPA. In long MD simulations, it was observed that transitions between both binding poses involve breaking and reforming the T686-E402 protein hydrogen bond. Simulating the ligand photo-isomerization process shows that the two possible configurations of the ligand azo-group have markedly different complex stabilities and equilibrium binding modes. A strong but slow protein response is observed after ligand configuration changes. This provides a microscopic foundation for the observed difference in ligand activity upon light-switching.

  19. New synthetic routes toward enantiopure nitrogen donor ligands.

    Science.gov (United States)

    Sala, Xavier; Rodríguez, Anna M; Rodríguez, Montserrat; Romero, Isabel; Parella, Teodor; von Zelewsky, Alexander; Llobet, Antoni; Benet-Buchholz, Jordi

    2006-12-08

    New polypyridylic chiral ligands, having either C3 or lower symmetry, have been prepared via a de novo construction of the pyridine nucleus by means of Kröhnke methodology in the key step. The chiral moieties of these ligands originate from the monoterpen chiral pool, namely (-)-alpha-pinene ((-)-14, (-)-15) and (-)-myrtenal ((-)-9, (-)-10). Extension of the above-mentioned asymmetric synthesis procedure to the preparation of enantiopure derivatives of some commonly used polypyridylic ligands has been achieved through a new aldehyde building block ((-)-16). As an example, the synthesis of a chiral derivative of N,N-bis(2-pyridylmethyl)ethylamine (bpea) ligand, (-)-19, has been performed to illustrate the viability of the method. The coordinative ability of the ligands has been tested through the synthesis and characterization of complexes [Mn((-)-19)Br2], (-)-20, and [RuCl((-)-10)(bpy)](BF4), (-)-21. Some preliminary results related to the enantioselective catalytic epoxidation of styrene with the ruthenium complex are also presented.

  20. Dissecting Orthosteric Contacts for a Reverse-Fragment-Based Ligand Design.

    Science.gov (United States)

    Chandramohan, Arun; Tulsian, Nikhil K; Anand, Ganesh S

    2017-08-01

    Orthosteric sites on proteins are formed typically from noncontiguous interacting sites in three-dimensional space where the composite binding interaction of a biological ligand is mediated by multiple synergistic interactions of its constituent functional groups. Through these multiple interactions, ligands stabilize both the ligand binding site and the local secondary structure. However, relative energetic contributions of the individual contacts in these protein-ligand interactions are difficult to resolve. Deconvolution of the contributions of these various functional groups in natural inhibitors/ligand would greatly aid in iterative fragment-based drug discovery (FBDD). In this study, we describe an approach of progressive unfolding of a target protein using a gradient of denaturant urea to reveal the individual energetic contributions of various ligand-functional groups to the affinity of the entire ligand. Through calibrated unfolding of two protein-ligand systems: cAMP-bound regulatory subunit of Protein Kinase A (RIα) and IBMX-bound phosphodiesterase8 (PDE8), monitored by amide hydrogen-deuterium exchange mass spectrometry, we show progressive disruption of individual orthosteric contacts in the ligand binding sites, allowing us to rank the energetic contributions of these individual interactions. In the two cAMP-binding sites of RIα, exocyclic phosphate oxygens of cAMP were identified to mediate stronger interactions than ribose 2'-OH in both the RIα-cAMP binding interfaces. Further, we have also ranked the relative contributions of the different functional groups of IBMX based on their interactions with the orthosteric residues of PDE8. This strategy for deconstruction of individual binding sites and identification of the strongest functional group interaction in enzyme orthosteric sites offers a rational starting point for FBDD.

  1. Relation of circulating concentrations of chemokine receptor CCR5 ligands to C-peptide, proinsulin and HbA1c and disease progression in type 1 diabetes

    DEFF Research Database (Denmark)

    Pfleger, C.; Kaas, A.; Hansen, L.

    2008-01-01

    Th1 related chemokines CCL3 and CCL5 and Th2 related CCL4 as ligands of the receptor CCR5 contribute to disease development in animal models of type 1 diabetes. In humans, no data are available addressing the role of these chemokines regarding disease progression and remission. We investigated...... longitudinally circulating concentrations of CCR5 ligands of 256 newly diagnosed patients with type 1 diabetes. CCR5 ligands were differentially associated with beta-cell function and clinical remission. CCL5 was decreased in remitters and positively associated with HbA1c suggestive of a Th1 associated...... of CCR5 by therapeutic agents such as maraviroc may provide a new therapeutic target to ameliorate disease progression in type 1 diabetes. (C) 2008 Elsevier Inc. All rights reserved Udgivelsesdato: 2008/7...

  2. Synthesis and properties of mixed-ligand ruthenium(II) complexes containing 2-(2-pyridyl)-benzimidazole and related ligands

    International Nuclear Information System (INIS)

    Haga, Masaaki; Tanaka, Toshio.

    1979-01-01

    Mixed-ligand ruthenium(II) complexes of the [Ru(bpy) 2 L]sup(n+) (ClO 4 )sub(n) type, where bpy= 2,2'-bipyridine; L= 2-(2-pyridyl)-benzimidazole (PBImH) when n= 2, and L= 2-(2-pyridyl)-benzimidazolate (PBIm) and 2-(o-hydroxyphenyl)-benzimidazole (OBImH) when n= 1, were prepared. Anodic peak potentials and ruthenium-to-bipyridine charge transfer bands of these complexes are rationalized in terms of the donor ability of L. (author)

  3. Synthesis and properties of mixed-ligand ruthenium(II) complexes containing 2-(2-pyridyl)-benzimidazole and related ligands

    Energy Technology Data Exchange (ETDEWEB)

    Haga, M [Mie Univ., Tsu (Japan); Tanaka, T

    1979-07-01

    Mixed-ligand ruthenium(II) complexes of the (Ru(bpy)/sub 2/L)sup(n+) (ClO/sub 4/)sub(n) type, where bpy= 2,2'-bipyridine; L= 2-(2-pyridyl)-benzimidazole (PBImH) when n= 2, and L= 2-(2-pyridyl)-benzimidazolate (PBIm) and 2-(o-hydroxyphenyl)-benzimidazole (OBImH) when n= 1, were prepared. Anodic peak potentials and ruthenium-to-bipyridine charge transfer bands of these complexes are rationalized in terms of the donor ability of L.

  4. Pyrazolyl conjugates of bombesin: a new tridentate ligand framework for the stabilization of fac-[M(CO){sub 3}]{sup +} moiety

    Energy Technology Data Exchange (ETDEWEB)

    Alves, Susana; Correia, Joao D.G.; Santos, Isabel [Departamento de Quimica, Instituto Tecnologico e Nuclear, 2686-953 Sacavem (Portugal); Veerendra, Bhadrasetty [Department of Radiology, University of Missouri-Columbia School of Medicine, Columbia, MO 65211 (United States); Sieckman, Gary L. [Research Division, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201 (United States); Hoffman, Timothy J. [Research Division, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201 (United States)]|[Department of Internal Medicine, University of Missouri-Columbia School of Medicine, Columbia, MO 65211 (United States)]|[Radiopharmaceutical Sciences Institute, University of Missouri-Columbia School of Medicine, Columbia, MO 65211 (United States); Rold, Tammy L. [Department of Internal Medicine, University of Missouri-Columbia School of Medicine, Columbia, MO 65211 (United States); Figueroa, Said Daibes [Radiopharmaceutical Sciences Institute, University of Missouri-Columbia School of Medicine, Columbia, MO 65211 (United States); Retzloff, Lauren [Department of Radiology, University of Missouri-Columbia School of Medicine, Columbia, MO 65211 (United States); McCrate, Joseph [Department of Radiology, University of Missouri-Columbia School of Medicine, Columbia, MO 65211 (United States); Prasanphanich, Adam [Department of Radiology, University of Missouri-Columbia School of Medicine, Columbia, MO 65211 (United States); Smith, Charles J. [Department of Radiology, University of Missouri-Columbia School of Medicine, Columbia, MO 65211 (United States)]|[University of Missouri Research Reactor Center, University of Missouri-Columbia, Columbia, MO 65211 (United States)]|[Research Division, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201 (United States)]|[Department of Internal Medicine, University of Missouri-Columbia School of Medicine, Columbia, MO 65211 (United States)]. E-mail: smithcj@health.missouri.edu

    2006-07-15

    We have described the synthesis of tridentate pyrazolyl ligand frameworks for coordination to the fac-[*M(CO){sub 3}]{sup +} metal fragment (*M={sup 186/188}Re or {sup 99m}Tc). These ligands impart a degree of kinetic inertness on the metal center, warranting their study in biological systems. We herein report in vitro/in vivo radiolabeling investigations of a new series of pyrazolyl bombesin (BBN) conjugates radiolabeled via the Isolink kit. These new conjugates are based on the general structure [{sup 99m}Tc-pyrazolyl-X-BBN[7-14]NH{sub 2}], where X={beta}-alanine, serylserylserine or glycylglycylglycine. The pyrazolyl ligand is a tridentate ligand framework that coordinates the metal center through nitrogen donor atoms. The results of these investigations demonstrate the ability of these new conjugates to specifically target the gastrin-releasing peptide receptor subtype 2, which is overexpressed on human prostate PC-3 cancerous tissues. Therefore, these studies suggest the tridentate pyrazolyl ligand framework to be an ideal candidate for the design and development of low-valent {sup 99m}Tc-based diagnostic radiopharmaceuticals based on BBN or other targeting vectors.

  5. Effects of electrostatic interactions on ligand dissociation kinetics

    Science.gov (United States)

    Erbaş, Aykut; de la Cruz, Monica Olvera; Marko, John F.

    2018-02-01

    We study unbinding of multivalent cationic ligands from oppositely charged polymeric binding sites sparsely grafted on a flat neutral substrate. Our molecular dynamics simulations are suggested by single-molecule studies of protein-DNA interactions. We consider univalent salt concentrations spanning roughly a 1000-fold range, together with various concentrations of excess ligands in solution. To reveal the ionic effects on unbinding kinetics of spontaneous and facilitated dissociation mechanisms, we treat electrostatic interactions both at a Debye-Hückel (DH) (or implicit ions, i.e., use of an electrostatic potential with a prescribed decay length) level and by the more precise approach of considering all ionic species explicitly in the simulations. We find that the DH approach systematically overestimates unbinding rates, relative to the calculations where all ion pairs are present explicitly in solution, although many aspects of the two types of calculation are qualitatively similar. For facilitated dissociation (FD) (acceleration of unbinding by free ligands in solution) explicit-ion simulations lead to unbinding at lower free-ligand concentrations. Our simulations predict a variety of FD regimes as a function of free-ligand and ion concentrations; a particularly interesting regime is at intermediate concentrations of ligands where nonelectrostatic binding strength controls FD. We conclude that explicit-ion electrostatic modeling is an essential component to quantitatively tackle problems in molecular ligand dissociation, including nucleic-acid-binding proteins.

  6. Mono- and Dinuclear Manganese Carbonyls Supported by 1,8-Disubstituted (L = Py, SMe, SH) Anthracene Ligand Scaffolds.

    Science.gov (United States)

    Manes, Taylor A; Rose, Michael J

    2016-06-06

    Presented herein is a synthetic scheme to generate symmetric and asymmetric ligands based on a 1,8-disubstituted anthracene scaffold. The metal-binding scaffolds were prepared by aryl chloride activation of 1,8-dichloroanthracene using Suzuki-type couplings facilitated by [Pd(dba)2] as a Pd source; the choice of cocatalyst (XPhos or SPhos) yielded symmetrically or asymmetrically substituted scaffolds (respectively): namely, Anth-SMe2 (3), Anth-N2 (4), and Anth-NSMe (6). The ligands exhibit a nonplanar geometry in the solid state (X-ray), owing to steric hindrance between the anthracene scaffold and the coupled aryl units. To determine the flexibility and binding characteristics of the anthracene-based ligands, the symmetric scaffolds were complexed with [Mn(CO)5Br] to afford the mononuclear species [(Anth-SMe2)Mn(CO)3Br] (8) and [(Anth-N2)Mn(CO)3Br] (9), in which the donor moieties chelate the Mn center in a cis fashion. The asymmetric ligand Anth-NSMe (6) binds preferentially through the py moieties, affording the bis-ligated complex [(Anth-NSMe)2Mn(CO)3Br] (10), wherein the thioether-S donors remain unbound. Alternatively, deprotection of the thioether in 6 affords the free thiol ligand Anth-NSH (7), which more readily binds the Mn center. Complexation of 7 ultimately affords the mixed-valence Mn(I)/Mn(II) dimer of formula [(Anth-NS)3Mn2(CO)3] (11), which exhibits a fac-{Mn(CO)3} unit supported by a triad of bridging thiolates, which are in turn ligated to a supporting Mn(II) center (EPR: |D| = 0.053 cm(-1), E/|D| = 0.3, Aiso = -150 MHz). All of the metal complexes have been characterized by single-crystal X-ray diffraction, IR spectroscopy and NMR/EPR measurements-all of which demonstrate that the meta-linked, anthracene-based ligand scaffold is a viable approach for the coordination of metal carbonyls.

  7. Mutual control of axial and equatorial ligands: model studies with [Ni]-bacteriochlorophyll-a.

    Science.gov (United States)

    Yerushalmi, Roie; Noy, Dror; Baldridge, Kim K; Scherz, Avigdor

    2002-07-17

    Modification of the metal's electronic environment by ligand association and dissociation in metalloenzymes is considered cardinal to their catalytic activity. We have recently presented a novel system that utilizes the bacteriochlorophyll (BChl) macrocycle as a ligand and reporter. This system allows for charge mobilization in the equatorial plane and experimental estimate of changes in the electronic charge density around the metal with no modification of the metal's chemical environment. The unique spectroscopy, electrochemistry and coordination chemistry of [Ni]-bacteriochlorophyll ([Ni]-BChl) enable us to follow directly fine details and steps involved in the function of the metal redox center. This approach is utilized here whereby electro-chemical reduction of [Ni]-BChl to the monoanion [Ni]-BChl(-) results in reversible dissociation of biologically relevant axial ligands. Similar ligand dissociation was previously detected upon photoexcitation of [Ni]-BChl (Musewald, C.; Hartwich, G.; Lossau, H.; Gilch, P.; Pollinger-Dammer, F.; Scheer, H.; Michel-Beyerle, M. E. J. Phys. Chem. B 1999, 103, 7055-7060 and Noy, D.; Yerushalmi, R.; Brumfeld, V.; Ashur, I.; Baldridge, K. K.; Scheer, H.; Scherz, A. J. Am. Chem. Soc. 2000, 122, 3937-3944). The electrochemical measurements and quantum mechanical (QM) calculations performed here for the neutral, singly reduced, monoligated, and singly reduced, monoligated [Ni]-BChl suggest the following: (a) Electroreduction, although resulting in a pi anion [Ni]-BChl(-) radical, causes electron density migration to the [Ni]-BChl core. (b) Reduction of nonligated [Ni]-BChl does not change the macrocycle conformation, whereas axial ligation results in a dramatic expansion of the metal core and a flattening of the highly ruffled macrocycle conformation. (c) In both the monoanion and singly excited [Ni]-BChl ([Ni]-BChl*), the frontier singly occupied molecular orbital (SOMO) has a small but nonnegligible metal character. Finally, (d

  8. Development of Ar-BINMOL-Derived Atropisomeric Ligands with Matched Axial and sp(3) Central Chirality for Catalytic Asymmetric Transformations.

    Science.gov (United States)

    Xu, Zheng; Xu, Li-Wen

    2015-10-01

    Recently, academic chemists have renewed their interest in the development of 1,1'-binaphthalene-2,2'-diol (BINOL)-derived chiral ligands. Six years ago, a working hypothesis, that the chirality matching of hybrid chirality on a ligand could probably lead to high levels of stereoselective induction, prompted us to use the axial chirality of BINOL derivatives to generate new stereogenic centers within the same molecule with high stereoselectivity, obtaining as a result sterically favorable ligands for applications in asymmetric catalysis. This Personal Account describes our laboratory's efforts toward the development of a novel class of BINOL-derived atropisomers bearing both axial and sp(3) central chirality, the so-called Ar-BINMOLs, for asymmetric synthesis. Furthermore, on the basis of the successful application of Ar-BINMOLs and their derivatives in asymmetric catalysis, the search for highly efficient and enantioselective processes also compelled us to give special attention to the BINOL-derived multifunctional ligands with multiple stereogenic centers for use in catalytic asymmetric reactions. Copyright © 2015 The Chemical Society of Japan and Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. LigandRFs: random forest ensemble to identify ligand-binding residues from sequence information alone

    KAUST Repository

    Chen, Peng

    2014-12-03

    Background Protein-ligand binding is important for some proteins to perform their functions. Protein-ligand binding sites are the residues of proteins that physically bind to ligands. Despite of the recent advances in computational prediction for protein-ligand binding sites, the state-of-the-art methods search for similar, known structures of the query and predict the binding sites based on the solved structures. However, such structural information is not commonly available. Results In this paper, we propose a sequence-based approach to identify protein-ligand binding residues. We propose a combination technique to reduce the effects of different sliding residue windows in the process of encoding input feature vectors. Moreover, due to the highly imbalanced samples between the ligand-binding sites and non ligand-binding sites, we construct several balanced data sets, for each of which a random forest (RF)-based classifier is trained. The ensemble of these RF classifiers forms a sequence-based protein-ligand binding site predictor. Conclusions Experimental results on CASP9 and CASP8 data sets demonstrate that our method compares favorably with the state-of-the-art protein-ligand binding site prediction methods.

  10. Molecular features related to HIV integrase inhibition obtained from structure- and ligand-based approaches.

    Directory of Open Access Journals (Sweden)

    Luciana L de Carvalho

    Full Text Available Among several biological targets to treat AIDS, HIV integrase is a promising enzyme that can be employed to develop new anti-HIV agents. The aim of this work is to propose a mechanistic interpretation of HIV-1 integrase inhibition and to rationalize the molecular features related to the binding affinity of studied ligands. A set of 79 HIV-1 integrase inhibitors and its relationship with biological activity are investigated employing 2D and 3D QSAR models, docking analysis and DFT studies. Analyses of docking poses and frontier molecular orbitals revealed important features on the main ligand-receptor interactions. 2D and 3D models presenting good internal consistency, predictive power and stability were obtained in all cases. Significant correlation coefficients (r(2 = 0.908 and q(2= 0.643 for 2D model; r(2= 0.904 and q(2= 0.719 for 3D model were obtained, indicating the potential of these models for untested compounds. The generated holograms and contribution maps revealed important molecular requirements to HIV-1 IN inhibition and several evidences for molecular modifications. The final models along with information resulting from molecular orbitals, 2D contribution and 3D contour maps should be useful in the design of new inhibitors with increased potency and selectivity within the chemical diversity of the data.

  11. Are superhalogens without halogen ligand capable of transcending traditional halogen-based superhalogens? Ab initio case study of binuclear anions based on pseudohalogen ligand

    Science.gov (United States)

    Li, Jin-Feng; Sun, Yin-Yin; Bai, Hongcun; Li, Miao-Miao; Li, Jian-Li; Yin, Bing

    2015-06-01

    The superhalogen properties of polynuclear structures without halogen ligand are theoretically explored here for several [M2(CN)5]-1 (M = Ca, Be) clusters. At CCSD(T) level, these clusters have been confirmed to be superhalogens due to their high vertical electron detachment energies (VDE). The largest one is 9.70 eV for [Ca2(CN)5]-1 which is even higher than those of corresponding traditional structures based on fluorine or chlorine ligands. Therefore the superhalogens stronger than the traditional halogen-based structures could be realized by ligands other than halogen atoms. Compared with CCSD(T), outer valence Green's function (OVGF) method either overestimates or underestimates the VDEs for different structures while MP2 results are generally consistent in the aspect of relative values. The extra electrons of the highest VDE anions here aggregate on the bridging CN units with non-negligible distribution occurring on other CN units too. These two features lower both the potential and kinetic energies of the extra electron respectively and thus lead to high VDE. Besides superhalogen properties, the structures, relative stabilities and thermodynamic stabilities with respect to the detachment of cyanide ligand were also investigated. The sum of these results identifies the potential of polynuclear structures with pseudohalogen ligand as suitable candidates with enhanced superhalogens properties.

  12. Automated ligand fitting by core-fragment fitting and extension into density

    International Nuclear Information System (INIS)

    Terwilliger, Thomas C.; Klei, Herbert; Adams, Paul D.; Moriarty, Nigel W.; Cohn, Judith D.

    2006-01-01

    An automated ligand-fitting procedure has been developed and tested on 9327 ligands and (F o − F c )exp(iϕ c ) difference density from macromolecular structures in the Protein Data Bank. A procedure for fitting of ligands to electron-density maps by first fitting a core fragment of the ligand to density and then extending the remainder of the ligand into density is presented. The approach was tested by fitting 9327 ligands over a wide range of resolutions (most are in the range 0.8-4.8 Å) from the Protein Data Bank (PDB) into (F o − F c )exp(iϕ c ) difference density calculated using entries from the PDB without these ligands. The procedure was able to place 58% of these 9327 ligands within 2 Å (r.m.s.d.) of the coordinates of the atoms in the original PDB entry for that ligand. The success of the fitting procedure was relatively insensitive to the size of the ligand in the range 10–100 non-H atoms and was only moderately sensitive to resolution, with the percentage of ligands placed near the coordinates of the original PDB entry for fits in the range 58–73% over all resolution ranges tested

  13. The met axial ligand determines the redox potential in Cu-A sites

    DEFF Research Database (Denmark)

    Ledesma, G.N.; Murgida, D.H.; Ly, H.K.

    2007-01-01

    The replacement of the axial methionine ligand in a native Cu-A protein rendered a series of stable mutants with spectroscopic features of a mixed valence center. The mutations resulted in minor perturbations of the electronic structure of this site but led to significant changes in the redox pot...

  14. Crystallization of protein–ligand complexes

    International Nuclear Information System (INIS)

    Hassell, Anne M.; An, Gang; Bledsoe, Randy K.; Bynum, Jane M.; Carter, H. Luke III; Deng, Su-Jun J.; Gampe, Robert T.; Grisard, Tamara E.; Madauss, Kevin P.; Nolte, Robert T.; Rocque, Warren J.; Wang, Liping; Weaver, Kurt L.; Williams, Shawn P.; Wisely, G. Bruce; Xu, Robert; Shewchuk, Lisa M.

    2007-01-01

    Methods presented for growing protein–ligand complexes fall into the categories of co-expression of the protein with the ligands of interest, use of the ligands during protein purification, cocrystallization and soaking the ligands into existing crystals. Obtaining diffraction-quality crystals has long been a bottleneck in solving the three-dimensional structures of proteins. Often proteins may be stabilized when they are complexed with a substrate, nucleic acid, cofactor or small molecule. These ligands, on the other hand, have the potential to induce significant conformational changes to the protein and ab initio screening may be required to find a new crystal form. This paper presents an overview of strategies in the following areas for obtaining crystals of protein–ligand complexes: (i) co-expression of the protein with the ligands of interest, (ii) use of the ligands during protein purification, (iii) cocrystallization and (iv) soaks

  15. Spectroscopic and electrochemical correlations in triangular ruthenium clusters containing N-heterocyclic ligands

    International Nuclear Information System (INIS)

    Cunha, C.J. da.

    1989-01-01

    A series of clusters of general formula [Ru sub(3) O (OOCCH sub(3)) sub(6) L sub(3)] sup(+), where L = N-heterocyclic ligands, were synthesized and characterized based on elemental analysis. UV-VIS and IR spectra. Voltametric studies revealed the existence of up to six acessible oxidation states, with a high degree of electronic delocalization. The Ru sub(3) O trigonal center possesses many delocalized electrons and can be visualized as a source of electrons. The ligands coordinated to the clusters tune their redox potentials, determine the differences in their electronic spectra, and are responsible for the special conditions required for their synthesis. (author)

  16. Public relations activities of the Karlsruhe Nuclear Research Center - a national research center contributes to opinion forming

    International Nuclear Information System (INIS)

    Koerting, K.

    1988-01-01

    At the Karlsruhe Nuclear Research Center, the Public Relations Department directly reports to the Chief Executive Officer. The head of the Public Relation Department acts as spokesman of the center in the public, which requires him to be fully informed of the work of all units and of the policy goals of the executive board. The key tools used by the Public Relations Department are KfK-Hausmitteilungen, accident information, the scientific journal KfK-Nachrichten, press releases, exhibitions, fairs, guided tours, and nuclear energy information staff. (DG)

  17. Strong Ligand-Protein Interactions Derived from Diffuse Ligand Interactions with Loose Binding Sites.

    Science.gov (United States)

    Marsh, Lorraine

    2015-01-01

    Many systems in biology rely on binding of ligands to target proteins in a single high-affinity conformation with a favorable ΔG. Alternatively, interactions of ligands with protein regions that allow diffuse binding, distributed over multiple sites and conformations, can exhibit favorable ΔG because of their higher entropy. Diffuse binding may be biologically important for multidrug transporters and carrier proteins. A fine-grained computational method for numerical integration of total binding ΔG arising from diffuse regional interaction of a ligand in multiple conformations using a Markov Chain Monte Carlo (MCMC) approach is presented. This method yields a metric that quantifies the influence on overall ligand affinity of ligand binding to multiple, distinct sites within a protein binding region. This metric is essentially a measure of dispersion in equilibrium ligand binding and depends on both the number of potential sites of interaction and the distribution of their individual predicted affinities. Analysis of test cases indicates that, for some ligand/protein pairs involving transporters and carrier proteins, diffuse binding contributes greatly to total affinity, whereas in other cases the influence is modest. This approach may be useful for studying situations where "nonspecific" interactions contribute to biological function.

  18. Ligand-mediated adhesive mechanics of two static, deformed spheres.

    Science.gov (United States)

    Sircar, Sarthok; Nguyen, Giang; Kotousov, Andrei; Roberts, Anthony J

    2016-10-01

    A self-consistent model is developed to investigate attachment/detachment kinetics of two static, deformable microspheres with irregular surface and coated with flexible binding ligands. The model highlights how the microscale binding kinetics of these ligands as well as the attractive/repulsive potential of the charged surface affects the macroscale static deformed configuration of the spheres. It is shown that in the limit of smooth, neutrally charged surface (i.e., the dimensionless inverse Debye length, [Formula: see text]), interacting via elastic binders (i.e., the dimensionless stiffness coefficient, [Formula: see text]) the adhesion mechanics approaches the regime of application of the JKR theory, and in this particular limit, the contact radius, R c , scales with the particle radius, R, according to the scaling law, [Formula: see text]. We show that static, deformed, highly charged, ligand-coated surface of micro-spheres exhibit strong adhesion. Normal stress distribution within the contact area adjusts with the binder stiffness coefficient, from a maximum at the center to a maximum at the periphery of the region. Although reported in some in vitro experiments involving particle adhesion, until now a physical interpretation for this variation of the stress distribution for deformable, charged, ligand-coated microspheres is missing. Surface roughness results in a diminished adhesion with a distinct reduction in the pull-off force, larger separation gap, weaker normal stress and limited area of adhesion. These results are in agreement with the published experimental findings.

  19. LigandRFs: random forest ensemble to identify ligand-binding residues from sequence information alone

    KAUST Repository

    Chen, Peng; Huang, Jianhua Z; Gao, Xin

    2014-01-01

    Protein-ligand binding is important for some proteins to perform their functions. Protein-ligand binding sites are the residues of proteins that physically bind to ligands. Despite of the recent advances in computational prediction

  20. Models of protein–ligand crystal structures: trust, but verify

    Science.gov (United States)

    Deller, Marc C.

    2015-01-01

    X-ray crystallography provides the most accurate models of protein–ligand structures. These models serve as the foundation of many computational methods including structure prediction, molecular modelling, and structure-based drug design. The success of these computational methods ultimately depends on the quality of the underlying protein–ligand models. X-ray crystallography offers the unparalleled advantage of a clear mathematical formalism relating the experimental data to the protein–ligand model. In the case of X-ray crystallography, the primary experimental evidence is the electron density of the molecules forming the crystal. The first step in the generation of an accurate and precise crystallographic model is the interpretation of the electron density of the crystal, typically carried out by construction of an atomic model. The atomic model must then be validated for fit to the experimental electron density and also for agreement with prior expectations of stereochemistry. Stringent validation of protein–ligand models has become possible as a result of the mandatory deposition of primary diffraction data, and many computational tools are now available to aid in the validation process. Validation of protein–ligand complexes has revealed some instances of overenthusiastic interpretation of ligand density. Fundamental concepts and metrics of protein–ligand quality validation are discussed and we highlight software tools to assist in this process. It is essential that end users select high quality protein–ligand models for their computational and biological studies, and we provide an overview of how this can be achieved. PMID:25665575

  1. Models of protein-ligand crystal structures: trust, but verify.

    Science.gov (United States)

    Deller, Marc C; Rupp, Bernhard

    2015-09-01

    X-ray crystallography provides the most accurate models of protein-ligand structures. These models serve as the foundation of many computational methods including structure prediction, molecular modelling, and structure-based drug design. The success of these computational methods ultimately depends on the quality of the underlying protein-ligand models. X-ray crystallography offers the unparalleled advantage of a clear mathematical formalism relating the experimental data to the protein-ligand model. In the case of X-ray crystallography, the primary experimental evidence is the electron density of the molecules forming the crystal. The first step in the generation of an accurate and precise crystallographic model is the interpretation of the electron density of the crystal, typically carried out by construction of an atomic model. The atomic model must then be validated for fit to the experimental electron density and also for agreement with prior expectations of stereochemistry. Stringent validation of protein-ligand models has become possible as a result of the mandatory deposition of primary diffraction data, and many computational tools are now available to aid in the validation process. Validation of protein-ligand complexes has revealed some instances of overenthusiastic interpretation of ligand density. Fundamental concepts and metrics of protein-ligand quality validation are discussed and we highlight software tools to assist in this process. It is essential that end users select high quality protein-ligand models for their computational and biological studies, and we provide an overview of how this can be achieved.

  2. Evidence for a Proangiogenic Activity of TNF-Related Apoptosis-Inducing Ligand

    Directory of Open Access Journals (Sweden)

    Paola Secchiero

    2004-07-01

    Full Text Available Starting from the observation that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/ Apo-2L protein is expressed in both malignant and inflammatory cells in some highly vascularized soft tissue sarcomas, the angiogenic potential of TRAIL was investigated in a series of in vitro assays. Recombinant soluble TRAIL induced endothelial cell migration and vessel tube formation to a degree comparable to vascular endothelial growth factor (VEGF, one of the best-characterized angiogenic factors. However, the proangiogenic activity of TRAIL was not mediated by endogenous expression of VEGF. Although TRAIL potentiated VEGF-induced extracellular signal-regulated kinase (ERK phosphorylation and endothelial cell proliferation, the combination of TRAIL + VEGF did not show additive effects with respect to VEGF alone in inducing vessel tube formation. Thus, although TRAIL has gained attention as a potential anticancer therapeutic for its ability to induce apoptosis in a variety of cancer cells, our present data suggest that TRAIL might also play an unexpected role in promoting angiogenesis, which might have therapeutic implications.

  3. Screening of ligands for the Ullmann synthesis of electron-rich diaryl ethers.

    Science.gov (United States)

    Otto, Nicola; Opatz, Till

    2012-01-01

    In the search for new ligands for the Ullmann diaryl ether synthesis, permitting the coupling of electron-rich aryl bromides at relatively low temperatures, 56 structurally diverse multidentate ligands were screened in a model system that uses copper iodide in acetonitrile with potassium phosphate as the base. The ligands differed largely in their performance, but no privileged structural class could be identified.

  4. Are superhalogens without halogen ligand capable of transcending traditional halogen-based superhalogens? Ab initio case study of binuclear anions based on pseudohalogen ligand

    International Nuclear Information System (INIS)

    Li, Jin-Feng; Sun, Yin-Yin; Li, Miao-Miao; Li, Jian-Li; Yin, Bing; Bai, Hongcun

    2015-01-01

    The superhalogen properties of polynuclear structures without halogen ligand are theoretically explored here for several [M 2 (CN) 5 ] −1 (M =  Ca, Be) clusters. At CCSD(T) level, these clusters have been confirmed to be superhalogens due to their high vertical electron detachment energies (VDE). The largest one is 9.70 eV for [Ca 2 (CN) 5 ] −1 which is even higher than those of corresponding traditional structures based on fluorine or chlorine ligands. Therefore the superhalogens stronger than the traditional halogen-based structures could be realized by ligands other than halogen atoms. Compared with CCSD(T), outer valence Green’s function (OVGF) method either overestimates or underestimates the VDEs for different structures while MP2 results are generally consistent in the aspect of relative values. The extra electrons of the highest VDE anions here aggregate on the bridging CN units with non-negligible distribution occurring on other CN units too. These two features lower both the potential and kinetic energies of the extra electron respectively and thus lead to high VDE. Besides superhalogen properties, the structures, relative stabilities and thermodynamic stabilities with respect to the detachment of cyanide ligand were also investigated. The sum of these results identifies the potential of polynuclear structures with pseudohalogen ligand as suitable candidates with enhanced superhalogens properties

  5. Are superhalogens without halogen ligand capable of transcending traditional halogen-based superhalogens? Ab initio case study of binuclear anions based on pseudohalogen ligand

    Energy Technology Data Exchange (ETDEWEB)

    Li, Jin-Feng; Sun, Yin-Yin; Li, Miao-Miao; Li, Jian-Li; Yin, Bing, E-mail: rayinyin@nwu.edu.cn [MOE Key Laboratory of Synthetic and Natural Functional Molecule Chemistry, Shaanxi Key Laboratory of Physico-Inorganic Chemistry, College of Chemistry and Materials Science, Northwest University, Xi’an 710069 (China); Bai, Hongcun [Key Laboratory of Energy Source and Chemical Engineering, Ningxia University, Yinchuan, Ningxia 750021 (China)

    2015-06-15

    The superhalogen properties of polynuclear structures without halogen ligand are theoretically explored here for several [M{sub 2}(CN){sub 5}]{sup −1} (M =  Ca, Be) clusters. At CCSD(T) level, these clusters have been confirmed to be superhalogens due to their high vertical electron detachment energies (VDE). The largest one is 9.70 eV for [Ca{sub 2}(CN){sub 5}]{sup −1} which is even higher than those of corresponding traditional structures based on fluorine or chlorine ligands. Therefore the superhalogens stronger than the traditional halogen-based structures could be realized by ligands other than halogen atoms. Compared with CCSD(T), outer valence Green’s function (OVGF) method either overestimates or underestimates the VDEs for different structures while MP2 results are generally consistent in the aspect of relative values. The extra electrons of the highest VDE anions here aggregate on the bridging CN units with non-negligible distribution occurring on other CN units too. These two features lower both the potential and kinetic energies of the extra electron respectively and thus lead to high VDE. Besides superhalogen properties, the structures, relative stabilities and thermodynamic stabilities with respect to the detachment of cyanide ligand were also investigated. The sum of these results identifies the potential of polynuclear structures with pseudohalogen ligand as suitable candidates with enhanced superhalogens properties.

  6. New bisaminoethanethiol (BAT) ligands which form two interconvertible Tc-99m complexes

    International Nuclear Information System (INIS)

    Oya, Shunichi; Kung, Mei-Ping; Frederick, Dana; Kung, Hank F.

    1995-01-01

    Most commonly used radiopharmaceuticals in diagnostic nuclear medicine are labeled with Tc-99m. This is due to its superior physical characteristics (T (1(2)) = 6 h and gamma energy 140 KeV) and convenient availability from the 99 Mo/ 99mm Tc generator. In an attempt to fine tune the properties of Tc-99m complexes, the synthesis and radiolabeling of two novel N 2 S 2 ligands, N,-2-mercaptobenzyl-N'-(1-oxo-2-mercapto-2-methyl)propyl ethylenediamine,8, and N,-2-methylthiobenzyl-N'-(1-oxo-2-mercapto-2-methyl)propyl ethylenediamine, 11, with an ionizable SH or unionizable SMe group, respectively, for the formation of complexes with Tc v O center cores, have been examined. Both ligands initially formed one apparently stable, lipophilic and neutral complex (HPLC, Rt = 7 min, reverse-phase column, acetonitrile: buffer, pH 7.0; (55(45)); V/V; partition coefficient between 1-octanol and buffer of 410 and 335, respectively) with [ 99m Tc]pertechnetate in the presence of stannous chloride. After treatment with a reducing agent, NaCNBH 3 , the initial [ 99m Tc]8 and 11 complexes were reduced; the reduced complexes were less lipophilic (shorter retention time, Rt = 5 min, on the same reversed phase HPLC). However, only the oxidized form showed sufficient stability. The reduced forms of both [ 99m Tc]8 and 11 were readily and completely converted back to the oxidized forms by a stream of air. Biodistribution studies in rats demonstrated that the [ 99m Tc]8 (oxidized form) penetrated the blood-brain barrier (0.67% dose/organ at 2 min postinjection), but washed out from the brain quickly (0.29% dose/organ at 30 min postinjection). On the contrary, [ 99m Tc]11 (oxidized form) did not show any brain uptake (0.03% dose/organ at 2 min postinjection), despite its higher lipophilicity. The disparity between these two Tc-99m complexes may be related to the relative instability of [ 99m Tc]11 (oxidized form) by the introduction of the unionizable methylated thiol group as one of the donor

  7. Binuclear trivalent and tetravalent uranium halides and cyanides supported by cyclooctatetraene ligands

    International Nuclear Information System (INIS)

    Wang, Cong-Zhi; Wu, Qun-Yan; Lan, Jian-Hui; Shi, Wei-Qun; Gibson, John K.

    2017-01-01

    Although the first organoactinide chloride Cp_3UCl (Cp = η"5-C_5H_5) was synthesized more than 50 years ago, binuclear uranium halides remain very rare in organoactinide chemistry. Herein, a series of binuclear trivalent and tetravalent uranium halides and cyanides with cyclooctatetraene ligands, (COT)_2U_2X_n (COT = η"8-C_8H_8; X=F, Cl, CN; n=2, 4), have been systematically studied using scalar-relativistic density functional theory (DFT). The structures with bridging halide or cyanide ligands were predicted to be the most stable complexes of (COT)_2U_2X_n, and all the complexes show weak antiferromagnetic interactions between the uranium centers. However, for each species, there is no significant uranium-uranium bonding interaction. The bonding between the metal and the ligands shows some degree of covalent character, especially between the metal and terminal halide or cyanide ligands. The U-5f and 6d orbitals are predominantly involved in the metal-ligand bonding. All the (COT)_2U_2X_n species were predicted to be more stable compared to the mononuclear half-sandwich complexes at room temperature in the gas phase such that (COT)_2U_2X_4 might be accessible through the known (COT)_2U complex. The tetravalent derivatives (COT)_2U_2X_4 are more energetically favorable than the trivalent (COT)_2U_2X_2 analogs, which may be attributed to the greater number of strong metal-ligand bonds in the former complexes.

  8. Explicit all-atom modeling of realistically sized ligand-capped nanocrystals

    KAUST Repository

    Kaushik, Ananth P.

    2012-01-01

    We present a study of an explicit all-atom representation of nanocrystals of experimentally relevant sizes (up to 6 nm), capped with alkyl chain ligands, in vacuum. We employ all-atom molecular dynamics simulation methods in concert with a well-tested intermolecular potential model, MM3 (molecular mechanics 3), for the studies presented here. These studies include determining the preferred conformation of an isolated single nanocrystal (NC), pairs of isolated NCs, and (presaging studies of superlattice arrays) unit cells of NC superlattices. We observe that very small NCs (3 nm) behave differently in a superlattice as compared to larger NCs (6 nm and above) due to the conformations adopted by the capping ligands on the NC surface. Short ligands adopt a uniform distribution of orientational preferences, including some that lie against the face of the nanocrystal. In contrast, longer ligands prefer to interdigitate. We also study the effect of changing ligand length and ligand coverage on the NCs on the preferred ligand configurations. Since explicit all-atom modeling constrains the maximum system size that can be studied, we discuss issues related to coarse-graining the representation of the ligands, including a comparison of two commonly used coarse-grained models. We find that care has to be exercised in the choice of coarse-grained model. The data provided by these realistically sized ligand-capped NCs, determined using explicit all-atom models, should serve as a reference standard for future models of coarse-graining ligands using united atom models, especially for self-assembly processes. © 2012 American Institute of Physics.

  9. Screening of ligands for the Ullmann synthesis of electron-rich diaryl ethers

    Directory of Open Access Journals (Sweden)

    Nicola Otto

    2012-07-01

    Full Text Available In the search for new ligands for the Ullmann diaryl ether synthesis, permitting the coupling of electron-rich aryl bromides at relatively low temperatures, 56 structurally diverse multidentate ligands were screened in a model system that uses copper iodide in acetonitrile with potassium phosphate as the base. The ligands differed largely in their performance, but no privileged structural class could be identified.

  10. Ammonia formation by metal-ligand cooperative hydrogenolysis of a nitrido ligand

    Science.gov (United States)

    Askevold, Bjorn; Nieto, Jorge Torres; Tussupbayev, Samat; Diefenbach, Martin; Herdtweck, Eberhardt; Holthausen, Max C.; Schneider, Sven

    2011-07-01

    Bioinspired hydrogenation of N2 to ammonia at ambient conditions by stepwise nitrogen protonation/reduction with metal complexes in solution has experienced remarkable progress. In contrast, the highly desirable direct hydrogenation with H2 remains difficult. In analogy to the heterogeneously catalysed Haber-Bosch process, such a reaction is conceivable via metal-centred N2 splitting and unprecedented hydrogenolysis of the nitrido ligands to ammonia. We report the synthesis of a ruthenium(IV) nitrido complex. The high nucleophilicity of the nitrido ligand is demonstrated by unusual N-C coupling with π-acidic CO. Furthermore, the terminal nitrido ligand undergoes facile hydrogenolysis with H2 at ambient conditions to produce ammonia in high yield. Kinetic and quantum chemical examinations of this reaction suggest cooperative behaviour of a phosphorus-nitrogen-phosphorus pincer ligand in rate-determining heterolytic hydrogen splitting.

  11. Reduction of dinitrogen ligands

    International Nuclear Information System (INIS)

    Richards, R.L.

    1983-01-01

    Processes of dinitrogen ligand reduction in complexes of transition metals are considered. The basic character of the dinitrogen ligand is underlined. Data on X-ray photoelectronic spectroscopy and intensities of bands ν (N 2 ) in IR-spectra of nitrogen complexes are given. The mechanism of protonation of an edge dinitrogen ligand is discussed. Model systems and mechanism of nitrogenogenase are compared

  12. O-fucosylation of the notch ligand mDLL1 by POFUT1 is dispensable for ligand function.

    Directory of Open Access Journals (Sweden)

    Julia Müller

    Full Text Available Fucosylation of Epidermal Growth Factor-like (EGF repeats by protein O-fucosyltransferase 1 (POFUT1 in vertebrates, OFUT1 in Drosophila is pivotal for NOTCH function. In Drosophila OFUT1 also acts as chaperone for Notch independent from its enzymatic activity. NOTCH ligands are also substrates for POFUT1, but in Drosophila OFUT1 is not essential for ligand function. In vertebrates the significance of POFUT1 for ligand function and subcellular localization is unclear. Here, we analyze the importance of O-fucosylation and POFUT1 for the mouse NOTCH ligand Delta-like 1 (DLL1. We show by mass spectral glycoproteomic analyses that DLL1 is O-fucosylated at the consensus motif C²XXXX(S/TC³ (where C² and C³ are the second and third conserved cysteines within the EGF repeats found in EGF repeats 3, 4, 7 and 8. A putative site with only three amino acids between the second cysteine and the hydroxy amino acid within EGF repeat 2 is not modified. DLL1 proteins with mutated O-fucosylation sites reach the cell surface and accumulate intracellularly. Likewise, in presomitic mesoderm cells of POFUT1 deficient embryos DLL1 is present on the cell surface, and in mouse embryonic fibroblasts lacking POFUT1 the same relative amount of overexpressed wild type DLL1 reaches the cell surface as in wild type embryonic fibroblasts. DLL1 expressed in POFUT1 mutant cells can activate NOTCH, indicating that POFUT1 is not required for DLL1 function as a Notch ligand.

  13. TNF-related apoptosis-inducing ligand (TRAIL) for bone sarcoma treatment: Pre-clinical and clinical data.

    Science.gov (United States)

    Gamie, Zakareya; Kapriniotis, Konstantinos; Papanikolaou, Dimitra; Haagensen, Emma; Da Conceicao Ribeiro, Ricardo; Dalgarno, Kenneth; Krippner-Heidenreich, Anja; Gerrand, Craig; Tsiridis, Eleftherios; Rankin, Kenneth Samora

    2017-11-28

    Bone sarcomas are rare, highly malignant mesenchymal tumours that affect teenagers and young adults, as well as older patients. Despite intensive, multimodal therapy, patients with bone sarcomas have poor 5-year survival, close to 50%, with lack of improvement over recent decades. TNF-related apoptosis-inducing ligand (TRAIL), a member of the tumour necrosis factor (TNF) ligand superfamily (TNFLSF), has been found to induce apoptosis in cancer cells while sparing nontransformed cells, and may therefore offer a promising new approach to treatment. We cover the existing preclinical and clinical evidence about the use of TRAIL and other death receptor agonists in bone sarcoma treatment. In vitro studies indicate that TRAIL and other death receptor agonists are generally potent against bone sarcoma cell lines. Ewing's sarcoma cell lines present the highest sensitivity, whereas osteosarcoma and chondrosarcoma cell lines are considered less sensitive. In vivo studies also demonstrate satisfactory results, especially in Ewing's sarcoma xenograft models. However, the few clinical trials in the literature show only low or moderate efficacy of TRAIL in treating bone sarcoma. Potential strategies to overcome the in vivo resistance reported include co-administration with other drugs and the potential to deliver TRAIL on the surface of primed mesenchymal or immune cells and the use of targeted single chain antibodies such as scFv-scTRAIL. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. New chiral ligands in asymmetric catalysis. Application in stabilization of metal nanoparticles

    OpenAIRE

    Axet Martí, M. Rosa

    2006-01-01

    Thesis M. Rosa AxetThis thesis deals with the development and application of diphosphite ligands derived from carbohydrates to rhodium-catalysed asymmetric hydroformylation and hydrogenation reactions. The use of various carbohydrate derivative ligands as stabilisers of metal nanoparticles is also studied. The synthesis and the characterisation of the series of diphosphite ligands are described in Chapter 2. The results of the asymmetric hydroformylation of styrene and related vinyl arenes ar...

  15. Ligand modeling and design

    Energy Technology Data Exchange (ETDEWEB)

    Hay, B.P. [Pacific Northwest National Lab., Richland, WA (United States)

    1997-10-01

    The purpose of this work is to develop and implement a molecular design basis for selecting organic ligands that would be used in the cost-effective removal of specific radionuclides from nuclear waste streams. Organic ligands with metal ion specificity are critical components in the development of solvent extraction and ion exchange processes that are highly selective for targeted radionuclides. The traditional approach to the development of such ligands involves lengthy programs of organic synthesis and testing, which in the absence of reliable methods for screening compounds before synthesis, results in wasted research effort. The author`s approach breaks down and simplifies this costly process with the aid of computer-based molecular modeling techniques. Commercial software for organic molecular modeling is being configured to examine the interactions between organic ligands and metal ions, yielding an inexpensive, commercially or readily available computational tool that can be used to predict the structures and energies of ligand-metal complexes. Users will be able to correlate the large body of existing experimental data on structure, solution binding affinity, and metal ion selectivity to develop structural design criteria. These criteria will provide a basis for selecting ligands that can be implemented in separations technologies through collaboration with other DOE national laboratories and private industry. The initial focus will be to select ether-based ligands that can be applied to the recovery and concentration of the alkali and alkaline earth metal ions including cesium, strontium, and radium.

  16. A Macrocyclic Agouti-Related Protein/[Nle4,DPhe7]α-Melanocyte Stimulating Hormone Chimeric Scaffold Produces Subnanomolar Melanocortin Receptor Ligands.

    Science.gov (United States)

    Ericson, Mark D; Freeman, Katie T; Schnell, Sathya M; Haskell-Luevano, Carrie

    2017-01-26

    The melanocortin system consists of five receptor subtypes, endogenous agonists, and naturally occurring antagonists. These receptors and ligands have been implicated in numerous biological pathways including processes linked to obesity and food intake. Herein, a truncation structure-activity relationship study of chimeric agouti-related protein (AGRP)/[Nle4,DPhe7]α-melanocyte stimulating hormone (NDP-MSH) ligands is reported. The tetrapeptide His-DPhe-Arg-Trp or tripeptide DPhe-Arg-Trp replaced the Arg-Phe-Phe sequence in the AGRP active loop derivative c[Pro-Arg-Phe-Phe-Xxx-Ala-Phe-DPro], where Xxx was the native Asn of AGRP or a diaminopropionic (Dap) acid residue previously shown to increase antagonist potency at the mMC4R. The Phe, Ala, and Dap/Asn residues were successively removed to generate a 14-member library that was assayed for agonist activity at the mouse MC1R, MC3R, MC4R, and MC5R. Two compounds possessed nanomolar agonist potency at the mMC4R, c[Pro-His-DPhe-Arg-Trp-Asn-Ala-Phe-DPro] and c[Pro-His-DPhe-Arg-Trp-Dap-Ala-DPro], and may be further developed to generate novel melanocortin probes and ligands for understanding and treating obesity.

  17. Schiff base ligand

    Indian Academy of Sciences (India)

    Unknown

    Low-temperature stoichiometric Schiff base reaction in air in 3 : 1 mole ratio between benz- aldehyde and triethylenetetramine (trien) in methanol yields a novel tetraaza µ-bis(bidentate) acyclic ligand L. It was .... electrochemical work was performed as reported in ..... change in ligand shape through change in oxidation.

  18. Crystal structures and luminescence of two cadmium-carboxylate cluster-based compounds with mixed ligands

    Energy Technology Data Exchange (ETDEWEB)

    Ma, Hui-Fang; Lei, Qian; Wang, Yu-Ling; Yin, Shun-Gao; Liu, Qing-Yan [College of Chemistry and Chemical Engineering and Key Lab. of Functional Small Organic Molecule of Ministry of Education, Jiangxi Normal Univ., Nanchang (China)

    2017-04-04

    Reactions of Cd(NO{sub 3}){sub 2}.4H{sub 2}O with 2-quinolinecarboxylic acid (H-QLC) in the presence of 1,4-benzenedicarboxylic acid (H{sub 2}-BDC) or 1,3,5-benzenetricarboxylic acid (H-BTC) in DMF/H{sub 2}O solvent afforded two compounds, namely, [Cd(QLC)(BDC){sub 1/2}(H{sub 2}O)]{sub n} (1) and [Cd(QLC)(BTC){sub 1/3}]{sub n} (2). Both compounds are two-dimensional (2D) frameworks but feature different cadmium-carboxylate clusters as a result of the presence of the polycarboxylate ligands with different geometries and coordination preference. The dinuclear Cd{sub 2}(QLC){sub 2} units in 1 are bridged by the pairs of bridging water ligands to give a one-dimensional (1D) chain, which is further linked by the second ligand of BDC{sup 2-} to form a 2D structure. Compound 2 is constructed from unique hexanuclear macrometallacyclic Cd{sub 6}(QLC){sub 6} clusters, which are linked by the surrounding BTC{sup 3-} ligands to generate a 2D structure. Photoluminescence studies showed both compounds exhibit ligand-centered luminescent emissions with emission maxima at 405 and 401 nm, respectively. (copyright 2017 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim)

  19. Tuning Confinement in Colloidal Silicon Nanocrystals with Saturated Surface Ligands

    Energy Technology Data Exchange (ETDEWEB)

    Neale, Nathan R [National Renewable Energy Laboratory (NREL), Golden, CO (United States); Carroll, Gerard [National Renewable Energy Laboratory (NREL), Golden, CO (United States); Limpens, Rens [National Renewable Energy Laboratory (NREL), Golden, CO (United States)

    2018-04-16

    The optical properties of silicon nanocrystals (Si NCs) are a subject of intense study and continued debate. In particular, Si NC photoluminescence (PL) properties are known to depend strongly on the surface chemistry, resulting in electron-hole recombination pathways derived from the Si NC band-edge, surface-state defects, or combined NC-conjugated ligand hybrid states. In this Letter, we perform a comparison of three different saturated surface functional groups - alkyls, amides, and alkoxides - on nonthermal plasma-synthesized Si NCs. We find a systematic and size-dependent high-energy (blue) shift in the PL spectrum of Si NCs with amide and alkoxy functionalization relative to alkyl. Time-resolved photoluminescence and transient absorption spectroscopies reveal no change in the excited-state dynamics between Si NCs functionalized with alkyl, amide, or alkoxide ligands, showing for the first time that saturated ligands - not only surface-derived charge-transfer states or hybridization between NC and low-lying ligand orbitals - are responsible for tuning the Si NC optical properties. To explain these PL shifts we propose that the atom bound to the Si NC surface strongly interacts with the Si NC electronic wave function and modulates the Si NC quantum confinement. These results reveal a potentially broadly applicable correlation between the optoelectronic properties of Si NCs and related quantum-confined structures based on the interaction between NC surfaces and the ligand binding group.

  20. Tuning Confinement in Colloidal Silicon Nanocrystals with Saturated Surface Ligands.

    Science.gov (United States)

    Carroll, Gerard M; Limpens, Rens; Neale, Nathan R

    2018-05-09

    The optical properties of silicon nanocrystals (Si NCs) are a subject of intense study and continued debate. In particular, Si NC photoluminescence (PL) properties are known to depend strongly on the surface chemistry, resulting in electron-hole recombination pathways derived from the Si NC band-edge, surface-state defects, or combined NC-conjugated ligand hybrid states. In this Letter, we perform a comparison of three different saturated surface functional groups-alkyls, amides, and alkoxides-on nonthermal plasma-synthesized Si NCs. We find a systematic and size-dependent high-energy (blue) shift in the PL spectrum of Si NCs with amide and alkoxy functionalization relative to alkyl. Time-resolved photoluminescence and transient absorption spectroscopies reveal no change in the excited-state dynamics between Si NCs functionalized with alkyl, amide, or alkoxide ligands, showing for the first time that saturated ligands-not only surface-derived charge-transfer states or hybridization between NC and low-lying ligand orbitals-are responsible for tuning the Si NC optical properties. To explain these PL shifts we propose that the atom bound to the Si NC surface strongly interacts with the Si NC electronic wave function and modulates the Si NC quantum confinement. These results reveal a potentially broadly applicable correlation between the optoelectronic properties of Si NCs and related quantum-confined structures based on the interaction between NC surfaces and the ligand binding group.

  1. Binuclear trivalent and tetravalent uranium halides and cyanides supported by cyclooctatetraene ligands

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Cong-Zhi; Wu, Qun-Yan; Lan, Jian-Hui; Shi, Wei-Qun [Chinese Academy of Sciences, Beijing (China). Laboratory of Nuclear Energy Chemistry and Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety; Chai, Zhi-Fang [Chinese Academy of Sciences, Beijing (China). Laboratory of Nuclear Energy Chemistry and Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety; Soochow Univ., Suzhou (China). School of Radiological and Interdisciplinary Sciences (RAD-X); Gibson, John K. [Lawrence Berkeley National Laboratory, CA (United States). Chemical Sciences Division

    2017-03-01

    Although the first organoactinide chloride Cp{sub 3}UCl (Cp = η{sup 5}-C{sub 5}H{sub 5}) was synthesized more than 50 years ago, binuclear uranium halides remain very rare in organoactinide chemistry. Herein, a series of binuclear trivalent and tetravalent uranium halides and cyanides with cyclooctatetraene ligands, (COT){sub 2}U{sub 2}X{sub n} (COT = η{sup 8}-C{sub 8}H{sub 8}; X=F, Cl, CN; n=2, 4), have been systematically studied using scalar-relativistic density functional theory (DFT). The structures with bridging halide or cyanide ligands were predicted to be the most stable complexes of (COT){sub 2}U{sub 2}X{sub n}, and all the complexes show weak antiferromagnetic interactions between the uranium centers. However, for each species, there is no significant uranium-uranium bonding interaction. The bonding between the metal and the ligands shows some degree of covalent character, especially between the metal and terminal halide or cyanide ligands. The U-5f and 6d orbitals are predominantly involved in the metal-ligand bonding. All the (COT){sub 2}U{sub 2}X{sub n} species were predicted to be more stable compared to the mononuclear half-sandwich complexes at room temperature in the gas phase such that (COT){sub 2}U{sub 2}X{sub 4} might be accessible through the known (COT){sub 2}U complex. The tetravalent derivatives (COT){sub 2}U{sub 2}X{sub 4} are more energetically favorable than the trivalent (COT){sub 2}U{sub 2}X{sub 2} analogs, which may be attributed to the greater number of strong metal-ligand bonds in the former complexes.

  2. ProBiS-ligands: a web server for prediction of ligands by examination of protein binding sites.

    Science.gov (United States)

    Konc, Janez; Janežič, Dušanka

    2014-07-01

    The ProBiS-ligands web server predicts binding of ligands to a protein structure. Starting with a protein structure or binding site, ProBiS-ligands first identifies template proteins in the Protein Data Bank that share similar binding sites. Based on the superimpositions of the query protein and the similar binding sites found, the server then transposes the ligand structures from those sites to the query protein. Such ligand prediction supports many activities, e.g. drug repurposing. The ProBiS-ligands web server, an extension of the ProBiS web server, is open and free to all users at http://probis.cmm.ki.si/ligands. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

  3. Rational Ligand Design for U(VI) and Pu(IV)

    International Nuclear Information System (INIS)

    Szigethy, Geza

    2009-01-01

    ligands exhibited increased uranyl affinity compared to bis-Me-3,2-HOPO ligands. This result is due in part to their increased denticity, but is primarily the result of the presence of the TAM moiety. In an effort to explore the relatively unexplored coordination chemistry of Pu(IV) with bidentate moieties, a series of Pu(IV) complexes were also crystallized using bidentate hydroxypyridinone and hydroxypyrone ligands. The geometries of these complexes are compared to that of the analogous Ce(IV) complexes. While in some cases these showed the expected structural similarities, some ligand systems led to significant coordination changes. A series of crystal structure analyses with Ce(IV) indicated that these differences are most likely the result of crystallization condition differences and solvent inclusion effects.

  4. Rational Ligand Design for U(VI) and Pu(IV)

    Energy Technology Data Exchange (ETDEWEB)

    Szigethy, Geza [Univ. of California, Berkeley, CA (United States)

    2009-08-12

    saturation, these ligands exhibited increased uranyl affinity compared to bis-Me-3,2-HOPO ligands. This result is due in part to their increased denticity, but is primarily the result of the presence of the TAM moiety. In an effort to explore the relatively unexplored coordination chemistry of Pu(IV) with bidentate moieties, a series of Pu(IV) complexes were also crystallized using bidentate hydroxypyridinone and hydroxypyrone ligands. The geometries of these complexes are compared to that of the analogous Ce(IV) complexes. While in some cases these showed the expected structural similarities, some ligand systems led to significant coordination changes. A series of crystal structure analyses with Ce(IV) indicated that these differences are most likely the result of crystallization condition differences and solvent inclusion effects.

  5. Transition-Metal-Controlled Inorganic Ligand-Supported Non-Precious Metal Catalysts for the Aerobic Oxidation of Amines to Imines.

    Science.gov (United States)

    Yu, Han; Zhai, Yongyan; Dai, Guoyong; Ru, Shi; Han, Sheng; Wei, Yongge

    2017-10-09

    Most state-of-art transition-metal catalysts usually require organic ligands, which are essential for controlling the reactivity and selectivity of reactions catalyzed by transition metals. However, organic ligands often suffer from severe problems including cost, toxicity, air/moisture sensitivity, and being commercially unavailable. Herein, we show a simple, mild, and efficient aerobic oxidation procedure of amines using inorganic ligand-supported non-precious metal catalysts 1, (NH 4 ) n [MMo 6 O 18 (OH) 6 ] (M=Cu 2+ ; Fe 3+ ; Co 3+ ; Ni 2+ ; Zn 2+ , n=3 or 4), synthesized by a simple one-step method in water at 100 °C, demonstrating that the catalytic activity and selectivity can be significantly improved by changing the central metal atom. In the presence of these catalysts, the catalytic oxidation of primary and secondary amines, as well as the coupling of alcohols and amines, can smoothly proceed to afford various imines with O 2 (1 atm) as the sole oxidant. In particular, the catalysts 1 have transition-metal ion core, and the planar arrangement of the six Mo VI centers at their highest oxidation states around the central heterometal can greatly enhance the Lewis acidity of catalytically active sites, and also enable the electrons in the center to delocalize onto the six edge-sharing MO 6 units, in the same way as ligands in traditional organometallic complexes. The versatility of this methodology maybe opens a path to catalytic oxidation through inorganic ligand-coordinated metal catalysis. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. Speciation of Pu(4) complexes with weak ligands from visible spectra

    International Nuclear Information System (INIS)

    Berg, J.M.; Veirs, D.K.

    2001-01-01

    Stoichiometries of early actinide metal ion complexes in solution equilibrium can sometimes be determined by modelling the dependence of a species-sensitive measurement on ligand concentration. Weak ligands present the additional problem that these measurements cannot be made in the simplifying limiting case of low ligand concentration relative to the background electrolyte. At high ligand concentrations, constant ionic strength no longer implies constant activity coefficients. Additional parameters must be included in the equilibrium model to account for the variation of activity coefficients with ligand concentration as well as with overall ionic strength. We present the formalism of such a model based on SIT theory and its implementation for simultaneous fitting of spectra over a wide range of ionic strengths. As a test case, we analyse a subset of the spectra we have collected on complexation of Pu(IV) by nitrate in aqueous acid solutions. (authors)

  7. 5D-QSAR for spirocyclic sigma1 receptor ligands by Quasar receptor surface modeling.

    Science.gov (United States)

    Oberdorf, Christoph; Schmidt, Thomas J; Wünsch, Bernhard

    2010-07-01

    Based on a contiguous and structurally as well as biologically diverse set of 87 sigma(1) ligands, a 5D-QSAR study was conducted in which a quasi-atomistic receptor surface modeling approach (program package Quasar) was applied. The superposition of the ligands was performed with the tool Pharmacophore Elucidation (MOE-package), which takes all conformations of the ligands into account. This procedure led to four pharmacophoric structural elements with aromatic, hydrophobic, cationic and H-bond acceptor properties. Using the aligned structures a 3D-model of the ligand binding site of the sigma(1) receptor was obtained, whose general features are in good agreement with previous assumptions on the receptor structure, but revealed some novel insights since it represents the receptor surface in more detail. Thus, e.g., our model indicates the presence of an H-bond acceptor moiety in the binding site as counterpart to the ligands' cationic ammonium center, rather than a negatively charged carboxylate group. The presented QSAR model is statistically valid and represents the biological data of all tested compounds, including a test set of 21 ligands not used in the modeling process, with very good to excellent accuracy [q(2) (training set, n=66; leave 1/3 out) = 0.84, p(2) (test set, n=21)=0.64]. Moreover, the binding affinities of 13 further spirocyclic sigma(1) ligands were predicted with reasonable accuracy (mean deviation in pK(i) approximately 0.8). Thus, in addition to novel insights into the requirements for binding of spirocyclic piperidines to the sigma(1) receptor, the presented model can be used successfully in the rational design of new sigma(1) ligands. Copyright (c) 2010 Elsevier Masson SAS. All rights reserved.

  8. Electron-mediating Cu(A) centers in proteins

    DEFF Research Database (Denmark)

    Epel, Boris; Slutter, Claire S; Neese, Frank

    2002-01-01

    High field (W-band, 95 GHz) pulsed electron-nuclear double resonance (ENDOR) measurements were carried out on a number of proteins that contain the mixed-valence, binuclear electron-mediating Cu(A) center. These include nitrous oxide reductase (N(2)OR), the recombinant water-soluble fragment...... of subunit II of Thermus thermophilus cytochrome c oxidase (COX) ba(3) (M160T9), its M160QT0 mutant, where the weak axial methionine ligand has been replaced by a glutamine, and the engineered "purple" azurin (purpAz). The three-dimensional (3-D) structures of these proteins, apart from the mutant, are known...... indicates differences in the positions of the imidazole rings relative to the Cu(2)S(2) core. Comparison of the spectral features of the weakly coupled protons of M160QT0 with those of the other investigated proteins shows that they are very similar to those of purpAz, where the Cu(A) center is the most...

  9. Tuning the Relative Stability and Reactivity of Manganese Dioxygen and Peroxo Intermediates via Systematic Ligand Modification.

    Science.gov (United States)

    Kovacs, Julie A

    2015-10-20

    Many fundamental processes of life depend on the chemical energy stored in the O–O bond of dioxygen (O2), the majority of which is derived from photosynthetic H2O oxidation. Key steps in these processes involve Mn-, Fe-, or Cu-promoted formation or cleavage of O–O and O–H bonds, the mechanisms of which are not fully understood, especially with Mn. Metal–peroxo and high-valent metal–oxo species are proposed to be involved as intermediates. The metal ion properties that favor O–O and O–H bond formation versus cleavage have yet to be systematically explored. Herein we examine the O2 reactivity of a series of structurally related Mn(II) complexes and show that several metastable intermediates are observed, the relative stabilities of which depend on subtle differences in ligand architecture. We show that in contrast to Fe and Cu complexes, O2 binds irreversibly to Mn(II). By crystallizing an entire series of the first reported examples of Mn(III)–OOR peroxos as well as an O2-derived binuclear trans-μ-1,2-bridged Mn(III)–peroxo with varying degrees of O–O bond activation, we demonstrate that there are distinct correlations between spectroscopic, structural, and reactivity properties. Rate-limiting O–O bond cleavage is shown to afford a reactive species capable of abstracting H atoms from 2,4-tBu2-PhOH or 1,4-cyclohexadiene, depending on the ligand substituents. The weakly coordinated N-heterocycle Mn···Npy,quino distance is shown to correlate with the peroxo O–O bond length and modulate the π overlap between the filled πv*(O–O) and Mn dxz orbitals. We also show that there is a strong correlation between the peroxo → Mn charge transfer (CT) band and the peroxo O–O bond length. The energy difference between the CT bands associated with the peroxos possessing the shortest and longest O–O bonds shows that these distances are spectroscopically distinguishable. We show that we can use this spectroscopic parameter to estimate the O

  10. D3R Grand Challenge 2: blind prediction of protein-ligand poses, affinity rankings, and relative binding free energies

    Science.gov (United States)

    Gaieb, Zied; Liu, Shuai; Gathiaka, Symon; Chiu, Michael; Yang, Huanwang; Shao, Chenghua; Feher, Victoria A.; Walters, W. Patrick; Kuhn, Bernd; Rudolph, Markus G.; Burley, Stephen K.; Gilson, Michael K.; Amaro, Rommie E.

    2018-01-01

    The Drug Design Data Resource (D3R) ran Grand Challenge 2 (GC2) from September 2016 through February 2017. This challenge was based on a dataset of structures and affinities for the nuclear receptor farnesoid X receptor (FXR), contributed by F. Hoffmann-La Roche. The dataset contained 102 IC50 values, spanning six orders of magnitude, and 36 high-resolution co-crystal structures with representatives of four major ligand classes. Strong global participation was evident, with 49 participants submitting 262 prediction submission packages in total. Procedurally, GC2 mimicked Grand Challenge 2015 (GC2015), with a Stage 1 subchallenge testing ligand pose prediction methods and ranking and scoring methods, and a Stage 2 subchallenge testing only ligand ranking and scoring methods after the release of all blinded co-crystal structures. Two smaller curated sets of 18 and 15 ligands were developed to test alchemical free energy methods. This overview summarizes all aspects of GC2, including the dataset details, challenge procedures, and participant results. We also consider implications for progress in the field, while highlighting methodological areas that merit continued development. Similar to GC2015, the outcome of GC2 underscores the pressing need for methods development in pose prediction, particularly for ligand scaffolds not currently represented in the Protein Data Bank (http://www.pdb.org), and in affinity ranking and scoring of bound ligands.

  11. Bitopic Ligands and Metastable Binding Sites

    DEFF Research Database (Denmark)

    Fronik, Philipp; Gaiser, Birgit I; Sejer Pedersen, Daniel

    2017-01-01

    of orthosteric binding sites. Bitopic ligands have been employed to address the selectivity problem by combining (linking) an orthosteric ligand with an allosteric modulator, theoretically leading to high-affinity subtype selective ligands. However, it remains a challenge to identify suitable allosteric binding...... that have been reported to date, this type of bitopic ligands would be composed of two identical pharmacophores. Herein, we outline the concept of bitopic ligands, review metastable binding sites, and discuss their potential as a new source of allosteric binding sites....

  12. Quantitative analysis of protein-ligand interactions by NMR.

    Science.gov (United States)

    Furukawa, Ayako; Konuma, Tsuyoshi; Yanaka, Saeko; Sugase, Kenji

    2016-08-01

    Protein-ligand interactions have been commonly studied through static structures of the protein-ligand complex. Recently, however, there has been increasing interest in investigating the dynamics of protein-ligand interactions both for fundamental understanding of the underlying mechanisms and for drug development. NMR is a versatile and powerful tool, especially because it provides site-specific quantitative information. NMR has widely been used to determine the dissociation constant (KD), in particular, for relatively weak interactions. The simplest NMR method is a chemical-shift titration experiment, in which the chemical-shift changes of a protein in response to ligand titration are measured. There are other quantitative NMR methods, but they mostly apply only to interactions in the fast-exchange regime. These methods derive the dissociation constant from population-averaged NMR quantities of the free and bound states of a protein or ligand. In contrast, the recent advent of new relaxation-based experiments, including R2 relaxation dispersion and ZZ-exchange, has enabled us to obtain kinetic information on protein-ligand interactions in the intermediate- and slow-exchange regimes. Based on R2 dispersion or ZZ-exchange, methods that can determine the association rate, kon, dissociation rate, koff, and KD have been developed. In these approaches, R2 dispersion or ZZ-exchange curves are measured for multiple samples with different protein and/or ligand concentration ratios, and the relaxation data are fitted to theoretical kinetic models. It is critical to choose an appropriate kinetic model, such as the two- or three-state exchange model, to derive the correct kinetic information. The R2 dispersion and ZZ-exchange methods are suitable for the analysis of protein-ligand interactions with a micromolar or sub-micromolar dissociation constant but not for very weak interactions, which are typical in very fast exchange. This contrasts with the NMR methods that are used

  13. New bisaminoethanethiol (BAT) ligands which form two interconvertible Tc-99m complexes

    Energy Technology Data Exchange (ETDEWEB)

    Oya, Shunichi; Kung, Mei-Ping; Frederick, Dana; Kung, Hank F

    1995-08-01

    Most commonly used radiopharmaceuticals in diagnostic nuclear medicine are labeled with Tc-99m. This is due to its superior physical characteristics (T{sub (1(2))} = 6 h and gamma energy 140 KeV) and convenient availability from the {sup 99}Mo/{sup 99mm}Tc generator. In an attempt to fine tune the properties of Tc-99m complexes, the synthesis and radiolabeling of two novel N{sub 2}S{sub 2} ligands, N,-2-mercaptobenzyl-N'-(1-oxo-2-mercapto-2-methyl)propyl ethylenediamine,8, and N,-2-methylthiobenzyl-N'-(1-oxo-2-mercapto-2-methyl)propyl ethylenediamine, 11, with an ionizable SH or unionizable SMe group, respectively, for the formation of complexes with Tc{sup v}O center cores, have been examined. Both ligands initially formed one apparently stable, lipophilic and neutral complex (HPLC, Rt = 7 min, reverse-phase column, acetonitrile: buffer, pH 7.0; (55(45)); V/V; partition coefficient between 1-octanol and buffer of 410 and 335, respectively) with [{sup 99m}Tc]pertechnetate in the presence of stannous chloride. After treatment with a reducing agent, NaCNBH{sub 3}, the initial [{sup 99m}Tc]8 and 11 complexes were reduced; the reduced complexes were less lipophilic (shorter retention time, Rt = 5 min, on the same reversed phase HPLC). However, only the oxidized form showed sufficient stability. The reduced forms of both [{sup 99m}Tc]8 and 11 were readily and completely converted back to the oxidized forms by a stream of air. Biodistribution studies in rats demonstrated that the [{sup 99m}Tc]8 (oxidized form) penetrated the blood-brain barrier (0.67% dose/organ at 2 min postinjection), but washed out from the brain quickly (0.29% dose/organ at 30 min postinjection). On the contrary, [{sup 99m}Tc]11 (oxidized form) did not show any brain uptake (0.03% dose/organ at 2 min postinjection), despite its higher lipophilicity. The disparity between these two Tc-99m complexes may be related to the relative instability of [{sup 99m}Tc]11 (oxidized form) by the introduction of the

  14. Beta-Phosphinoethylboranes as Ambiphilic Ligands in Nickel-Methyl Complexes

    Energy Technology Data Exchange (ETDEWEB)

    Fischbach, Andreas; Bazinet, Patrick R.; Waterman, Rory; Tilley, T. Don

    2007-10-28

    The ambiphilic {beta}-phosphinoethylboranes Ph{sub 2}PCH{sub 2}CH{sub 2}BR{sub 2} (BR{sub 2} = BCy{sub 2} (1a), BBN (1b)), which feature a ethano spacer CH{sub 2}CH{sub 2} between the Lewis acidic boryl and Lewis basic phosphino groups, were synthesized in nearly quantitative yields via the hydroboration of vinyldiphenylphosphine. Compounds 1a and 1b were fully characterized by elemental analysis, and by NMR and IR spectroscopy. X-ray crystallographic studies of compound 1b revealed infinite helical chains of the molecules connected through P{hor_ellipsis}B donor-acceptor interactions. The ability of these ambiphilic ligands to concurrently act as donors and acceptors was highlighted by their reactions with (dmpe)NiMe{sub 2}. Zwitterionic complexes (dmpe)NiMe(Ph{sub 2}PCH{sub 2}CH{sub 2}BCy{sub 2}Me) (2a) and (dmpe)NiMe(Ph{sub 2}PCH{sub 2}CH{sub 2}[BBN]Me) (2b) were generated via the abstraction of one of the methyl groups, forming a borate, and intramolecular coordination of the phosphine moiety to the resulting cationic metal center. Compound 2b was characterized by X-ray crystallography. Furthermore, B(C{sub 6}F{sub 5}){sub 3} abstracts the methyl group of a coordinated borate ligand to generate a free, 3-coordinate borane center in [(dmpe)NiMe(1a)]{sup +}[MeB(C{sub 6}F{sub 5}){sub 3}]{sup -} (3).

  15. Astrophysics related programs at center for underground physics (CUP)

    Science.gov (United States)

    Kim, Yeongduk

    2018-04-01

    We are developing experimental programs related to particle astrophysics at the Center for Underground Physics (CUP); searching for neutrino-less double beta decay (0νββ) of 100Mo nuclei and sterile neutrinos in the mass range of eV using reactor neutrinos. Expected sensitivities of AMoRE double beta decay experiment and the results from recent NEOS experiment are described. Utilizing the facilities for ultra-low radioactivity measurement at the center, we are planning to measure the decay of 180mTa which is important to the nucleosynthesis of heavy nuclei.

  16. Spectrophotometric method for determination of bifunctional macrocyclic ligands in macrocyclic ligand-protein conjugates

    International Nuclear Information System (INIS)

    Dadachova, E.; Chappell, L.L.; Brechbiel, M.W.

    1999-01-01

    A simple spectrophotometric assay for determination of bifunctional polyazacarboxylate-macrocyclic ligands of different sizes that are conjugated to proteins has been developed for: 12-membered macrocycle DOTA (2-[4-nitrobenzyl]-1, 4, 7, 10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid) and analogs, the 15-membered PEPA macrocycle (2-[4-nitrobenzyl]-1,4,7,10,13-pentaazacyclopentadecane-N,N',N'',N''',N'''' -pentaacetic acid), and the large 18-membered macrocycle HEHA (1,4,7,10,13,16-hexaazacyclooctadecane-N,N',N'',N''',N''''-hexaacetic acid). The method is based on titration of the blue-colored 1:1 Pb(II)-Arsenazo III (AAIII) complex with the polyazacarboxylate macrocyclic ligand in the concentration range of 0-2.5 μM, wherein color change occurring upon transchelation of the Pb(II) from the AAIII to the polyazamacrocyclic ligand is monitored at 656 nm. The assay is performed at ambient temperature within 20 min without any interfering interaction between the protein and Pb(II)-AA(III) complex. Thus, this method also provides a ligand-to-protein ratio (L/P ratio) that reflects the effective number of ligands per protein molecule available to radiolabeling. The method is not suitable for 14-membered TETA macrocycle (2-[4-nitrobenzyl]-1, 4, 8, 11-tetraazacyclotetradecane N,N',N'',N'''-tetraacetic acid) because of low stability constant of Pb(II)-TETA complex. The method is rapid, simple and may be customized for other polyazacarboxylate macrocyclic ligands

  17. Rosetta Ligand docking with flexible XML protocols.

    Science.gov (United States)

    Lemmon, Gordon; Meiler, Jens

    2012-01-01

    RosettaLigand is premiere software for predicting how a protein and a small molecule interact. Benchmark studies demonstrate that 70% of the top scoring RosettaLigand predicted interfaces are within 2Å RMSD from the crystal structure [1]. The latest release of Rosetta ligand software includes many new features, such as (1) docking of multiple ligands simultaneously, (2) representing ligands as fragments for greater flexibility, (3) redesign of the interface during docking, and (4) an XML script based interface that gives the user full control of the ligand docking protocol.

  18. Ligand-receptor Interactions by NMR Spectroscopy

    Directory of Open Access Journals (Sweden)

    Novak. P.

    2008-04-01

    Full Text Available Today NMR spectroscopy is a method of choice for elucidation of interactions between biomolecules and the potential ligands. Knowledge on these interactions is an essential prerequisite for the rational drug design. The most important contribution of NMR to drug design a few years ago was the 3D structure determination of proteins. Besides delivering the 3D structures of the free proteins as a raw material for the modeling studies on ligand binding, NMR can directly yield valuable experimental data on the biologically important protein-ligand complexes. In addition to X-ray diffraction, NMR spectroscopy can provide information on the internal protein dynamics ordynamics of intermolecular interactions. Changes in NMR parameters allow us to detect ("SAR by NMR" and quantitatively determine binding affinities (titration, diffusion NMR experiments, etc. of potential ligands. Also, it is possible to determine the binding site and conformations of ligands, receptors and receptor-ligand complexes with the help of NMR methods such as tr-NOESY. Epitopes or functional groups responsible for binding of ligands to the receptor can be identified by employing STD or WaterLOGSY experiments. In this review are described some of the most frequent NMR methods for the characterization of the interactions between biomolecules and ligands, together with their advantages and disadvantages.

  19. Provider-Related Linkages Between Primary Care Clinics and Community-Based Senior Centers Associated With Diabetes-Related Outcomes.

    Science.gov (United States)

    Noël, Polly Hitchcock; Wang, Chen-Pin; Finley, Erin P; Espinoza, Sara E; Parchman, Michael L; Bollinger, Mary J; Hazuda, Helen P

    2018-06-01

    The Institute of Medicine (IOM) suggests that linkages between primary care practices and community-based resources can improve health in lower income and minority patients, but examples of these are rare. We conducted a prospective, mixed-methods observational study to identify indicators of primary care-community linkage associated with the frequency of visits to community-based senior centers and improvements in diabetes-related outcomes among 149 new senior center members (72% Hispanic). We used semistructured interviews at baseline and 9-month follow-up, obtaining visit frequency from member software and clinical assessments including hemoglobin A1c (HbA1c) from colocated primary care clinics. Members' discussion of their activities with their primary care providers (PCPs) was associated with increased visits to the senior centers, as well as diabetes-related improvements. Direct feedback from the senior centers to their PCPs was desired by the majority of members and may help to reinforce use of community resources for self-management support.

  20. Probes of the metal-to-ligand charge-transfer excited states in ruthenium-Am(m)ine-bipyridine complexes: the effects of NH/ND and CH/CD isotopic substitution on the 77 K luminescence.

    Science.gov (United States)

    Chen, Yuan-Jang; Xie, Puhui; Endicott, John F; Odongo, Onduru S

    2006-06-29

    The effects of ligand perdeuteration on the metal-to-ligand charge-transfer (MLCT) excited-state emission properties at 77 K are described for several [Ru(L)(4)bpy](2+) complexes in which the emission process is nominally [uIII,bpy-] --> [RuII,bpy]. The perdeuteration of the 2,2'-bipyridine (bpy) ligand is found to increase the zero-point energy differences between the ground states and MLCT excited states by amounts that vary from 0 +/- 10 to 70 +/- 10 cm(-1) depending on the ligands L. This indicates that there are some vibrational modes with smaller force constants in the excited states than in the ground states for most of these complexes. These blue shifts increase approximately as the energy difference between the excited and ground states decreases, but they are otherwise not strongly correlated with the number of bipyridine ligands in the complex. Careful comparisons of the [Ru(L)(4)(d(8)-bpy)](2+) and [Ru(L)(4)(h(8)-bpy](2+) emission spectra are used to resolve the very weak vibronic contributions of the C-H stretching modes as the composite contributions of the corresponding vibrational reorganizational energies. The largest of these, 25 +/- 10 cm(-1), is found for the complexes with L = py or bpy/2 and smaller when L = NH(3). Perdeuteration of the am(m)ine ligands (NH(3), en, or [14]aneN(4)) has no significant effect on the zero-point energy difference, and the contributions of the NH stretching vibrational modes to the emission band shape are too weak to resolve. Ligand perdeuteration does increase the excited-state lifetimes by a factor that is roughly proportional to the excited-state-ground-state energy difference, even though the CH and NH vibrational reorganizational energies are too small for nuclear tunneling involving these modes to dominate the relaxation process. It is proposed that metal-ligand skeletal vibrational modes and configurational mixing between metal-centered, bpy-ligand-centered, and MLCT excited states are important in

  1. Using physics-based pose predictions and free energy perturbation calculations to predict binding poses and relative binding affinities for FXR ligands in the D3R Grand Challenge 2

    Science.gov (United States)

    Athanasiou, Christina; Vasilakaki, Sofia; Dellis, Dimitris; Cournia, Zoe

    2018-01-01

    Computer-aided drug design has become an integral part of drug discovery and development in the pharmaceutical and biotechnology industry, and is nowadays extensively used in the lead identification and lead optimization phases. The drug design data resource (D3R) organizes challenges against blinded experimental data to prospectively test computational methodologies as an opportunity for improved methods and algorithms to emerge. We participated in Grand Challenge 2 to predict the crystallographic poses of 36 Farnesoid X Receptor (FXR)-bound ligands and the relative binding affinities for two designated subsets of 18 and 15 FXR-bound ligands. Here, we present our methodology for pose and affinity predictions and its evaluation after the release of the experimental data. For predicting the crystallographic poses, we used docking and physics-based pose prediction methods guided by the binding poses of native ligands. For FXR ligands with known chemotypes in the PDB, we accurately predicted their binding modes, while for those with unknown chemotypes the predictions were more challenging. Our group ranked #1st (based on the median RMSD) out of 46 groups, which submitted complete entries for the binding pose prediction challenge. For the relative binding affinity prediction challenge, we performed free energy perturbation (FEP) calculations coupled with molecular dynamics (MD) simulations. FEP/MD calculations displayed a high success rate in identifying compounds with better or worse binding affinity than the reference (parent) compound. Our studies suggest that when ligands with chemical precedent are available in the literature, binding pose predictions using docking and physics-based methods are reliable; however, predictions are challenging for ligands with completely unknown chemotypes. We also show that FEP/MD calculations hold predictive value and can nowadays be used in a high throughput mode in a lead optimization project provided that crystal structures of

  2. A Ferrocene-Based Catecholamide Ligand: the Consequences of Ligand Swivel for Directed Supramolecular Self-Assembly

    Energy Technology Data Exchange (ETDEWEB)

    Mugridge, Jeffrey; Fiedler, Dorothea; Raymond, Kenneth

    2010-02-04

    A ferrocene-based biscatecholamide ligand was prepared and investigated for the formation of metal-ligand supramolecular assemblies with different metals. Reaction with Ge(IV) resulted in the formation of a variety of Ge{sub n}L{sub m} coordination complexes, including [Ge{sub 2}L{sub 3}]{sup 4-} and [Ge{sub 2}L{sub 2}({mu}-OMe){sub 2}]{sup 2-}. The ligand's ability to swivel about the ferrocenyl linker and adopt different conformations accounts for formation of many different Ge{sub n}L{sub m} species. This study demonstrates why conformational ligand rigidity is essential in the rational design and directed self-assembly of supramolecular complexes.

  3. Positional cloning identifies zebrafish one-eyed pinhead as a permissive EGF-related ligand required during gastrulation.

    Science.gov (United States)

    Zhang, J; Talbot, W S; Schier, A F

    1998-01-23

    The zebrafish one-eyed pinhead (oep) mutation disrupts embryonic development, resulting in cyclopia and defects in endoderm, prechordal plate, and ventral neuroectoderm formation. We report the molecular isolation of oep using a positional cloning approach. The oep gene encodes a novel EGF-related protein with similarity to the EGF-CFC proteins cripto, cryptic, and FRL-1. Wild-type oep protein contains a functional signal sequence and is membrane-associated. Following ubiquitous maternal and zygotic expression, highest levels of oep mRNA are found in the gastrula margin and in axial structures and forebrain. Widespread misexpression of both membrane-attached and secreted forms of oep rescues prechordal plate and forebrain development in mutant embryos but does not lead to the ectopic induction of these cell types in wild-type fish. These results establish an essential but permissive role for an EGF-related ligand during vertebrate gastrulation.

  4. Macrocyclic G-quadruplex ligands

    DEFF Research Database (Denmark)

    Nielsen, M C; Ulven, Trond

    2010-01-01

    are macrocyclic structures which have been modeled after the natural product telomestatin or from porphyrin-based ligands discovered in the late 1990s. These two structural classes of G-quadruplex ligands are reviewed here with special attention to selectivity and structure-activity relationships, and with focus...

  5. Free energy calculations offer insights into the influence of receptor flexibility on ligand-receptor binding affinities.

    Science.gov (United States)

    Dolenc, Jožica; Riniker, Sereina; Gaspari, Roberto; Daura, Xavier; van Gunsteren, Wilfred F

    2011-08-01

    Docking algorithms for computer-aided drug discovery and design often ignore or restrain the flexibility of the receptor, which may lead to a loss of accuracy of the relative free enthalpies of binding. In order to evaluate the contribution of receptor flexibility to relative binding free enthalpies, two host-guest systems have been examined: inclusion complexes of α-cyclodextrin (αCD) with 1-chlorobenzene (ClBn), 1-bromobenzene (BrBn) and toluene (MeBn), and complexes of DNA with the minor-groove binding ligands netropsin (Net) and distamycin (Dist). Molecular dynamics simulations and free energy calculations reveal that restraining of the flexibility of the receptor can have a significant influence on the estimated relative ligand-receptor binding affinities as well as on the predicted structures of the biomolecular complexes. The influence is particularly pronounced in the case of flexible receptors such as DNA, where a 50% contribution of DNA flexibility towards the relative ligand-DNA binding affinities is observed. The differences in the free enthalpy of binding do not arise only from the changes in ligand-DNA interactions but also from changes in ligand-solvent interactions as well as from the loss of DNA configurational entropy upon restraining.

  6. Oligomerization of ethylene catalysed by nickel complexes associated with nitrogen ligands in ionic liquids; Oligomerisation de l'ethylene catalysee par des complexes du nickel associes a des ligands azotes dans les liquides ioniques

    Energy Technology Data Exchange (ETDEWEB)

    Lecocq, V.

    2003-09-01

    We report here the use of a new class of catalytic systems based on a nickel active center associated with nitrogen ligands, such as di-imines, or imino-pyridines, for the oligomerization of ethylene in a biphasic medium using ionic liquids as the catalyst solvent. The nickel catalyst is immobilized in the ionic liquid phase in which the olefinic reaction products are poorly miscible. This biphasic system makes possible an easy separation and recycle of the catalyst. Numerous di-imine and imino-pyridine ligands with different steric and electronic properties have been synthesized and their corresponding nickel complexes isolated and characterized. Different ionic liquids, based on chloro-aluminates or non-chloro-aluminates anions, have also been prepared and characterized. The effect of the nature of the ligand, the ionic liquid, the nickel precursor and its mode of activation have been studied and correlated with the selectivity and activity of the transformation of ethylene. (author)

  7. Parameterization of phosphine ligands demonstrates enhancement of nickel catalysis via remote steric effects

    Science.gov (United States)

    Wu, Kevin; Doyle, Abigail G.

    2017-08-01

    The field of Ni-catalysed cross-coupling has seen rapid recent growth because of the low cost of Ni, its earth abundance, and its ability to promote unique cross-coupling reactions. Whereas advances in the related field of Pd-catalysed cross-coupling have been driven by ligand design, the development of ligands specifically for Ni has received minimal attention. Here, we disclose a class of phosphines that enable the Ni-catalysed Csp3 Suzuki coupling of acetals with boronic acids to generate benzylic ethers, a reaction that failed with known ligands for Ni and designer phosphines for Pd. Using parameters to quantify phosphine steric and electronic properties together with regression statistical analysis, we identify a model for ligand success. The study suggests that effective phosphines feature remote steric hindrance, a concept that could guide future ligand design tailored to Ni. Our analysis also reveals that two classic descriptors for ligand steric environment—cone angle and % buried volume—are not equivalent, despite their treatment in the literature.

  8. Conformational diversity of flexible ligand in metal-organic frameworks controlled by size-matching mixed ligands

    International Nuclear Information System (INIS)

    Hua, Xiu-Ni; Qin, Lan; Yan, Xiao-Zhi; Yu, Lei; Xie, Yi-Xin; Han, Lei

    2015-01-01

    Hydrothermal reactions of N-auxiliary flexible exo-bidentate ligand 1,3-bis(4-pyridyl)propane (bpp) and carboxylates ligands naphthalene-2,6-dicarboxylic acid (2,6-H_2ndc) or 4,4′-(hydroxymethylene)dibenzoic acid (H_2hmdb), in the presence of cadmium(II) salts have given rise to two novel metal-organic frameworks based on flexible ligands (FL-MOFs), namely, [Cd_2(2,6-ndc)_2(bpp)(DMF)]·2DMF (1) and [Cd_3(hmdb)_3(bpp)]·2DMF·2EtOH (2) (DMF=N,N-Dimethylformamide). Single-crystal X-ray diffraction analyses revealed that compound 1 exhibits a three-dimensional self-penetrating 6-connected framework based on dinuclear cluster second building unit. Compound 2 displays an infinite three-dimensional ‘Lucky Clover’ shape (2,10)-connected network based on the trinuclear cluster and V-shaped organic linkers. The flexible bpp ligand displays different conformations in 1 and 2, which are successfully controlled by size-matching mixed ligands during the self-assembly process. - Graphical abstract: Compound 1 exhibits a 3D self-penetrating 6-connected framework based on dinuclear cluster, and 2 displays an infinite 3D ‘Lucky Clover’ shape (2,10)-connected network based on the trinuclear cluster. The flexible 1,3-bis(4-pyridyl)propane ligand displays different conformations in 1 and 2, which successfully controlled by size-matching mixed ligands during the self-assembly process.

  9. Conformational diversity of flexible ligand in metal-organic frameworks controlled by size-matching mixed ligands

    Energy Technology Data Exchange (ETDEWEB)

    Hua, Xiu-Ni; Qin, Lan; Yan, Xiao-Zhi; Yu, Lei; Xie, Yi-Xin; Han, Lei, E-mail: hanlei@nbu.edu.cn

    2015-12-15

    Hydrothermal reactions of N-auxiliary flexible exo-bidentate ligand 1,3-bis(4-pyridyl)propane (bpp) and carboxylates ligands naphthalene-2,6-dicarboxylic acid (2,6-H{sub 2}ndc) or 4,4′-(hydroxymethylene)dibenzoic acid (H{sub 2}hmdb), in the presence of cadmium(II) salts have given rise to two novel metal-organic frameworks based on flexible ligands (FL-MOFs), namely, [Cd{sub 2}(2,6-ndc){sub 2}(bpp)(DMF)]·2DMF (1) and [Cd{sub 3}(hmdb){sub 3}(bpp)]·2DMF·2EtOH (2) (DMF=N,N-Dimethylformamide). Single-crystal X-ray diffraction analyses revealed that compound 1 exhibits a three-dimensional self-penetrating 6-connected framework based on dinuclear cluster second building unit. Compound 2 displays an infinite three-dimensional ‘Lucky Clover’ shape (2,10)-connected network based on the trinuclear cluster and V-shaped organic linkers. The flexible bpp ligand displays different conformations in 1 and 2, which are successfully controlled by size-matching mixed ligands during the self-assembly process. - Graphical abstract: Compound 1 exhibits a 3D self-penetrating 6-connected framework based on dinuclear cluster, and 2 displays an infinite 3D ‘Lucky Clover’ shape (2,10)-connected network based on the trinuclear cluster. The flexible 1,3-bis(4-pyridyl)propane ligand displays different conformations in 1 and 2, which successfully controlled by size-matching mixed ligands during the self-assembly process.

  10. Palladium-catalyzed, asymmetric Baeyer–Villiger oxidation of prochiral cyclobutanones with PHOX ligands

    KAUST Repository

    Petersen, Kimberly S.

    2011-06-01

    Described in this report is a general method for the conversion of prochiral 3-substituted cyclobutanones to enantioenriched γ-lactones through a palladium-catalyzed Baeyer-Villiger oxidation using phosphinooxazoline ligands in up to 99% yield and 81% ee. Lactones of enantiopurity ≥93% could be obtained through a single recrystallization step. Importantly, 3,3-disubtituted cyclobutanones produced enantioenriched lactones containing a β-quaternary center. © 2011 Elsevier Ltd. All rights reserved.

  11. Construction of Polynuclear Lanthanide (Ln = Dy(III), Tb(III), and Nd(III)) Cage Complexes Using Pyridine-Pyrazole-Based Ligands: Versatile Molecular Topologies and SMM Behavior.

    Science.gov (United States)

    Bala, Sukhen; Sen Bishwas, Mousumi; Pramanik, Bhaskar; Khanra, Sumit; Fromm, Katharina M; Poddar, Pankaj; Mondal, Raju

    2015-09-08

    Employment of two different pyridyl-pyrazolyl-based ligands afforded three octanuclear lanthanide(III) (Ln = Dy, Tb) cage compounds and one hexanuclear neodymium(III) coordination cage, exhibiting versatile molecular architectures including a butterfly core. Relatively less common semirigid pyridyl-pyrazolyl-based asymmetric ligand systems show an interesting trend of forming polynuclear lanthanide cage complexes with different coordination environments around the metal centers. It is noteworthy here that construction of lanthanide complex itself is a challenging task in a ligand system as soft N-donor rich as pyridyl-pyrazol. We report herein some lanthanide complexes using ligand containing only one or two O-donors compare to five N-coordinating sites. The resultant multinuclear lanthanide complexes show interesting magnetic and spectroscopic features originating from different spatial arrangements of the metal ions. Alternating current (ac) susceptibility measurements of the two dysprosium complexes display frequency- and temperature-dependent out-of-phase signals in zero and 0.5 T direct current field, a typical characteristic feature of single-molecule magnet (SMM) behavior, indicating different energy reversal barriers due to different molecular topologies. Another aspect of this work is the occurrence of the not-so-common SMM behavior of the terbium complex, further confirmed by ac susceptibility measurement.

  12. Contrasting roles for TLR ligands in HIV-1 pathogenesis.

    Directory of Open Access Journals (Sweden)

    Beda Brichacek

    2010-09-01

    Full Text Available The first line of a host's response to various pathogens is triggered by their engagement of cellular pattern recognition receptors (PRRs. Binding of microbial ligands to these receptors leads to the induction of a variety of cellular factors that alter intracellular and extracellular environment and interfere directly or indirectly with the life cycle of the triggering pathogen. Such changes may also affect any coinfecting microbe. Using ligands to Toll-like receptors (TLRs 5 and 9, we examined their effect on human immunodeficiency virus (HIV-1 replication in lymphoid tissue ex vivo. We found marked differences in the outcomes of such treatment. While flagellin (TLR5 agonist treatment enhanced replication of CC chemokine receptor 5 (CCR 5-tropic and CXC chemokine receptor 4 (CXCR4-tropic HIV-1, treatment with oligodeoxynucleotide (ODN M362 (TLR9 agonist suppressed both viral variants. The differential effects of these TLR ligands on HIV-1 replication correlated with changes in production of CC chemokines CCL3, CCL4, CCL5, and of CXC chemokines CXCL10, and CXCL12 in the ligand-treated HIV-1-infected tissues. The nature and/or magnitude of these changes were dependent on the ligand as well as on the HIV-1 viral strain. Moreover, the tested ligands differed in their ability to induce cellular activation as evaluated by the expression of the cluster of differentiation markers (CD 25, CD38, CD39, CD69, CD154, and human leukocyte antigen D related (HLA-DR as well as of a cell proliferation marker, Ki67, and of CCR5. No significant effect of the ligand treatment was observed on apoptosis and cell death/loss in the treated lymphoid tissue ex vivo. Our results suggest that binding of microbial ligands to TLRs is one of the mechanisms that mediate interactions between coinfected microbes and HIV-1 in human tissues. Thus, the engagement of appropriate TLRs by microbial molecules or their mimetic might become a new strategy for HIV therapy or prevention.

  13. Quantitation of species differences in albumin–ligand interactions for bovine, human and rat serum albumins using fluorescence spectroscopy: A test case with some Sudlow's site I ligands

    International Nuclear Information System (INIS)

    Poór, Miklós; Li, Yin; Matisz, Gergely; Kiss, László; Kunsági-Máté, Sándor; Kőszegi, Tamás

    2014-01-01

    Albumin, the most abundant plasma protein is an approximately 67 kDa sized water-soluble macromolecule. Since several drugs and xenobiotics circulate in the blood at least partially in albumin-bound form, albumin plays a key role in the pharmacokinetics/toxicokinetics of these chemicals. Most of the drugs and xenobiotics are Sudlow's site I ligands. In numerous studies, bovine serum albumin (BSA) is used for modeling albumin–ligand interactions and the results are extrapolated to human serum albumin (HSA). Furthermore, only limited information is available related to albumin–ligand interactions of different albumin species. Therefore, in our study, we have focused on the quantification of differences between bovine, human and rat serum albumin (RSA) using four Sudlow's site I ligands (luteolin, ochratoxin A, phenylbutazone and warfarin). Interactions were analyzed by fluorescence spectroscopy. Stability constants as well as competing capacities of the ligands were determined, and thermodynamic study was also performed. Our results highlight that there could be major differences between BSA, HSA and RSA in their ligand binding properties. Based on our observations we emphasize that in molecular aspects BSA behaves considerably differently from HSA or from albumins of other species therefore, it is strongly recommended to apply at least some confirmatory measurements when data obtained from other species are attempted to be extrapolated to HSA. -- Highlights: • Albumin–ligand interactions of human, bovine and rat albumins were studied. • Four Sudlow's site I ligands were tested by fluorescence spectroscopy. • Substantial differences were found in stability constants among albumin complexes. • Competing capacity of ligands showed major differences in the studied species. • Data obtained for BSA cannot be directly extrapolated to human albumin

  14. A General Ligand Design for Gold Catalysis allowing Ligand-Directed Anti Nucleophilic Attack of Alkynes

    Science.gov (United States)

    Wang, Yanzhao; Wang, Zhixun; Li, Yuxue; Wu, Gongde; Cao, Zheng; Zhang, Liming

    2014-01-01

    Most homogenous gold catalyses demand ≥0.5 mol % catalyst loading. Due to the high cost of gold, these reactions are unlikely to be applicable in medium or large scale applications. Here we disclose a novel ligand design based on the privileged biphenyl-2-phosphine framework that offers a potentially general approach to dramatically lowering catalyst loading. In this design, an amide group at the 3’ position of the ligand framework directs and promotes nucleophilic attack at the ligand gold complex-activated alkyne, which is unprecedented in homogeneous gold catalysis considering the spatial challenge of using ligand to reach antiapproaching nucleophile in a linear P-Au-alkyne centroid structure. With such a ligand, the gold(I) complex becomes highly efficient in catalyzing acid addition to alkynes, with a turnover number up to 99,000. Density functional theory calculations support the role of the amide moiety in directing the attack of carboxylic acid via hydrogen bonding. PMID:24704803

  15. Secondary ligand-directed assembly of Co(II) coordination polymers based on a pyridine carboxylate ligand

    International Nuclear Information System (INIS)

    Cao, Ke-Li; Zhang, Yi-Ping; Cai, Yi-Ni; Xu, Xiao-Wei; Feng, Yun-Long

    2014-01-01

    To investigate the influence of hydrogen bonds and secondary ligands on the structures and properties of the resulting frameworks, five new Co(II) compounds have been synthesized by the reactions of Co(II) salts and 3,5-bis(pyridin-4-ylmethoxy)benzoic acid (HL) with four rationally selected dicarboxylic acid ligands. Without secondary ligand, we got one compound [CoL 2 (H 2 O) 2 ] n ·2nH 2 O (1), which possesses a 1D chain structure. In the presence of ancillary ligands, namely, 1,3-adamantanedicarboxylic acid (H 2 adbc), terephthalic acid (H 2 tpa), thiophene-2,5-dicarboxylic acid (H 2 tdc) and 1,4-benzenedithioacetic acid (H 2 bdtc), four 3D structures [Co 2 L 2 (adbc)] n ·nH 2 O (2), [Co 2 L 2 (tpa)] n (3), [Co 2 L 2 (tdc)] n (4), [Co 2 L 2 (bdtc)(H 2 O)] n (5) were obtained, respectively. It can be observed from the architectures of 1–5 that hydrogen bonds and secondary ligands both have great effects on the spatial connective fashions, resulting in the formation of various dimensional compounds. The XRPD, TGA data of title polymers and the magnetic properties for 2 and 5 have also been investigated. - Graphical abstract: The structural differences show that the ancillary ligands have great effects on the spatial connective fashions, resulting in the formation of various dimensional compounds. - Highlights: • Five new Co(II) coordination polymers have been synthesized by solvothermal reactions based on 3,5-bis(pyridin-4-ylmethoxy)benzoic acid (HL). • The long-flexible ligand (HL) is a good candidate to produce interpenetrating architectures. • The secondary dicarboxylic acid ligands play important roles in the spatial connective fashions and the formation of various dimensional compounds. • The magnetism studies show that both 2 and 5 exhibit antiferromagnetic interactions

  16. Relation of circulating concentrations of chemokine receptor CCR5 ligands to C-peptide, proinsulin and HbA1c and disease progression in type 1 diabetes

    DEFF Research Database (Denmark)

    Pfleger, C; Kaas, A; Hansen, L

    2008-01-01

    Th1 related chemokines CCL3 and CCL5 and Th2 related CCL4 as ligands of the receptor CCR5 contribute to disease development in animal models of type 1 diabetes. In humans, no data are available addressing the role of these chemokines regarding disease progression and remission. We investigated lo...

  17. Calculation of relative free energies for ligand-protein binding, solvation, and conformational transitions using the GROMOS software.

    Science.gov (United States)

    Riniker, Sereina; Christ, Clara D; Hansen, Halvor S; Hünenberger, Philippe H; Oostenbrink, Chris; Steiner, Denise; van Gunsteren, Wilfred F

    2011-11-24

    The calculation of the relative free energies of ligand-protein binding, of solvation for different compounds, and of different conformational states of a polypeptide is of considerable interest in the design or selection of potential enzyme inhibitors. Since such processes in aqueous solution generally comprise energetic and entropic contributions from many molecular configurations, adequate sampling of the relevant parts of configurational space is required and can be achieved through molecular dynamics simulations. Various techniques to obtain converged ensemble averages and their implementation in the GROMOS software for biomolecular simulation are discussed, and examples of their application to biomolecules in aqueous solution are given. © 2011 American Chemical Society

  18. Specific ability of sulfur-ligands on removal of 203Hg-labeled organomercury from hemoglobin in comparison with nitrogen-ligands

    International Nuclear Information System (INIS)

    Hojo, Yasuji; Sugiura, Yukio; Tanaka, Hisashi

    1975-01-01

    Removal of 203 Hg-labeled organomercurials, bound to sulfhydryl groups of hemoglobin, by various chelating agents was investigated by the use of equilibrium dialysis. Organomercurials employed were chlormerodrin, methylmercury, ethylmercury and phenylmercury compounds. Higher and more specific effects of the sulfur-ligands, such as penicillamine and glutathione, on removal of organomercurial were found as compared with those of the nitrogen-ligands such as EDTA, glycine and polymethylenediamines. Linear correlation was observed between the degree of organomercury elimination from hemoglobin and the stability constant (log K 1 ) of 1:1 organomercury complex in both the sulfur- and nitrogen-ligand systems and at the same value of log K 1 , the elimination-effect of sulfur-ligands was extremely greater than that of the nitrogen-ligands. The relationship between the average percentage of removal and the Taft's polar substituent constant of organic moiety of the metal was also linear among the organomercury compounds other than chlormerodrin. The average removal percentage by sulfur-ligands increased in the order, ethylmercury>methylmercury>phenylmercury, while that of the nitrogen-ligands was not different among the organomercurials investigated. In addition, direct ligand-exchange reaction between hemoglobin-SH and the ligand coordinating-atom (S or N) against organomercurials rather than Ssub(N2) reaction via the ternary complex, hemoglobin-S-RHg-ligand, is postulated. (auth.)

  19. Progress on the application of ligand receptor binding assays in radiopharmaceuticals

    International Nuclear Information System (INIS)

    Zhou Xue; Qian Jinping; Kong Aiying; Zhu Lin

    2010-01-01

    Receptor binding assay is an important drug screening method, which can quickly and inexpensively study the interactions between the targeted receptor and the potential ligands in vitro and provide the information of the relative binding affinity of ligand-receptor. The imaging of many radiopharmaceuticals is based on highly selective radioligand-receptor binding. The technique plays an important role in the design and screening of receptor-targeting radiopharmaceuticals. (authors)

  20. Mechanistic Insights into Solvent and Ligand Dependency in Cu(I)-Catalyzed Allylic Alkylation with gem-Diborylalkanes.

    Science.gov (United States)

    Zhang, Qi; Wang, Bing; Liu, Jia-Qin; Fu, Yao; Wu, Yu-Cheng

    2018-01-19

    The recent Cu-catalyzed allylic substitution reaction between gem-diboryalkane and allyl electrophiles shows intriguing solvent and ligand-controlled regioselectivity. The α-alkylation product was obtained in DMF solvent, while γ-alkylation product was obtained in dioxane solvent and the dioxane and NHC ligand situation. In the present study, density functional theory calculations have been used to investigate the reaction mechanism and origin of the regioselectivity. For both dioxane and DMF, γ-alkylation undergoes successive oxidative addition (CH 2 Bpin trans to leaving group) and direct Cγ-C reductive elimination. The α-alkylation is found to undergo oxidative addition (CH 2 Bpin trans to leaving group), isomerization, and Cα-C reductive elimination rather than the previously proposed oxidative addition (-CH 2 Bpin cis to the leaving group) and Cα-C reductive elimination. The γ-alkylation and α-alkylation is, respectively, favorable for dioxane and DMF solvent, which is consistent with the γ- and α-selectivity in experiment. The solvent interferes the isomerization step, thereby affects the relative facility of the α- and γ-alkylation. Further investigation shows that η 1 -intermediate formation promoted by solvent is the rate-determining step of the isomerization. The stronger electron-donating ability of DMF than dioxane facilitates the η 1 -intermediate formation and finally results in the easier isomerization in DMF. For dioxane and NHC situation, in the presence of neutral NHC ligand, the -PO 4 Et 2 group tightly coordinates with the Cu center after the oxidative addition, preventing the isomerization process. The regioselectivity is determined by the relative facility of the oxidative addition step. Therefore, the favorable oxidative addition (in which -CH 2 Bpin trans to the leaving group) results in the facility of γ-alkylation.

  1. Probing Ligand Exchange in the P450 Enzyme CYP121 from Mycobacterium tuberculosis: Dynamic Equilibrium of the Distal Heme Ligand as a Function of pH and Temperature.

    Science.gov (United States)

    Fielding, Andrew J; Dornevil, Kednerlin; Ma, Li; Davis, Ian; Liu, Aimin

    2017-12-06

    CYP121 is a cytochrome P450 enzyme from Mycobacterium tuberculosis that catalyzes the formation of a C-C bond between the aromatic groups of its cyclodityrosine substrate (cYY). The crystal structure of CYP121 in complex with cYY reveals that the solvent-derived ligand remains bound to the ferric ion in the enzyme-substrate complex. Whereas in the generally accepted P450 mechanism, binding of the primary substrate in the active-site triggers the release of the solvent-derived ligand, priming the metal center for reduction and subsequent O 2 binding. Here we employed sodium cyanide to probe the metal-ligand exchange of the enzyme and the enzyme-substrate complex. The cyano adducts were characterized by UV-vis, EPR, and ENDOR spectroscopies and X-ray crystallography. A 100-fold increase in the affinity of cyanide binding to the enzyme-substrate complex over the ligand-free enzyme was observed. The crystal structure of the [CYP121(cYY)CN] ternary complex showed a rearrangement of the substrate in the active-site, when compared to the structure of the binary [CYP121(cYY)] complex. Transient kinetic studies showed that cYY binding resulted in a lower second-order rate constant (k on (CN) ) but a much more stable cyanide adduct with 3 orders of magnitude slower k off (CN) rate. A dynamic equilibrium between multiple high- and low-spin species for both the enzyme and enzyme-substrate complex was also observed, which is sensitive to changes in both pH and temperature. Our data reveal the chemical and physical properties of the solvent-derived ligand of the enzyme, which will help to understand the initial steps of the catalytic mechanism.

  2. Identification of putative agouti-related protein(87-132)-melanocortin-4 receptor interactions by homology molecular modeling and validation using chimeric peptide ligands.

    Science.gov (United States)

    Wilczynski, Andrzej; Wang, Xiang S; Joseph, Christine G; Xiang, Zhimin; Bauzo, Rayna M; Scott, Joseph W; Sorensen, Nicholas B; Shaw, Amanda M; Millard, William J; Richards, Nigel G; Haskell-Luevano, Carrie

    2004-04-22

    Agouti-related protein (AGRP) is one of only two naturally known antagonists of G-protein-coupled receptors (GPCRs) identified to date. Specifically, AGRP antagonizes the brain melanocortin-3 and -4 receptors involved in energy homeostasis. Alpha-melanocyte stimulating hormone (alpha-MSH) is one of the known endogenous agonists for these melanocortin receptors. Insight into putative interactions between the antagonist AGRP amino acids with the melanocortin-4 receptor (MC4R) may be important for the design of unique ligands for the treatment of obesity related diseases and is currently lacking in the literature. A three-dimensional homology molecular model of the mouse MC4 receptor complex with the hAGRP(87-132) ligand docked into the receptor has been developed to identify putative antagonist ligand-receptor interactions. Key putative AGRP-MC4R interactions include the Arg111 of hAGRP(87-132) interacting in a negatively charged pocket located in a cavity formed by transmembrane spanning (TM) helices 1, 2, 3, and 7, capped by the acidic first extracellular loop (EL1) and specifically with the conserved melanocortin receptor residues mMC4R Glu92 (TM2), mMC4R Asp114 (TM3), and mMC4R Asp118 (TM3). Additionally, Phe112 and Phe113 of hAGRP(87-132) putatively interact with an aromatic hydrophobic pocket formed by the mMC4 receptor residues Phe176 (TM4), Phe193 (TM5), Phe253 (TM6), and Phe254 (TM6). To validate the AGRP-mMC4R model complex presented herein from a ligand perspective, we generated nine chimeric peptide ligands based on a modified antagonist template of the hAGRP(109-118) (Tyr-c[Asp-Arg-Phe-Phe-Asn-Ala-Phe-Dpr]-Tyr-NH(2)). In these chimeric ligands, the antagonist AGRP Arg-Phe-Phe residues were replaced by the melanocortin agonist His/D-Phe-Arg-Trp amino acids. These peptides resulted in agonist activity at the mouse melanocortin receptors (mMC1R and mMC3-5Rs). The most notable results include the identification of a novel subnanomolar melanocortin peptide

  3. Emerging role of chemokine CC motif ligand 4 related mechanisms in diabetes mellitus and cardiovascular disease: friends or foes?

    Science.gov (United States)

    Chang, Ting-Ting; Chen, Jaw-Wen

    2016-08-24

    Chemokines are critical components in pathology. The roles of chemokine CC motif ligand 4 (CCL4) and its receptor are associated with diabetes mellitus (DM) and atherosclerosis cardiovascular diseases. However, due to the complexity of these diseases, the specific effects of CCL4 remain unclear, although recent reports have suggested that multiple pathways are related to CCL4. In this review, we provide an overview of the role and potential mechanisms of CCL4 and one of its major receptors, fifth CC chemokine receptor (CCR5), in DM and cardiovascular diseases. CCL4-related mechanisms, including CCL4 and CCR5, might provide potential therapeutic targets in DM and/or atherosclerosis cardiovascular diseases.

  4. Room-temperature synthesis of pure perovskite-related Cs4PbBr6 nanocrystals and their ligand-mediated evolution into highly luminescent CsPbBr3 nanosheets

    Science.gov (United States)

    Yang, Liu; Li, Dongmei; Wang, Cong; Yao, Wei; Wang, Hao; Huang, Kaixiang

    2017-07-01

    Currently, all-inorganic cesium lead-halide perovskite nanocrystals have attracted enormous attentions owing to their excellent optical performances. While great efforts have been devoted to CsPbBr3 nanocrystals, the perovskite-related Cs4PbBr6 nanocrystals, which were newly reported, still remained poorly understood. Here, we reported a novel room-temperature reaction strategy to synthesize pure perovskite-related Cs4PbBr6 nanocrystals. Size of the products could be adjusted through altering the amount of ligands, simply. A mixture of two good solvents with different polarity was innovatively used as precursor solvent, being one key to the high-yield Cs4PbBr6 nanocrystals synthesis. Other two keys were Cs+ precursor concentration and surface ligands. Ingenious experiments were designed to reveal the underlying reaction mechanism. No excitonic emission was observed from the prepared Cs4PbBr6 nanocrystals in our work. We considered the green emission which was observed in other reports originated from the avoidless transformation of Cs4PbBr6 into CsPbBr3 nanocrystals. Indeed, the new-prepared Cs4PbBr6 nanocrystals could transform into CsPbBr3 nanosheets with surface ligands mediated. The new-transformed two-dimensional CsPbBr3 nanosheets could evolve into large-size nanosheets. The influences of surface ligand density on the fluorescent intensity and stability of transformed CsPbBr3 nanosheets were also explained. Notably, the photoluminescence quantum yield of the as-transformed CsPbBr3 nanosheets could reach as high as 61.6% in the form of thin film. The fast large-scale synthesis of Cs4PbBr6 nanocrystals and their ligand-mediated transformation into high-fluorescent CsPbBr3 nanosheets will be beneficial to the future optoelectronic applications. Our work provides new approaches to understand the structural evolution and light-emitting principle of perovskite nanocrystals. [Figure not available: see fulltext.

  5. Solid-state thermolysis of a fac-rhenium(I) carbonyl complex with a redox non-innocent pincer ligand.

    Science.gov (United States)

    Jurca, Titel; Chen, Wen-Ching; Michel, Sheila; Korobkov, Ilia; Ong, Tiow-Gan; Richeson, Darrin S

    2013-03-25

    The development of rhenium(I) chemistry has been restricted by the limited structural and electronic variability of the common pseudo-octahedral products fac-[ReX(CO)3L2] (L2 = α-diimine). We address this constraint by first preparing the bidentate bis(imino)pyridine complexes [(2,6-{2,6-Me2C6H3N=CPh}2C5H3N)Re(CO)3X] (X = Cl 2, Br 3), which were characterized by spectroscopic and X-ray crystallographic means, and then converting these species into tridentate pincer ligand compounds, [(2,6-{2,6-Me2C6H3N=CPh}2C5H3N)Re(CO)2X] (X = Cl 4, Br 5). This transformation was performed in the solid-state by controlled heating of 2 or 3 above 200 °C in a tube furnace under a flow of nitrogen gas, giving excellent yields (≥95 %). Compounds 4 and 5 define a new coordination environment for rhenium(I) carbonyl chemistry where the metal center is supported by a planar, tridentate pincer-coordinated bis(imino)pyridine ligand. The basic photophysical features of these compounds show significant elaboration in both number and intensity of the d-π* transitions observed in the UV/Vis spec tra relative to the bidentate starting materials, and these spectra were analyzed using time-dependent DFT computations. The redox nature of the bis(imino)pyridine ligand in compounds 2 and 4 was examined by electrochemical analysis, which showed two ligand reduction events and demonstrated that the ligand reduction shifts to a more positive potential when going from bidentate 2 to tridentate 4 (+160 mV for the first reduction step and +90 mV for the second). These observations indicate an increase in electrostatic stabilization of the reduced ligand in the tridentate conformation. Elaboration on this synthetic methodology documented its generality through the preparation of the pseudo-octahedral rhenium(I) triflate complex [(2,6-{2,6-Me2C6H3N=CPh}2C5H3N)Re(CO)2OTf] (7, 93 % yield). Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. Reactivity of halide and pseudohalide ligands

    International Nuclear Information System (INIS)

    Kukushkin, Yu.N.

    1987-01-01

    Reactivity of halide and pseudohalide (cyanide, azide, thiocyanate, cyanate) ligands tending to form bridge bonds in transition metal (Re, Mo, W) complexes is considered. Complexes where transition metal salts are ligands of other, complex-forming ion, are described. Transformation of innerspheric pseudohalide ligands is an important way of directed synthesis of these metal coordination compounds

  7. Chiral ligand-protected gold nanoclusters: Considering the optical activity from a viewpoint of ligand dissymmetric field

    Directory of Open Access Journals (Sweden)

    Hiroshi Yao

    2016-10-01

    Full Text Available Chirality is a geometric property of a physical, chemical, or biological object, which is not superimposable on its mirror image. Its significant presence has led to a strong demand in the development of chiral drugs, sensors, catalysts, and photofunctional materials. In recent years, chirality of nanoscale organic/inorganic hybrids has received tremendous attention owing to potential applications in chiral nanotechnology. In particular, with the recent progress in the syntheses and characterizations of atomically precise gold nanoclusters protected by achiral thiolates, atomic level origins of their chirality have been unveiled. On the other hand, chirality or optical activity in metal nanoclusters can also be introduced via the surface chiral ligands, which should be universal for the nanosystems. This tutorial review presents some optically-active metal (gold nanoclusters protected by chiral thiolates or phosphines, and their chiroptical (or circular dichroism; CD properties are discussed mostly from a viewpoint of the ligand dissymmetric field scheme. The examples are the gold nanoclusters protected by (R-/(S-2-phenylpropane-1-thiol, (R-/(S-mercaptosuccinic acid, phenylboronate-D/L-fructose complexes, phosphine sulfonate-ephedrinium ion pairs, or glutathione. Some methodologies for versatile asymmetric transformation and chiroptical controls of the nanocluster compounds are also described. In the dissymmetric field model as the origin of optical activity, the chiroptical responses of the gold nanoclusters are strongly associated with coupled oscillator and/or CD stealing mechanisms based on the concept of induced CD (ICD derived from a perturbation theory, so on this basis, some characteristic features of the observed CD responses of chiral ligand-protected gold nanoclusters are presented in detail. We believe that various kinds of origins of chirality found in ligand-protected gold nanoclusters may provide models for understanding those of

  8. Metal-ligand cooperative activation of nitriles by a ruthenium complex with a de-aromatized PNN pincer ligand

    NARCIS (Netherlands)

    Eijsink, Linda E; Perdriau, Sébastien C P; de Vries, Johannes G; Otten, Edwin

    2016-01-01

    The pincer complex (PNN)RuH(CO), with a de-aromatized pyridine in the ligand backbone, is shown to react with nitriles in a metal-ligand cooperative manner. This leads to the formation of a series of complexes with new Ru-N(nitrile) and C(ligand)-C(nitrile) bonds. The initial nitrile cycloaddition

  9. Synthesis, structures, and dearomatization by deprotonation of iron complexes featuring bipyridine-based PNN pincer ligands.

    Science.gov (United States)

    Zell, Thomas; Langer, Robert; Iron, Mark A; Konstantinovski, Leonid; Shimon, Linda J W; Diskin-Posner, Yael; Leitus, Gregory; Balaraman, Ekambaram; Ben-David, Yehoshoa; Milstein, David

    2013-08-19

    The synthesis and characterization of new iron pincer complexes bearing bipyridine-based PNN ligands is reported. Three phosphine-substituted pincer ligands, namely, the known (t)Bu-PNN (6-((di-tert-butylphosphino)methyl)-2,2'-bipyridine) and the two new (i)Pr-PNN (6-((di-iso-propylphosphino)methyl)-2,2'-bipyridine) and Ph-PNN (6-((diphenylphosphino)methyl)-2,2'-bipyridine) ligands were synthesized and studied in ligation reactions with iron(II) chloride and bromide. These reactions lead to the formation of two types of complexes: mono-chelated neutral complexes of the type [(R-PNN)Fe(X)2] and bis-chelated dicationic complexes of the type [(R-PNN)2Fe](2+). The complexes [(R-PNN)Fe(X)2] (1: R = (t)Bu, X = Cl, 2: R = (t)Bu, X = Br, 3: R = (i)Pr, X = Cl, and 4: R = (i)Pr, X = Br) are readily prepared from reactions of FeX2 with the free R-PNN ligand in a 1:1 ratio. Magnetic susceptibility measurements show that these complexes have a high-spin ground state (S = 2) at room temperature. Employing a 2-fold or higher excess of (i)Pr-PNN, diamagnetic hexacoordinated dicationic complexes of the type [((i)Pr-PNN)2Fe](X)2 (5: X = Cl, and 6: X = Br) are formed. The reactions of Ph-PNN with FeX2 in a 1:1 ratio lead to similar complexes of the type [(Ph-PNN)2Fe](FeX4) (7: X = Cl, and 8: X = Br). Single crystal X-ray studies of 1, 2, 4, 6, and 8 do not indicate electron transfer from the Fe(II) centers to the neutral bipyridine unit based on the determined bond lengths. Density functional theory (DFT) calculations were performed to compare the relative energies of the mono- and bis-chelated complexes. The doubly deprotonated complexes [(R-PNN*)2Fe] (9: R = (i)Pr, and 10: R = Ph) were synthesized by reactions of the dicationic complexes 6 and 8 with KO(t)Bu. The dearomatized nature of the central pyridine of the pincer ligand was established by X-ray diffraction analysis of single crystals of 10. Reactivity studies show that 9 and 10 have a slightly different behavior in

  10. Metal-Ligand Cooperative Reactivity in the (pseudo)-Dearomatized PNX(P) Systems: the Influence of the Zwitterionic Form in Dearomatized Pincer Complexes

    KAUST Repository

    Goncalves, Theo

    2017-09-01

    The concept of aromaticity in pincer ligands and complexes was discussed in order to provide insights into their metal-ligand cooperative activities. The aromatic PNx(P) and dearomatized PNx(P)* pincer ligands and the corresponding transition metal complexes were studied with the nucleus-independent chemical shift (NICSzz), anisotropy of the current (induced) density (ACID), isochemical shielding surfaces (ICSSzz), harmonic oscillator model of aromaticity (HOMA), MCBO, Shannon aromaticity, and natural bond order (NBO) analyses. The study on the model systems showed that for the dearomatized species the decrease of the NICS(1)zz value comes with the larger contribution of the aromatic zwitterionic mesomeric form. In all examples, the incorporation of the metal center into the pincer ligand decreases the NICS(1)zz values. The DFT calculations support the dearomatized pyridine ring in PNP* or PNN* ligand indeed being nonaromatic, in contrast to the PN3(P)* ligand which has partial aromatic character due to the larger contribution of the zwitterionic resonance structure. The difference in aromaticity between the rings contributes to the thermodynamic balance of the metal ligand cooperative reactions, changing the energetics of the process when different dearomatized pincer ligands are used. This was further exemplified by aromaticity analysis of the heterolytic hydrogen cleavage reaction of ruthenium PNN complexes of Milstein and the PN3 of Huang, with similar geometries but distinctive thermodynamic preference.

  11. Metal-Ligand Cooperative Reactivity in the (pseudo)-Dearomatized PNX(P) Systems: the Influence of the Zwitterionic Form in Dearomatized Pincer Complexes

    KAUST Repository

    Goncalves, Theo; Huang, Kuo-Wei

    2017-01-01

    The concept of aromaticity in pincer ligands and complexes was discussed in order to provide insights into their metal-ligand cooperative activities. The aromatic PNx(P) and dearomatized PNx(P)* pincer ligands and the corresponding transition metal complexes were studied with the nucleus-independent chemical shift (NICSzz), anisotropy of the current (induced) density (ACID), isochemical shielding surfaces (ICSSzz), harmonic oscillator model of aromaticity (HOMA), MCBO, Shannon aromaticity, and natural bond order (NBO) analyses. The study on the model systems showed that for the dearomatized species the decrease of the NICS(1)zz value comes with the larger contribution of the aromatic zwitterionic mesomeric form. In all examples, the incorporation of the metal center into the pincer ligand decreases the NICS(1)zz values. The DFT calculations support the dearomatized pyridine ring in PNP* or PNN* ligand indeed being nonaromatic, in contrast to the PN3(P)* ligand which has partial aromatic character due to the larger contribution of the zwitterionic resonance structure. The difference in aromaticity between the rings contributes to the thermodynamic balance of the metal ligand cooperative reactions, changing the energetics of the process when different dearomatized pincer ligands are used. This was further exemplified by aromaticity analysis of the heterolytic hydrogen cleavage reaction of ruthenium PNN complexes of Milstein and the PN3 of Huang, with similar geometries but distinctive thermodynamic preference.

  12. Andrographolide induces apoptotic and non-apoptotic death and enhances tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in gastric cancer cells

    OpenAIRE

    Lim, Sung-Chul; Jeon, Ho Jong; Kee, Keun Hong; Lee, Mi Ja; Hong, Ran; Han, Song Iy

    2017-01-01

    Andrographolide, a natural compound isolated from Andrographis paniculata, has been reported to possess antitumor activity. In the present study, the effect of andrographolide in human gastric cancer (GC) cells was investigated. Andrographolide induced cell death with apoptotic and non-apoptotic features. At a low concentration, andrographolide potentiated apoptosis and reduction of clonogenicity triggered by recombinant human tumor necrosis factor-related apoptosis-inducing ligand (rhTRAIL)....

  13. XAFS Study of the Ferro- and Antiferromagnetic Binuclear Copper(II) Complexes of Azomethine Based Tridentate Ligands

    International Nuclear Information System (INIS)

    Vlasenko, Valery G.; Vasilchenko, Igor S.; Shestakova, Tatiana E.; Uraev, Ali I.; Burlov, Anatolii S.; Garnovskii, Alexander D.; Pirog, Irina V.

    2007-01-01

    Binuclear copper complexes are known to be models for metalloenzymes containing copper active sites, and some of them are of considerable interest due to their magnetic and charge transfer properties. The reactions of the complex formation of bibasic tridentate heterocyclic imines with copper acetate leads to two types of chelates with mono deprotonated ligands and with totally deprotonated ligands. Cu K-edge EXAFS has been applied to determine the local structure around the metal center in copper(II) azomethine complexes with five tridentate ligands: 1-(salycilideneimino)- or 1-(2-tosylaminobenzilideneimino)-2-amino(oxo, thio)benzimidazoles. It has been found that some of the chelates studied are bridged binuclear copper complexes, and others are mononuclear complexes. The copper-copper interatomic distances in the bridged binuclear copper complexes were found to be 2.85-3.01 A. Variable temperature magnetic susceptibility data indicate the presence of both ferromagnetic and antiferromagnetic interactions within the dimer, the former is dominating at low temperatures and the latter at high temperatures

  14. Autocrine signal transmission with extracellular ligand degradation

    Science.gov (United States)

    Muratov, C B; Posta, F; Shvartsman, S Y

    2009-03-01

    Traveling waves of cell signaling in epithelial layers orchestrate a number of important processes in developing and adult tissues. These waves can be mediated by positive feedback autocrine loops, a mode of cell signaling where binding of a diffusible extracellular ligand to a cell surface receptor can lead to further ligand release. We formulate and analyze a biophysical model that accounts for ligand-induced ligand release, extracellular ligand diffusion and ligand-receptor interaction. We focus on the case when the main mode for ligand degradation is extracellular and analyze the problem with the sharp threshold positive feedback nonlinearity. We derive expressions that link the speed of propagation and other characteristics of traveling waves to the parameters of the biophysical processes, such as diffusion rates, receptor expression level, etc. Analyzing the derived expressions we found that traveling waves in such systems can exhibit a number of unusual properties, e.g. non-monotonic dependence of the speed of propagation on ligand diffusivity. Our results for the fully developed traveling fronts can be used to analyze wave initiation from localized perturbations, a scenario that frequently arises in the in vitro models of epithelial wound healing, and guide future modeling studies of cell communication in epithelial layers.

  15. Cell-specific targeting by heterobivalent ligands.

    Science.gov (United States)

    Josan, Jatinder S; Handl, Heather L; Sankaranarayanan, Rajesh; Xu, Liping; Lynch, Ronald M; Vagner, Josef; Mash, Eugene A; Hruby, Victor J; Gillies, Robert J

    2011-07-20

    Current cancer therapies exploit either differential metabolism or targeting to specific individual gene products that are overexpressed in aberrant cells. The work described herein proposes an alternative approach--to specifically target combinations of cell-surface receptors using heteromultivalent ligands ("receptor combination approach"). As a proof-of-concept that functionally unrelated receptors can be noncovalently cross-linked with high avidity and specificity, a series of heterobivalent ligands (htBVLs) were constructed from analogues of the melanocortin peptide ligand ([Nle(4), dPhe(7)]-α-MSH) and the cholecystokinin peptide ligand (CCK-8). Binding of these ligands to cells expressing the human Melanocortin-4 receptor and the Cholecystokinin-2 receptor was analyzed. The MSH(7) and CCK(6) were tethered with linkers of varying rigidity and length, constructed from natural and/or synthetic building blocks. Modeling data suggest that a linker length of 20-50 Å is needed to simultaneously bind these two different G-protein coupled receptors (GPCRs). These ligands exhibited up to 24-fold enhancement in binding affinity to cells that expressed both (bivalent binding), compared to cells with only one (monovalent binding) of the cognate receptors. The htBVLs had up to 50-fold higher affinity than that of a monomeric CCK ligand, i.e., Ac-CCK(6)-NH(2). Cell-surface targeting of these two cell types with labeled heteromultivalent ligand demonstrated high avidity and specificity, thereby validating the receptor combination approach. This ability to noncovalently cross-link heterologous receptors and target individual cells using a receptor combination approach opens up new possibilities for specific cell targeting in vivo for therapy or imaging.

  16. Synthesis and Crystal Structures of Ni(II)/(III) and Zn(II) Complexes with Schiff Base Ligands

    International Nuclear Information System (INIS)

    Koo, Bon Kweon

    2013-01-01

    Coordination polymers are of great interest due to their intriguing structural motifs and potential applications in optical, electronic, magnetic, and porous materials. The most commonly used strategy for designing such materials relies on the utilization of multidentate N- or Odonor ligands which have the capacity to bridge between metal centers to form polymeric structures. The Schiff bases with N,O,S donor atoms are an useful source as they are readily available and easily form stable complexes with most transition metal ions. Schiff bases are also important intermediates in synthesis of some bioactive compounds and are potent anti-bacterial, anti-fungal, anticancer and antiviral compounds. In this work, the Schiff bases, Hapb and Hbpb, derived from 2-acetylpyridene or 2-benzoylpyridine and benzhydrazide were taken as trifunctional (N,N,O) monobasic ligand (Scheme 1). This ligand is of important because the π-delocalization of charge and the configurational flexibility of their molecular chain can give rise to a great variety of coordination modes. Although many metal.Schiff base complexes have been reported, the 1D, 2D, and 3D networks of coordination polymers linked through the bridging of ligands such as dicyanamide, N(CN) 2 - as coligand have been little published. In the process of working to extend the dimensionality of the metal-Schiff base complexes using benzilic acid as a bridging ligand, we obtained three simple metal (II)/(III) complexes of acetylpyridine/2-benzoyl pyridine based benzhydrazide ligand. Therefore, we report here the synthesis and crystal structures of the complexes

  17. What a difference a 5f element makes: trivalent and tetravalent uranium halide complexes supported by one and two bis[2-(diisopropylphosphino)-4-methylphenyl]amido (PNP) ligands.

    Science.gov (United States)

    Cantat, Thibault; Scott, Brian L; Morris, David E; Kiplinger, Jaqueline L

    2009-03-02

    The coordination behavior of the bis[2-(diisopropylphosphino)-4-methylphenyl]amido ligand (PNP) toward UI3(THF)4 and UCl4 has been investigated to access new uranium(III) and uranium(IV) halide complexes supported by one and two PNP ligands. The reaction between (PNP)K (6) and 1 equiv of UI3(THF)4 afforded the trivalent halide complex (PNP)UI2(4-tBu-pyridine)2 (7) in the presence of 4-tert-butylpyridine. The same reaction carried out with UCl4 and no donor ligand gave [(PNP)UCl3]2 (8), in which the uranium coordination sphere in the (PNP)UCl3 unit is completed by a bridging chloride ligand. When UCl4 is reacted with 1 equiv (PNP)K (6) in the presence of THF, trimethylphosphine oxide (TMPO), or triphenylphosphineoxide (TPPO), the tetravalent halide complexes (PNP)UCl3(THF) (9), (PNP)UCl3(TMPO)2 (10), and (PNP)UCl3(TPPO) (11), respectively, are formed in excellent yields. The bis(PNP) complexes of uranium(III), (PNP)2UI (12), and uranium(IV), (PNP)2UCl2 (13), were easily isolated from the analogous reactions between 2 equiv of 6 and UI3(THF)4 or UCl4, respectively. Complexes 12 and 13 represent the first examples of complexes featuring two PNP ligands coordinated to a single metal center. Complexes 7-13 have been characterized by single-crystal X-ray diffraction and 1H and 31P NMR spectroscopy. The X-ray structures demonstrate the ability of the PNP ligand to adopt new coordination modes upon coordination to uranium. The PNP ligand can adopt both pseudo-meridional and pseudo-facial geometries when it is kappa3-(P,N,P) coordinated, depending on the steric demand at the uranium metal center. Additionally, its hemilabile character was demonstrated with an unusual kappa2-(P,N) coordination mode that is maintained in both the solid-state and in solution. Comparison of the structures of the mono(PNP) and bis(PNP) complexes 7, 9, 11-13 with their respective C5Me5 analogues 1-4 undoubtedly show that a more sterically congested environment is provided by the PNP ligand. The

  18. Satisfaction and Related Factors among the Service Users of Private Rehabilitation Centers

    Directory of Open Access Journals (Sweden)

    Shahrzad Pakjouei

    2014-12-01

    Full Text Available Objectives: The aim of present study was determining the level of satisfaction and its relative factors among parents of mentally retarded children using the services of private rehabilitation centers. Methods: This was a descriptive-analytical study that was conducted on parents of 150 mentally retarded children, who were selected by quota sampling from eight private rehabilitation centers in Tehran. Questionnaires were used to collect data, and correlation tests, independent t-test, and one-way analysis of variance were utilized to analyze data. Results: Upon the results, overall 88% of participants expressed their satisfaction. The major related factors were the behavior of managers and employees, receiving training for follow-up rehabilitation and education programs for the child at home, and the child's progress. The factors related to dissatisfaction included nutrition services, physical condition of the center and lack of parental participation in decision- making on matters related to the child. A significant relationship was found between parental satisfaction and family size, father's job, and the number of other disabled people in the family. Discussion: According to the findings, it seems that patient satisfaction is also affected by the behavioral aspects of care, in addition to the technical aspects. Considering the humans’ need for respect and compassion and the sense of being valuable, this finding could be anticipated. The managers of private rehabilitation centers, for attracting and retain clients, need to pay attention to the factors which have impact on service users’ satisfaction.

  19. Acetylcholinesterase complexed with bivalent ligands related to huperzine a: experimental evidence for species-dependent protein-ligand complementarity.

    Science.gov (United States)

    Wong, Dawn M; Greenblatt, Harry M; Dvir, Hay; Carlier, Paul R; Han, Yi-Fan; Pang, Yuan-Ping; Silman, Israel; Sussman, Joel L

    2003-01-15

    active-site gorge explain the switch in inhibitory potency of (-)-2a and 2b and the larger dimer/(-)-HupA potency ratios observed for TcAChE relative to rat AChE. The results offer new insights into factors affecting protein-ligand complementarity within the gorge and should assist the further development of improved AChE inhibitors.

  20. Role of ligands in permanganate oxidation of organics.

    Science.gov (United States)

    Jiang, Jin; Pang, Su-Yan; Ma, Jun

    2010-06-01

    We previously demonstrated that several ligands such as phosphate, pyrophosphate, EDTA, and humic acid could significantly enhance permanganate oxidation of triclosan (one phenolic biocide), which was explained by the contribution of ligand-stabilized reactive manganese intermediates in situ formed upon permanganate reduction. To further understand the underlying mechanism, we comparatively investigated the influence of ligands on permanganate oxidation of bisphenol A (BPA, one phenolic endocrine-disrupting chemical), carbamazepine (CBZ, a pharmaceutical containing the olefinic group), and methyl p-tolyl sulfoxide (TMSO, a typical oxygen-atom acceptor). Selected ligands exerted oxidation enhancement for BPA but had negligible influence for CBZ and TMSO. This was mainly attributed to the effects of identified Mn(III) complexes, which would otherwise disproportionate spontaneously in the absence of ligands. The one-electron oxidant Mn(III) species exhibited no reactivity toward CBZ and TMSO for which the two-electron oxygen donation may be the primary oxidation mechanism but readily oxidized BPA. The latter case was a function of pH, the complexing ligand, and the molar [Mn(III)]:[ligand] ratio, generally consistent with the patterns of ligand-affected permanganate oxidation. Moreover, the combination of the one-electron reduction of Mn(III) (Mn(III) + e(-) -->Mn(II)) and the Mn(VII)/Mn(II) reaction in excess ligands (Mn(VII) + 4Mn(II) ----> (ligands) 5Mn(III)) suggested a catalytic role of the Mn(III)/Mn(II) pair in permanganate oxidation of some phenolics in the presence of ligands.

  1. Crystal structure of di-μ-chlorido-bis[dichloridobis(methanol-κOiridium(III] dihydrate: a surprisingly simple chloridoiridium(III dinuclear complex with methanol ligands

    Directory of Open Access Journals (Sweden)

    Joseph S. Merola

    2015-05-01

    Full Text Available The reaction between IrCl3·xH2O in methanol led to the formation of small amounts of the title compound, [Ir2Cl6(CH3OH4]·2H2O, which consists of two IrCl4O2 octahedra sharing an edge via chloride bridges. The molecule lies across an inversion center. Each octahedron can be envisioned as being comprised of four chloride ligands in the equatorial plane with methanol ligands in the axial positions. A lattice water molecule is strongly hydrogen-bonded to the coordinating methanol ligands and weak interactions with coordinating chloride ligands lead to the formation of a three-dimensional network. This is a surprising structure given that, while many reactions of iridium chloride hydrate are carried out in alcoholic solvents, especially methanol and ethanol, this is the first structure of a chloridoiridium compound with only methanol ligands.

  2. Determination of ligand binding modes in weak protein–ligand complexes using sparse NMR data

    Energy Technology Data Exchange (ETDEWEB)

    Mohanty, Biswaranjan; Williams, Martin L.; Doak, Bradley C.; Vazirani, Mansha; Ilyichova, Olga [Monash University, Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences (Australia); Wang, Geqing [La Trobe University, La Trobe Institute for Molecular Bioscience (Australia); Bermel, Wolfgang [Bruker Biospin GmbH (Germany); Simpson, Jamie S.; Chalmers, David K. [Monash University, Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences (Australia); King, Glenn F. [The University of Queensland, Institute for Molecular Bioscience (Australia); Mobli, Mehdi, E-mail: m.mobli@uq.edu.au [The University of Queensland, Centre for Advanced Imaging (Australia); Scanlon, Martin J., E-mail: martin.scanlon@monash.edu [Monash University, Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences (Australia)

    2016-11-15

    We describe a general approach to determine the binding pose of small molecules in weakly bound protein–ligand complexes by deriving distance constraints between the ligand and methyl groups from all methyl-containing residues of the protein. We demonstrate that using a single sample, which can be prepared without the use of expensive precursors, it is possible to generate high-resolution data rapidly and obtain the resonance assignments of Ile, Leu, Val, Ala and Thr methyl groups using triple resonance scalar correlation data. The same sample may be used to obtain Met {sup ε}CH{sub 3} assignments using NOESY-based methods, although the superior sensitivity of NOESY using [U-{sup 13}C,{sup 15}N]-labeled protein makes the use of this second sample more efficient. We describe a structural model for a weakly binding ligand bound to its target protein, DsbA, derived from intermolecular methyl-to-ligand nuclear Overhauser enhancements, and demonstrate that the ability to assign all methyl resonances in the spectrum is essential to derive an accurate model of the structure. Once the methyl assignments have been obtained, this approach provides a rapid means to generate structural models for weakly bound protein–ligand complexes. Such weak complexes are often found at the beginning of programs of fragment based drug design and can be challenging to characterize using X-ray crystallography.

  3. Automating crystallographic structure solution and refinement of protein–ligand complexes

    International Nuclear Information System (INIS)

    Echols, Nathaniel; Moriarty, Nigel W.; Klei, Herbert E.; Afonine, Pavel V.; Bunkóczi, Gábor; Headd, Jeffrey J.; McCoy, Airlie J.; Oeffner, Robert D.; Read, Randy J.; Terwilliger, Thomas C.; Adams, Paul D.

    2013-01-01

    A software system for automated protein–ligand crystallography has been implemented in the Phenix suite. This significantly reduces the manual effort required in high-throughput crystallographic studies. High-throughput drug-discovery and mechanistic studies often require the determination of multiple related crystal structures that only differ in the bound ligands, point mutations in the protein sequence and minor conformational changes. If performed manually, solution and refinement requires extensive repetition of the same tasks for each structure. To accelerate this process and minimize manual effort, a pipeline encompassing all stages of ligand building and refinement, starting from integrated and scaled diffraction intensities, has been implemented in Phenix. The resulting system is able to successfully solve and refine large collections of structures in parallel without extensive user intervention prior to the final stages of model completion and validation

  4. Regulation mechanisms of the FLT3-ligand after irradiation; Mecanismes de regulation du FLT3-ligand apres irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Prat-Lepesant, M

    2005-06-15

    The hematopoietic compartment is one of the most severely damaged after chemotherapy, radiotherapy or accidental irradiations. Whatever its origin, the resulting damage to the bone marrow remains difficult to evaluate. Thus, it would be of great interest to get a biological indicator of residual hematopoiesis in order to adapt the treatment to each clinical situation. Recent results indicated that the plasma Flt3 ligand concentration was increased in patients suffering from either acquired or induced aplasia, suggesting that Flt3 ligand might be useful as a biological indicator of bone marrow status. We thus followed in a mouse model as well as in several clinical situations the variations in plasma Flt3 ligand concentration, after either homogeneous or heterogeneous irradiations. These variations were correlated to the number of hematopoietic progenitors and to other parameters such as duration and depth of pancytopenia. The results indicated that the concentration of Flt3 ligand in the blood reflects the bone marrow status, and that the follow-up of plasma Flt3 ligand concentration could give predictive information about the bone marrow function and the duration and severity of pancytopenia and thrombocytopenia. Nevertheless, the clinical use of Flt3 ligand as a biological indicator of bone marrow damage require the knowledge of the mechanisms regulating the variations in plasma Flt3 ligand concentration. We thus developed a study in the mouse model. The results indicated that the variations in plasma Flt3 ligand variations were not solely due to a balance between its production by lymphoid cells and its consumption by hematopoietic cells. Moreover, we showed that T lymphocytes are not the main regulator of plasma Flt3 ligand concentration as previously suggested, and that other cell types, possibly including bone marrow stromal cells, might be strongly implicated. These results also suggest that the Flt3 ligand is a main systemic regulator of hematopoiesis

  5. Synthesis and characterization of mixed ligand chiral nanoclusters

    KAUST Repository

    Guven, Zekiye P.; Ustbas, Burcin; Harkness, Kellen M.; Coskun, Hikmet; Joshi, Chakra Prasad; Besong, Tabot M.D.; Stellacci, Francesco; Bakr, Osman; Akbulut, Ozge

    2016-01-01

    Chiral mixed ligand silver nanoclusters were synthesized in the presence of a chiral and an achiral ligand. While the chiral ligand led mostly to the formation of nanoparticles, the presence of the achiral ligand drastically increased the yield of nanoclusters with enhanced chiral properties. © 2016 The Royal Society of Chemistry.

  6. Synthesis and characterization of mixed ligand chiral nanoclusters

    KAUST Repository

    Guven, Zekiye P.

    2016-06-22

    Chiral mixed ligand silver nanoclusters were synthesized in the presence of a chiral and an achiral ligand. While the chiral ligand led mostly to the formation of nanoparticles, the presence of the achiral ligand drastically increased the yield of nanoclusters with enhanced chiral properties. © 2016 The Royal Society of Chemistry.

  7. Identifying Marine Copper-Binding Ligands in Seawater

    Science.gov (United States)

    Whitby, H.; Hollibaugh, J. T.; Maldonado, M. T.; Ouchi, S.; van den Berg, S. M.

    2016-02-01

    Complexation reactions are important because they affect the bioavailability of trace metals such as copper and iron. For example, organic complexation can determine whether copper is a limiting or a toxic micronutrient at natural levels. Copper competes with iron for complexing ligands, and when iron is limiting, copper can also substitute for iron in some metabolic pathways. The speciation of copper can be measured using complexing capacity titrations, which provide the concentration of individual ligand classes (L1, L2 etc.) and the complex stabilities (log K). Using methods recently developed in our laboratory, we show that the ligands within these classes can be measured independently of titrations, thus confirming the titration method and simultaneously identifying the ligands within each class. Thiols were identified as the L1 ligand class and humic compounds as the weaker L2 class in samples from coastal Georgia, USA, collected monthly from April to December. Log K values of the ligand complexes were consistent with values expected for thiols and humic substances. Recent results from culture studies and from samples collected along Line P, a coastal - oceanic transect in the HNLC region of the NE subarctic Pacific, will be presented in comparison to the estuarine results. This comparison will help to broaden our perspective on copper complexation and the ligands responsible, furthering our understanding of ligand sources and life cycles.

  8. Substrate coated with receptor and labelled ligand for assays

    International Nuclear Information System (INIS)

    1980-01-01

    Improvements in the procedures for assaying ligands are described. The assay consists of a polystyrene tube on which receptors are present for both the ligand to be assayed and a radioactively labelled form of the ligand. The receptors on the bottom portion of the tube are also coated with labelled ligands, thus eliminating the necessity for separate addition of the labelled ligand and sample during an assay. Examples of ligands to which this method is applicable include polypeptides, nucleotides, nucleosides and proteins. Specific examples are given in which the ligand to be assayed is digoxin, the labelled form of the ligand is 3-0-succinyl digoxyigenin tyrosine ( 125 I) and the receptor is digoxin antibody. (U.K.)

  9. Quantitation of species differences in albumin–ligand interactions for bovine, human and rat serum albumins using fluorescence spectroscopy: A test case with some Sudlow's site I ligands

    Energy Technology Data Exchange (ETDEWEB)

    Poór, Miklós [Institute of Laboratory Medicine, University of Pécs, Ifjúság u. 13, Pécs H-7624 (Hungary); Li, Yin; Matisz, Gergely [Department of General and Physical Chemistry, University of Pécs, Pécs H-7624 (Hungary); János Szentágothai Research Center, Pécs H-7624 (Hungary); Kiss, László [Department of General and Physical Chemistry, University of Pécs, Pécs H-7624 (Hungary); Kunsági-Máté, Sándor [Department of General and Physical Chemistry, University of Pécs, Pécs H-7624 (Hungary); János Szentágothai Research Center, Pécs H-7624 (Hungary); Kőszegi, Tamás, E-mail: koszegit@freemail.hu [Institute of Laboratory Medicine, University of Pécs, Ifjúság u. 13, Pécs H-7624 (Hungary)

    2014-01-15

    Albumin, the most abundant plasma protein is an approximately 67 kDa sized water-soluble macromolecule. Since several drugs and xenobiotics circulate in the blood at least partially in albumin-bound form, albumin plays a key role in the pharmacokinetics/toxicokinetics of these chemicals. Most of the drugs and xenobiotics are Sudlow's site I ligands. In numerous studies, bovine serum albumin (BSA) is used for modeling albumin–ligand interactions and the results are extrapolated to human serum albumin (HSA). Furthermore, only limited information is available related to albumin–ligand interactions of different albumin species. Therefore, in our study, we have focused on the quantification of differences between bovine, human and rat serum albumin (RSA) using four Sudlow's site I ligands (luteolin, ochratoxin A, phenylbutazone and warfarin). Interactions were analyzed by fluorescence spectroscopy. Stability constants as well as competing capacities of the ligands were determined, and thermodynamic study was also performed. Our results highlight that there could be major differences between BSA, HSA and RSA in their ligand binding properties. Based on our observations we emphasize that in molecular aspects BSA behaves considerably differently from HSA or from albumins of other species therefore, it is strongly recommended to apply at least some confirmatory measurements when data obtained from other species are attempted to be extrapolated to HSA. -- Highlights: • Albumin–ligand interactions of human, bovine and rat albumins were studied. • Four Sudlow's site I ligands were tested by fluorescence spectroscopy. • Substantial differences were found in stability constants among albumin complexes. • Competing capacity of ligands showed major differences in the studied species. • Data obtained for BSA cannot be directly extrapolated to human albumin.

  10. Correcting binding parameters for interacting ligand-lattice systems

    Science.gov (United States)

    Hervy, Jordan; Bicout, Dominique J.

    2017-07-01

    Binding of ligands to macromolecules is central to many functional and regulatory biological processes. Key parameters characterizing ligand-macromolecule interactions are the stoichiometry, inducing the number of ligands per macromolecule binding site, and the dissociation constant, quantifying the ligand-binding site affinity. Both these parameters can be obtained from analyses of classical saturation experiments using the standard binding equation that offers the great advantage of mathematical simplicity but becomes an approximation for situations of interest when a ligand binds and covers more than one single binding site on the macromolecule. Using the framework of car-parking problem with latticelike macromolecules where each ligand can cover simultaneously several consecutive binding sites, we showed that employing the standard analysis leads to underestimation of binding parameters, i.e., ligands appear larger than they actually are and their affinity is also greater than it is. Therefore, we have derived expressions allowing to determine the ligand size and true binding parameters (stoichiometry and dissociation constant) as a function of apparent binding parameters retrieved from standard saturation experiments.

  11. THERMODYNAMICS OF PROTEIN-LIGAND INTERACTIONS AND THEIR ANALYSIS

    Directory of Open Access Journals (Sweden)

    Rummi Devi Saini

    2017-11-01

    Full Text Available Physiological processes are controlled mainly by intermolecular recognition mechanisms which involve protein–protein and protein–ligand interactions with a high specificity and affinity to form a specific complex. Proteins being an important class of macromolecules in biological systems, it is important to understand their actions through binding to other molecules of proteins or ligands. In fact, the binding of low molecular weight ligands to proteins plays a significant role in regulating biological processes such as cellular metabolism and signal transmission. Therefore knowledge of the protein–ligand interactions and the knowledge of the mechanisms involved in the protein-ligand recognition and binding are key in understanding biology at molecular level which will facilitate the discovery, design, and development of drugs. In this review, the mechanisms involved in protein–ligand binding, the binding kinetics, thermodynamic concepts and binding driving forces are discussed. Thermodynamic mechanisms involved in a few important protein-ligand binding are described. Various spectroscopic, non-spectroscopic and computational method for analysis of protein–ligand binding are also discussed.

  12. Development of immobilized ligands for actinide separations

    International Nuclear Information System (INIS)

    Paine, R.T.

    1994-01-01

    Primary goals during this grant period were to (1) synthesize new bifunctional chelating ligands, (2) characterize the structural features of the Ln and An coordination complexes formed by these ligands, (3) use structural data to iteratively design new classes of multifunctional ligands, and (4) explore additional routes for attachment of key ligands to solid supports that could be useful for chromatographic separations. Some highlights of recently published work as well as a summary of submitted, unpublished and/or still in progress research are outlined

  13. Entangled zinc-ditetrazolate frameworks involving in situ ligand synthesis and topological modulation by various secondary N-donor ligands

    International Nuclear Information System (INIS)

    Li Yunwu; Chen Weilin; Wang Yonghui; Li Yangguang; Wang Enbo

    2009-01-01

    The introduction of various secondary N-donor ligands into an in situ ditetrazolate-ligand synthesis system of terephthalonitrile, NaN 3 and ZnCl 2 led to the formation of three new entangled frameworks Zn(pdtz)(4,4'-bipy).3H 2 O (1), [Zn(pdtz)(bpp)] 2 .3H 2 O (2) and Zn(pdtz) 0.5 (N 3 )(2,2'-bipy) (3) (4,4'-bipy=4,4'-bipyridine; bpp=1,3-bis(4-pyridyl)propane; 2,2'-bipy=2,2'-bipyridine; H 2 pdtz=5,5'-1,4-phenylene-ditetrazole). The formation of pdtz 2- ligand involves the Sharpless [2+3] cycloaddition reaction between terephthalonitrile and NaN 3 in the presence of Zn 2+ ion as a Lewis-acid catalyst under hydrothermal conditions. Compound 1 exhibits a fivefold interpenetrating 3D framework based on the diamondoid topology. Compound 2 displays a twofold parallel interpenetrating framework based on the wavelike individual network. Compound 3 possesses a 2D puckered network. These new Zn-ditetrazolate frameworks are highly dependent on the modulation of different secondary N-donor ligands. Their luminescent properties were investigated. - Graphical abstract: Three new entangled frameworks were prepared by an in situ ditetrazolate-ligand synthesis system assisted with various auxiliary N-donor ligands. The entangled structures can be modulated by different secondary ligands.

  14. A Novel Bis(phosphido)pyridine [PNP] 2− Pincer Ligand and Its Potassium and Bis(dimethylamido)zirconium(IV) Complexes

    KAUST Repository

    Winston, Matthew S.

    2010-12-13

    A novel PNP bis(secondary phosphine)pyridine pincer ligand, 2,6-bis(2-(phenylphosphino)phenyl)pyridine, has been prepared in high yield, and the properties of the doubly deprotonated form as a ligand in K 4(PNP)2(THF)6 and (PNP)Zr(NMe2) 2 have been investigated. The neutral PNP ligand has been isolated as a mixture of noninterconverting diastereomers, due to the presence of two chirogenic phosphorus atoms of the secondary phopshines, but coordination of the dianionic form to potassium and zirconium allows for isolation of a single diastereomer in near-quantitative yield. The structure of a bis(dimethylamido) zirconium(IV) derivative of the bis(phosphido)pyridine ligand and DFT calculations suggest that the phosphides do not π-bond to early transition metals, likely due to geometric strain and possibly orbital size mismatch between phosphorus and zirconium. As a result, the soft phosphides are prone to formation of insoluble oligomers with substantial bridging of the phosphido lone pairs to other zirconium centers. © 2010 American Chemical Society.

  15. A Novel Bis(phosphido)pyridine [PNP] 2− Pincer Ligand and Its Potassium and Bis(dimethylamido)zirconium(IV) Complexes

    KAUST Repository

    Winston, Matthew S.; Bercaw, John E.

    2010-01-01

    A novel PNP bis(secondary phosphine)pyridine pincer ligand, 2,6-bis(2-(phenylphosphino)phenyl)pyridine, has been prepared in high yield, and the properties of the doubly deprotonated form as a ligand in K 4(PNP)2(THF)6 and (PNP)Zr(NMe2) 2 have been investigated. The neutral PNP ligand has been isolated as a mixture of noninterconverting diastereomers, due to the presence of two chirogenic phosphorus atoms of the secondary phopshines, but coordination of the dianionic form to potassium and zirconium allows for isolation of a single diastereomer in near-quantitative yield. The structure of a bis(dimethylamido) zirconium(IV) derivative of the bis(phosphido)pyridine ligand and DFT calculations suggest that the phosphides do not π-bond to early transition metals, likely due to geometric strain and possibly orbital size mismatch between phosphorus and zirconium. As a result, the soft phosphides are prone to formation of insoluble oligomers with substantial bridging of the phosphido lone pairs to other zirconium centers. © 2010 American Chemical Society.

  16. Transformations of functional groups attached to cyclopentadienyl or related ligands in group 4 metal complexes

    Czech Academy of Sciences Publication Activity Database

    Pinkas, Jiří; Lamač, Martin

    2015-01-01

    Roč. 296, JUL 2015 (2015), s. 45-90 ISSN 0010-8545 R&D Projects: GA ČR(CZ) GA14-08531S Institutional support: RVO:61388955 Keywords : Zirconium * Functionalized cyclopentadienyl ligands * Titanium Subject RIV: CF - Physical ; Theoretical Chemistry Impact factor: 12.994, year: 2015

  17. Selective extraction of trivalent actinides with hard-soft mixed donor ligands: role of intra-ligand synergism

    International Nuclear Information System (INIS)

    Ghanty, Tapan K.

    2016-01-01

    In recent years, considerable attention has been given to understand the coordination chemistry of trivalent lanthanide (Ln) and actinide (An) with various ligands because of its close link with the nuclear waste management processes. It is well known that lanthanide-actinide separation is a challenging and difficult task because of very similar chemical properties of these two series of ions, which are associated with similar ionic radii and coordination numbers. Recently, we have introduced a new concept, 'intra-ligand synergism', where hard donor atom, such as, oxygen preferentially binds to trivalent actinides (An(III)) as compared to the valence iso-electronic trivalent lanthanides (Ln(III)) in presence of another soft donor centre. In the present work, the conventional concept of selective complexation of actinides with soft donor ligands (either S or N donor) has been modified through exploiting this concept, and thereby the higher selectivity of 1,10-phenanthroline-2,9-dicarboxylamide (PDAM) based ligands, namely PDAM and its isobutyl and decyl derivatives towards Am(III) ion has been predicted theoretically through density functional calculations. Subsequently, several such amide derivatives have been synthesized to optimize the solubility of the ligands in organic phase. Finally, solvent extraction experiments have been carried out to validate the theoretical prediction on the selectivity of oxygen donor ligands towards Am(III) as compared to Eu(III), and a maximum separation factor of about 51 has been achieved experimentally using 2,9-bis(N-decylaminocarbonyl)-1,10-phenanthroline ligand. The separation factor is increased with the decrease in pH, which is very interesting since extraction of the Am 3+ ion is considered to be important under highly acidic conditions from the nuclear waste management point of view. (author)

  18. Anions mediate ligand binding in Adineta vaga glutamate receptor ion channels.

    Science.gov (United States)

    Lomash, Suvendu; Chittori, Sagar; Brown, Patrick; Mayer, Mark L

    2013-03-05

    AvGluR1, a glutamate receptor ion channel from the primitive eukaryote Adineta vaga, is activated by alanine, cysteine, methionine, and phenylalanine, which produce lectin-sensitive desensitizing responses like those to glutamate, aspartate, and serine. AvGluR1 LBD crystal structures reveal an unusual scheme for binding dissimilar ligands that may be utilized by distantly related odorant/chemosensory receptors. Arginine residues in domain 2 coordinate the γ-carboxyl group of glutamate, whereas in the alanine, methionine, and serine complexes a chloride ion acts as a surrogate ligand, replacing the γ-carboxyl group. Removal of Cl(-) lowers affinity for these ligands but not for glutamate or aspartate nor for phenylalanine, which occludes the anion binding site and binds with low affinity. AvGluR1 LBD crystal structures and sedimentation analysis also provide insights into the evolutionary link between prokaryotic and eukaryotic iGluRs and reveal features unique to both classes, emphasizing the need for additional structure-based studies on iGluR-ligand interactions. Copyright © 2013 Elsevier Ltd. All rights reserved.

  19. Synthesis, spectral, thermal and biological studies of mixed ligand complexes with newly prepared Schiff base and 1,10-phenanthroline ligands

    Science.gov (United States)

    Abd El-Halim, Hanan F.; Mohamed, Gehad G.; Khalil, Eman A. M.

    2017-10-01

    A series of mixed ligand complexes were prepared from the Schiff base (L1) as a primary ligand, prepared by condensation of oxamide and furan-2-carbaldehyde, and 1,10-phenanthroline (1,10-phen) as a secondary ligand. The Schiff base ligand and its mixed ligand chelates were characterized based on elemental analysis, IR, 1H NMR, thermal analysis, UV-Visible, mass, molar conductance, magnetic moment. X-ray diffraction, solid reflectance and ESR also have been studied. The mixed ligand complexes were found to have the formulae of [M(L1) (1,10-phen)]Clm.nH2O (M = Cr(III) and Fe(III) (m = 3) (n = 0); M = Mn(II), Cu(II) and Cd(II) (m = 2) (n = 0); and M = Co(II) (m = 2) (n = 1), Ni(II) (m = 2) (n = 2) and Zn(II) (m = 2) (n = 3)) and that the geometrical structure of the complexes were octahedral. The parameters of thermodynamic using Coats-Redfern and Horowitz-Metzger equations were calculated. The synthesized Schiff base ligand, 1,10-phenanthroline ligand and Their mixed ligand complexes were also investigated for their antibacterial and antifungal activity against bacterial species (Gram-Ve bacteria: Pseudomonas aeruginosa and Escherichia coli) and (Gram + Ve bacteria: Bacillus subtilis and Streptococcus pneumonia) and fungi (Aspergillus fumigates and Candida albicans). The anticancer activity of the new compounds had been tested against breast (MFC7) and colon (HCT-116) cell lines. The results showed high activity for the synthesized compounds.

  20. Passivating ligand and solvent contribution to the electronics properties of semiconductor nanocrystals

    Energy Technology Data Exchange (ETDEWEB)

    Tretiak, Sergei [Los Alamos National Laboratory; Crotty, Angela [Los Alamos National Laboratory; Fischer, Sean [Los Alamos National Laboratory; Kilina, Svetlana [NON LANL

    2010-10-04

    Expanding on previous work, we examine in detail the impact passivating ligands have on the electronic properties of CdSe quantum dots (QDs). We also explore the importance of the inclusion of solvent in simulating passivated QDs. Most ligand states are found well removed from the band edges, with pyridine being the exception and contributing states that sit right on the conduction band edge. Localized trap states are found for trimethylphosphine and pyridine capped QDs, with solvent helping to eliminate these. The effect of losing a ligand on the electronic properties of the system is observed to vary in proportion with the binding energy and steric bulk of the ligand. More disruption of the electronic properties is seen for tight-binding, sterically large ligands. We also look at the validity of using the single-particle Kohn-Sham (KS) representation to approximate optical absorption spectra. Besides a systematic blue-shift relative to the time-dependent density functional theory spectra, the KS spectra are in very good agreement with the more accurate method for these systems. Such agreement here justifies the use of the KS approach for calculating absorption spectra of QD systems.

  1. Autocrine signal transmission with extracellular ligand degradation

    International Nuclear Information System (INIS)

    Muratov, C B; Posta, F; Shvartsman, S Y

    2009-01-01

    Traveling waves of cell signaling in epithelial layers orchestrate a number of important processes in developing and adult tissues. These waves can be mediated by positive feedback autocrine loops, a mode of cell signaling where binding of a diffusible extracellular ligand to a cell surface receptor can lead to further ligand release. We formulate and analyze a biophysical model that accounts for ligand-induced ligand release, extracellular ligand diffusion and ligand–receptor interaction. We focus on the case when the main mode for ligand degradation is extracellular and analyze the problem with the sharp threshold positive feedback nonlinearity. We derive expressions that link the speed of propagation and other characteristics of traveling waves to the parameters of the biophysical processes, such as diffusion rates, receptor expression level, etc. Analyzing the derived expressions we found that traveling waves in such systems can exhibit a number of unusual properties, e.g. non-monotonic dependence of the speed of propagation on ligand diffusivity. Our results for the fully developed traveling fronts can be used to analyze wave initiation from localized perturbations, a scenario that frequently arises in the in vitro models of epithelial wound healing, and guide future modeling studies of cell communication in epithelial layers

  2. Dockomatic - automated ligand creation and docking.

    Science.gov (United States)

    Bullock, Casey W; Jacob, Reed B; McDougal, Owen M; Hampikian, Greg; Andersen, Tim

    2010-11-08

    The application of computational modeling to rationally design drugs and characterize macro biomolecular receptors has proven increasingly useful due to the accessibility of computing clusters and clouds. AutoDock is a well-known and powerful software program used to model ligand to receptor binding interactions. In its current version, AutoDock requires significant amounts of user time to setup and run jobs, and collect results. This paper presents DockoMatic, a user friendly Graphical User Interface (GUI) application that eases and automates the creation and management of AutoDock jobs for high throughput screening of ligand to receptor interactions. DockoMatic allows the user to invoke and manage AutoDock jobs on a single computer or cluster, including jobs for evaluating secondary ligand interactions. It also automates the process of collecting, summarizing, and viewing results. In addition, DockoMatic automates creation of peptide ligand .pdb files from strings of single-letter amino acid abbreviations. DockoMatic significantly reduces the complexity of managing multiple AutoDock jobs by facilitating ligand and AutoDock job creation and management.

  3. Dockomatic - automated ligand creation and docking

    Directory of Open Access Journals (Sweden)

    Hampikian Greg

    2010-11-01

    Full Text Available Abstract Background The application of computational modeling to rationally design drugs and characterize macro biomolecular receptors has proven increasingly useful due to the accessibility of computing clusters and clouds. AutoDock is a well-known and powerful software program used to model ligand to receptor binding interactions. In its current version, AutoDock requires significant amounts of user time to setup and run jobs, and collect results. This paper presents DockoMatic, a user friendly Graphical User Interface (GUI application that eases and automates the creation and management of AutoDock jobs for high throughput screening of ligand to receptor interactions. Results DockoMatic allows the user to invoke and manage AutoDock jobs on a single computer or cluster, including jobs for evaluating secondary ligand interactions. It also automates the process of collecting, summarizing, and viewing results. In addition, DockoMatic automates creation of peptide ligand .pdb files from strings of single-letter amino acid abbreviations. Conclusions DockoMatic significantly reduces the complexity of managing multiple AutoDock jobs by facilitating ligand and AutoDock job creation and management.

  4. Structural biology of the lanthanides-mining rare earths in the Protein Data Bank.

    Science.gov (United States)

    Djinovic-Carugo, Kristina; Carugo, Oliviero

    2015-02-01

    With its about 100,000 three-dimensional structures, the Protein Data Bank is a copious source of information: it contains also some hundreds of structures of macromolecules complexed with lanthanide cations, which are examined here. These cations, which are found in a wide variety of protein types, were introduced to determine the structures, by exploiting their anomalous dispersion (in crystallographic studies, where they are also used as crystallization additives) or the paramagnetic pseudocontact shifts (in NMR analyses). The coordination numbers in the first coordination sphere are very variable, though they tend to be close to those that are observed in small molecules or in water solution. The coordination polyhedra are also quite variable as it can be expected for large cations. Interestingly, lanthanide cations are frequently observed in packing bridges between symmetry equivalent molecules in crystals, where they tend to form polynuclear complexes, with up to seven cations bridged by water/hydroxide ligands. Copyright © 2014 Elsevier Inc. All rights reserved.

  5. Paramagnetic properties of the low- and high-spin states of yeast cytochrome c peroxidase

    International Nuclear Information System (INIS)

    Vanwetswinkel, Sophie; Nuland, Nico A. J. van; Volkov, Alexander N.

    2013-01-01

    Here we describe paramagnetic NMR analysis of the low- and high-spin forms of yeast cytochrome c peroxidase (CcP), a 34 kDa heme enzyme involved in hydroperoxide reduction in mitochondria. Starting from the assigned NMR spectra of a low-spin CN-bound CcP and using a strategy based on paramagnetic pseudocontact shifts, we have obtained backbone resonance assignments for the diamagnetic, iron-free protein and the high-spin, resting-state enzyme. The derived chemical shifts were further used to determine low- and high-spin magnetic susceptibility tensors and the zero-field splitting constant (D) for the high-spin CcP. The D value indicates that the latter contains a hexacoordinate heme species with a weak field ligand, such as water, in the axial position. Being one of the very few high-spin heme proteins analyzed in this fashion, the resting state CcP expands our knowledge of the heme coordination chemistry in biological systems

  6. Paramagnetic properties of the low- and high-spin states of yeast cytochrome c peroxidase

    Energy Technology Data Exchange (ETDEWEB)

    Vanwetswinkel, Sophie; Nuland, Nico A. J. van; Volkov, Alexander N., E-mail: ovolkov@vub.ac.be [Vrije Universiteit Brussel, Jean Jeener NMR Centre, Structural Biology Brussels (Belgium)

    2013-09-15

    Here we describe paramagnetic NMR analysis of the low- and high-spin forms of yeast cytochrome c peroxidase (CcP), a 34 kDa heme enzyme involved in hydroperoxide reduction in mitochondria. Starting from the assigned NMR spectra of a low-spin CN-bound CcP and using a strategy based on paramagnetic pseudocontact shifts, we have obtained backbone resonance assignments for the diamagnetic, iron-free protein and the high-spin, resting-state enzyme. The derived chemical shifts were further used to determine low- and high-spin magnetic susceptibility tensors and the zero-field splitting constant (D) for the high-spin CcP. The D value indicates that the latter contains a hexacoordinate heme species with a weak field ligand, such as water, in the axial position. Being one of the very few high-spin heme proteins analyzed in this fashion, the resting state CcP expands our knowledge of the heme coordination chemistry in biological systems.

  7. Readability of Spine-Related Patient Education Materials From Leading Orthopedic Academic Centers.

    Science.gov (United States)

    Ryu, Justine H; Yi, Paul H

    2016-05-01

    Cross-sectional analysis of online spine-related patient education materials from leading academic centers. To assess the readability levels of spine surgery-related patient education materials available on the websites of academic orthopedic surgery departments. The Internet is becoming an increasingly popular resource for patient education. Yet many previous studies have found that Internet-based orthopedic-related patient education materials from subspecialty societies are written at a level too difficult for the average American; however, no prior study has assessed the readability of spine surgery-related patient educational materials from leading academic centers. All spine surgery-related articles from the online patient education libraries of the top five US News & World Report-ranked orthopedic institutions were assessed for readability using the Flesch-Kincaid (FK) readability test. Mean readability levels of articles amongst the five academic institutions and articles were compared. We also determined the number of articles with readability levels at or below the recommended sixth- or eight-grade levels. Intraobserver and interobserver reliability of readability assessment were assessed. A total of 122 articles were reviewed. The mean overall FK grade level was 11.4; the difference in mean FK grade level between each department varied significantly (range, 9.3-13.4; P Online patient education materials related to spine from academic orthopedic centers are written at a level too high for the average patient, consistent with spine surgery-related patient education materials provided by the American Academy of Orthopaedic Surgeons and spine subspecialty societies. This study highlights the potential difficulties patients might have in reading and comprehending the information in publicly available education materials related to spine. N/A.

  8. Teachers' Beliefs, Perceived Practice and Actual Classroom Practice in Relation to Traditional (Teacher-Centered) and Constructivist (Learner-Centered) Teaching (Note 1)

    Science.gov (United States)

    Kaymakamoglu, Sibel Ersel

    2018-01-01

    This study explored the EFL teachers' beliefs, perceived practice and actual classroom practice in relation to Traditional (teacher-centered) and Constructivist (learner-centered) teaching in Cyprus Turkish State Secondary Schools context. For this purpose, semi-structured interviews and structured observations were employed with purposively…

  9. Metal-ligand interactions

    Science.gov (United States)

    Ervin, Kent M.

    Experimental studies of the interactions of small transition-metal cluster anions with carbonyl ligands are reviewed and compared with neutral and cationic clusters. Under thermal conditions, the reaction rates of transition-metal clusters with carbon monoxide are measured as a function of cluster size. Saturation limits for carbon monoxide addition can be related to the geometric structures of the clusters. Both energy-resolved threshold collision-induced dissociation experiments and time-resolved photodissociation experiments are used to measure metal-carbonyl binding energies. For platinum and palladium trimer anions, the carbonyl binding energies are assigned to different geometric binding sites. Platinum and palladium cluster anions catalyse the oxidation of carbon monoxide to carbon dioxide in a full catalytic cycle at thermal energies.

  10. Synthesis of novel '4+1' Tc(III)/Re(III) mixed-ligand complexes with dendritically modified ligands

    International Nuclear Information System (INIS)

    Gniazdowska, E.; Kuenstler, J.U.; Stephan, H.; Pietzsch, H.J.

    2006-01-01

    Coordination chemistry of technetium and rhenium attracts a considerable interest due to the nuclear medicine applications of their radionuclides. Inert, so-called '3+1' or '4+1' technetium/rhenium mixed-ligand complexes open a new way to application of 99 mTc/ 188 Re labeled compounds in tumor diagnosis and therapy. In the presented paper, authors describe the synthesis and study of novel 99 mTc/ 188 Re complexes with dendritically functionalized tetradentate (tripodal chelator 2,2',2''-nitrilotris(ethanethiol), NS 3 and carboxyl group-bearing ligand, NS 3 (COOH) 3 ) and monodentate (dendritically modified isocyanide, CN-R(COOMe) 3 and isocyanide-modified peptide, CN-GGY) ligands. To verify the identity of the prepared n.c.a. complexes, non-radioactive analogous '4+1' Re compounds were synthesized. The experimental data show that a dendritic modification of the tetradentate/monodentate ligands changes the complex lipophilicity and does not influence its stability

  11. Bexarotene ligand pharmaceuticals.

    Science.gov (United States)

    Hurst, R E

    2000-12-01

    Bexarotene (LGD-1069), from Ligand, was the first retinoid X receptor (RXR)-selective, antitumor retinoid to enter clinical trials. The company launched the drug for the treatment of cutaneous T-cell lymphoma (CTCL), as Targretin capsules, in the US in January 2000 [359023]. The company filed an NDA for Targretin capsules in June 1999, and for topical gel in December 1999 [329011], [349982] specifically for once-daily oral administration for the treatment of patients with early-stage CTCL who have not tolerated other therapies, patients with refractory or persistent early stage CTCL and patients with refractory advanced stage CTCL. The FDA approved Targretin capsules at the end of December 1999 for once-daily oral treatment of all stages of CTCL in patients refractory to at least one prior systemic therapy, at an initial dose of 300 mg/m2/day. After an NDA was submitted in December 1999 for Targretin gel, the drug received Priority Review status for use as a treatment of cutaneous lesions in patients with stage IA, IB or IIA CTCL [354836]. The FDA issued an approvable letter in June 2000, and granted marketing clearance for CTCL in the same month [370687], [372768], [372769], [373279]. Ligand had received Orphan Drug designation for this indication [329011]. At the request of the FDA, Ligand agreed to carry out certain post-approval phase IV and pharmacokinetic studies [351604]. The company filed an MAA with the EMEA for Targretin Capsules to treat lymphoma in November 1999 [348944]. The NDA for Targretin gel is based on a multicenter phase III trial that was conducted in the US, Canada, Europe and Australia involving 50 patients and a multicenter phase I/II clinical program involving 67 patients. Targretin gel was evaluated for the treatment of patients with early stage CTCL (IA-IIA) who were refractory to, intolerant to, or reached a response plateau for at least 6 months on at least two prior therapies. Efficacy results exceeded the protocol-defined response

  12. Heterogeneity and dynamics of the ligand recognition mode in purine-sensing riboswitches.

    Science.gov (United States)

    Jain, Niyati; Zhao, Liang; Liu, John D; Xia, Tianbing

    2010-05-04

    High-resolution crystal structures and biophysical analyses of purine-sensing riboswitches have revealed that a network of hydrogen bonding interactions appear to be largey responsible for discrimination of cognate ligands against structurally related compounds. Here we report that by using femtosecond time-resolved fluorescence spectroscopy to capture the ultrafast decay dynamics of the 2-aminopurine base as the ligand, we have detected the presence of multiple conformations of the ligand within the binding pockets of one guanine-sensing and two adenine-sensing riboswitches. All three riboswitches have similar conformational distributions of the ligand-bound state. The known crystal structures represent the global minimum that accounts for 50-60% of the population, where there is no significant stacking interaction between the ligand and bases of the binding pocket, but the hydrogen-bonding cage collectively provides an electronic environment that promotes an ultrafast ( approximately 1 ps) charge transfer pathway. The ligand also samples multiple conformations in which it significantly stacks with either the adenine or the uracil bases of the A21-U75 and A52-U22 base pairs that form the ceiling and floor of the binding pocket, respectively, but favors the larger adenine bases. These alternative conformations with well-defined base stacking interactions are approximately 1-1.5 kcal/mol higher in DeltaG degrees than the global minimum and have distinct charge transfer dynamics within the picosecond to nanosecond time regime. Inside the pocket, the purine ligand undergoes dynamic motion on the low nanosecond time scale, sampling the multiple conformations based on time-resolved anisotropy decay dynamics. These results allowed a description of the energy landscape of the bound ligand with intricate details and demonstrated the elastic nature of the ligand recognition mode by the purine-sensing riboswitches, where there is a dynamic balance between hydrogen bonding

  13. Molecualr-scale multicoordinating ligands for coating luminescent QDs and gold nanoparticles

    Science.gov (United States)

    Zhan, Naiqian

    Colloidal semiconductor quantum dots (QDs) are inorganic nanocrystals that possess several unique photophysical properties, including tunable narrow emission and remarkable photo- and chemical stability. They have large surface area, and thus can be decorated with large numbers and a variety of molecular vectors. These properties combined offer a potentially superior alternative to traditional organic fluorophore for advanced applications in bio-imaging and bio-sensing. Herein, our effort has centered on developing a series of metal coordinating ligands with controllable structures to modify the QD surfaces and construct biocompatible nanocrystals. The ligand architecture accounts for several factors: (i) variable coordination number, (ii) nature of the hydrophilic moiety, polyethylene glycol (PEG) or zwitterion, and (iii) versatility of end-reactive groups including amine, azide, carboxylic acid and aldehyde. The ligand design is combined with a newly developed photoligation strategy to promote the dispersion of luminescent QDs in buffer media. The dissertation is organized in six chapters: In chapter 1, we provide a brief introduction of the basic photophysical properties of QDs and the synthesis history for growing high quality semiconductor nanocrystals. We also present some of the most effective methods reported to date to prepare aqueous QD dispersions, discuss the effective chemical coupling strategies for conjugating biomolecules, and review the recent literatures that have used QD-bioconjugates for imaging and sensing purposes. In Chapter 2, we describe a novel photoligation strategy to promote the transfer of luminescent QDs from hydrophobic to hydrophilic media using lipic acid (LA)-based ligands. We also discusse the experimental conditions, mechanismfor in-situ ligand exchange and the generosity of the method towards the diverse functionality while maintaining the optical properties of the nanocrystals. In chapter 3, we present the design and synthesis

  14. Mix-and-match: ligand-receptor pairs in stomatal development and beyond.

    Science.gov (United States)

    Torii, Keiko U

    2012-12-01

    Stomata are small valves on the plant epidermis balancing gas exchange and water loss. Stomata are formed according to positional cues. In Arabidopsis, two EPIDERMAL PATTERNING FACTOR (EPF) peptides, EPF1 and EPF2, are secreted from stomatal precursors enforcing proper stomatal patterning. Here, I review recent studies revealing the ligand-receptor pairs and revising the previously predicted relations between receptors specifying stomatal patterning: ERECTA-family and TOO MANY MOUTHS (TMM). Furthermore, EPF-LIKE9 (EPFL9/Stomagen) promotes stomatal differentiation from internal tissues. Two EPFL peptides specify inflorescence architecture, a process beyond stomatal development, as ligands for ERECTA. Thus, broadly expressed receptor kinases may regulate multiple developmental processes through perceiving different peptide ligands, each with a specialized expression pattern. TMM in the epidermis may fine-tune multiple EPF/EPFL signals to prevent signal interference. Copyright © 2012 Elsevier Ltd. All rights reserved.

  15. Triamide mercaptide (N/sub 3/S) ligands for Tc-99m as potential Tc-99m renal function agents

    International Nuclear Information System (INIS)

    Fritzberg, A.R.; Kasina, S.; Johnson, D.L.; Eshima, D.

    1985-01-01

    A number of diamide dimercaptide (N/sub 2/S/sub 2/) complexes of Tc-99m have shown potential as renal tubular function radiopharmaceuticals that could replace radioiodinated hippurate (OIH). Evaluation of such ligands suggested that maximum efficiency for tubular secretion and specificity resulted from addition of a carboxylate group. However, such derivatives resulted in chelate ring stereoisomers that were differently transported by the renal tubular system. The problem of stereoisomers was obviated by replacing one sulfur with an effectively planar amido nitrogen. Groups on the nitrogen then result in diastereomers only when an additional asymetric center is present. A series of triamide mercaptide compounds have been synthesized to evaluate this class as ligands for Tc-99m. One of the simplest of the series, mercaptoacetylglycylglycylglycine (MAG/sub 3/), formed a single Tc-99m product in high yield as determined by HPLC. Preliminary results with pmr and ms of the Tc-99 complex indicate a structure consistent with a 1:1 metal to ligand ratio and monooxo technetium group. Biological evaluation of Tc-99m MAG/sub 3/ showed high renal specificity and rate of excretion exceeding OIH in several species including humans. Members of the N/sub 3/S series studied include mercaptoacetylglycylglycyl-amino acids. In some cases with second asymmetric centers, two components were seen on HPLC. In mice several dianionic Tc-99m complexes were excreted faster than OIH, Tc-99m MAG/sub 2/-ala, -asn, and -gln. Trianionic Tc-99m MAG/sub 2/-asp and -glu were excreted more slowly, and Tc-99m MAG/sub 2/-phe showed hepatobiliary excretion. Triamide mercaptides represent a new ligand class for Tc-99m

  16. Silicon vacancy-related centers in non-irradiated 6H-SiC nanostructur

    Czech Academy of Sciences Publication Activity Database

    Bagraev, N.T.; Danilovskii, E.Yu.; Gets, D.S.; Kalabukhova, E.N.; Klyachkin, L.E.; Koudryavtsev, A.A.; Malyarenko, A.M.; Mashkov, V.A.; Savchenko, Dariia; Shanina, B.D.

    2015-01-01

    Roč. 49, č. 5 (2015), 649-657 ISSN 1063-7826 R&D Projects: GA ČR GP13-06697P; GA MŠk(CZ) LM2011029 Grant - others:SAFMAT(XE) CZ.2.16/3.1.00/22132 Institutional support: RVO:68378271 Keywords : electron spin resonance * 6H-SiC nanostructures * silicon vacancy related centers * NV centers Subject RIV: BM - Solid Matter Physics ; Magnetism Impact factor: 0.701, year: 2015

  17. Synthesis and characterization β-ketoamine ligands

    Science.gov (United States)

    Zaid, Nurzati Amani Mohamed; Hassan, Nur Hasyareeda; Karim, Nurul Huda Abd

    2018-04-01

    β-ketoamine ligands are important members of heterodonor ligand because of their ease of preparation and modification of both steric and/or electronic effects. Complexes with β-ketoamine has received much less attention and there has been no study about this complex with β-ketoamine in ionic liquid reported. Two type of β-ketoamine ligands which are 4-amino-3-pentene-2-onato (A) and 3-amino-2-butenoic acid methyl ester (B) have been synthesized in this work. The resulting compound formed was characterized using standard spectroscopic and structural techniques which includes 1H and 13C, NMR spectroscopy and FTIR spectroscopy. The 1H and 13C NMR spectrum displayed all the expected signals with correct integration and multiplicity. And it is proved that there are some differences between two ligands as observed in NMR and FTIR spectrum.

  18. Designer TGFβ superfamily ligands with diversified functionality.

    Directory of Open Access Journals (Sweden)

    George P Allendorph

    Full Text Available Transforming Growth Factor--beta (TGFβ superfamily ligands, including Activins, Growth and Differentiation Factors (GDFs, and Bone Morphogenetic Proteins (BMPs, are excellent targets for protein-based therapeutics because of their pervasiveness in numerous developmental and cellular processes. We developed a strategy termed RASCH (Random Assembly of Segmental Chimera and Heteromer, to engineer chemically-refoldable TGFβ superfamily ligands with unique signaling properties. One of these engineered ligands, AB208, created from Activin-βA and BMP-2 sequences, exhibits the refolding characteristics of BMP-2 while possessing Activin-like signaling attributes. Further, we find several additional ligands, AB204, AB211, and AB215, which initiate the intracellular Smad1-mediated signaling pathways more strongly than BMP-2 but show no sensitivity to the natural BMP antagonist Noggin unlike natural BMP-2. In another design, incorporation of a short N-terminal segment from BMP-2 was sufficient to enable chemical refolding of BMP-9, without which was never produced nor refolded. Our studies show that the RASCH strategy enables us to expand the functional repertoire of TGFβ superfamily ligands through development of novel chimeric TGFβ ligands with diverse biological and clinical values.

  19. Plant twitter: ligands under 140 amino acids enforcing stomatal patterning.

    Science.gov (United States)

    Rychel, Amanda L; Peterson, Kylee M; Torii, Keiko U

    2010-05-01

    Stomata are an essential land plant innovation whose patterning and density are under genetic and environmental control. Recently, several putative ligands have been discovered that influence stomatal density, and they all belong to the epidermal patterning factor-like family of secreted cysteine-rich peptides. Two of these putative ligands, EPF1 and EPF2, are expressed exclusively in the stomatal lineage cells and negatively regulate stomatal density. A third, EPFL6 or CHALLAH, is also a negative regulator of density, but is expressed subepidermally in the hypocotyl. A fourth, EPFL9 or STOMAGEN, is expressed in the mesophyll tissues and is a positive regulator of density. Genetic evidence suggests that these ligands may compete for the same receptor complex. Proper stomatal patterning is likely to be an intricate process involving ligand competition, regional specificity, and communication between tissue layers. EPFL-family genes exist in the moss Physcomitrella patens, the lycophyte Selaginella moellendorffii, and rice, Oryza sativa, and their sequence analysis yields several genes some of which are related to EPF1, EPF2, EPFL6, and EPFL9. Presence of these EPFL family members in the basal land plants suggests an exciting hypothesis that the genetic components for stomatal patterning originated early in land plant evolution.

  20. Influence of lead-related centers on luminescence of Ce3+ and Pr3+ centers in single crystalline films of aluminium perovskites and garnets

    International Nuclear Information System (INIS)

    Babin, V.; Gorbenko, V.; Krasnikov, A.; Makhov, A.; Nikl, M.; Zazubovich, S.; Zorenko, Yu.

    2010-01-01

    Luminescence characteristics of Ce 3+ - and Pr 3+ -doped aluminium perovskite (LuAlO 3 , YAlO 3 ) and garnet (Lu 3 Al 5 O 12 , Y 3 Al 5 O 12 ) single crystalline films, prepared by the liquid phase epitaxy method with the use of the PbO-based flux, were investigated by the time-resolved spectroscopy methods in the 80-300 K temperature range. The influence of various lead-related centers on the characteristics of the Ce 3+ - and Pr 3+ -related luminescence centers was studied. It was found that the presence of lead-related centers in the single crystalline films results in a decrease of the quantum efficiency and appearance of undesirable slow components in the luminescence decay kinetics. The possibilities of improving the scintillation characteristics of the single crystalline films were considered.

  1. Phosphorescent heterobimetallic complexes involving platinum(iv) and rhenium(vii) centers connected by an unsupported μ-oxido bridge.

    Science.gov (United States)

    Molaee, Hajar; Nabavizadeh, S Masoud; Jamshidi, Mahboubeh; Vilsmeier, Max; Pfitzner, Arno; Samandar Sangari, Mozhgan

    2017-11-28

    Heterobimetallic compounds [(C^N)LMe 2 Pt(μ-O)ReO 3 ] (C^N = ppy, L = PPh 3 , 2a; C^N = ppy, L = PMePh 2 , 2b; C^N = bhq, L = PPh 3 , 2c; C^N = bhq, L = PMePh 2 , 2d) containing a discrete unsupported Pt(iv)-O-Re(vii) bridge have been synthesized through a targeted synthesis route. The compounds have been prepared by a single-pot synthesis in which the Pt(iv) precursor [PtMe 2 I(C^N)L] complexes are allowed to react easily with AgReO 4 in which the iodide ligand of the starting Pt(iv) complex is replaced by an ReO 4 - anion. In these Pt-O-Re complexes, the Pt(iv) centers have an octahedral geometry, completed by a cyclometalated bidentate ligand (C^N), two methyl groups and a phosphine ligand, while the Re(vii) centers have a tetrahedral geometry. Elemental analysis, single crystal X-ray diffraction analysis and multinuclear NMR spectroscopy are used to establish their identities. The new complexes exhibit phosphorescence emission in the solid and solution states at 298 and 77 K, which is an uncommon property of platinum complexes with an oxidation state of +4. According to DFT calculations, we found that this emission behavior in the new complexes originates from ligand centered 3 LC (C^N) character with a slight amount of metal to ligand charge transfer ( 3 MLCT). The solid-state emission data of the corresponding cycloplatinated(iv) precursor complexes [PtMe 2 I(C^N)L], 1a-1d, pointed out that the replacement of I - by an ReO 4 - anion helps enhancing the emission efficiency besides shifting the emission wavelengths.

  2. Relation of people-centered public health and person-centered healthcare management: a case study to reduce burn-out.

    Science.gov (United States)

    Stoyanov, Drozdstoj S; Cloninger, C Robert

    2012-01-01

    Healthcare management is one practical tool for mediation and implementation of public health into clinical healthcare outcomes and is taken in our case study as an exemplar arena to demonstrate the vital importance of the person-centered approach. Healthcare personnel are frequently at risk for the 'burn-out' syndrome. However, modern measures of burn-out recognize burn-out only at a late stage when it is fully developed. There are no available methods to assess the risk for vulnerability to burnout in healthcare systems. Our aim was therefore to design a complex person-centered model for detection of high risk for burn-out at an early stage, that has been termed 'flame-out'. We accept the observation that decreased personal performance is one crucial expression of burn-out. Low personal performance and negative emotions are strongly related to low self-directedness as measured by the Temperament and Character Inventory (TCI). At the same time, burn-out is characterized by decreased interest and positive emotions from work. Decreased positive emotion is directly related to low self-transcendence as measured by the TCI. Burn-out is also frequently associated with feelings of social alienation or inadequacy of support, which is in turn related to low TCI Cooperativeness. However, high Persistence and Harm Avoidance are predisposing traits for burn-out in healthcare professionals who are often overly perfectionistic and compulsive, predisposing them to anxiety, depression, suicide and burn-out. Hence, people at risk for future burn-out are often highly conscientious over-achievers with intense mixtures of positive and negative emotions. The high demand for perfection comes from both intrinsic characteristics and from features of the social milieu in their psychological climate. Letting go of the unfulfillable desire to be perfect by increasing self-transcendence allows acceptance of the imperfection of the human condition, thereby preventing burn-out and other

  3. Prediction of GPCR-Ligand Binding Using Machine Learning Algorithms

    Directory of Open Access Journals (Sweden)

    Sangmin Seo

    2018-01-01

    Full Text Available We propose a novel method that predicts binding of G-protein coupled receptors (GPCRs and ligands. The proposed method uses hub and cycle structures of ligands and amino acid motif sequences of GPCRs, rather than the 3D structure of a receptor or similarity of receptors or ligands. The experimental results show that these new features can be effective in predicting GPCR-ligand binding (average area under the curve [AUC] of 0.944, because they are thought to include hidden properties of good ligand-receptor binding. Using the proposed method, we were able to identify novel ligand-GPCR bindings, some of which are supported by several studies.

  4. New pinene-derived pyridines as bidentate chiral ligands

    Czech Academy of Sciences Publication Activity Database

    Malkov, A. V.; Stewart-Liddon, A.; Teplý, Filip; Kobr, L.; Muir, K. W.; Haigh, D.; Kočovský, P.

    2008-01-01

    Roč. 64, č. 18 (2008), s. 4011-4025 ISSN 0040-4020 Institutional research plan: CEZ:AV0Z40550506 Keywords : chiral ligands * transition metal catalysis * asymmetric catalysis * pyridine ligands * oxazoline ligands Subject RIV: CC - Organic Chemistry Impact factor: 2.897, year: 2008

  5. Glucagon-like peptide-1 receptor ligand interactions: structural cross talk between ligands and the extracellular domain.

    Directory of Open Access Journals (Sweden)

    Graham M West

    Full Text Available Activation of the glucagon-like peptide-1 receptor (GLP-1R in pancreatic β-cells potentiates insulin production and is a current therapeutic target for the treatment of type 2 diabetes mellitus (T2DM. Like other class B G protein-coupled receptors (GPCRs, the GLP-1R contains an N-terminal extracellular ligand binding domain. N-terminal truncations on the peptide agonist generate antagonists capable of binding to the extracellular domain, but not capable of activating full length receptor. The main objective of this study was to use Hydrogen/deuterium exchange (HDX to identify how the amide hydrogen bonding network of peptide ligands and the extracellular domain of GLP-1R (nGLP-1R were altered by binding interactions and to then use this platform to validate direct binding events for putative GLP-1R small molecule ligands. The HDX studies presented here for two glucagon-like peptide-1 receptor (GLP-1R peptide ligands indicates that the antagonist exendin-4[9-39] is significantly destabilized in the presence of nonionic detergents as compared to the agonist exendin-4. Furthermore, HDX can detect stabilization of exendin-4 and exendin-4[9-39] hydrogen bonding networks at the N-terminal helix [Val19 to Lys27] upon binding to the N-terminal extracellular domain of GLP-1R (nGLP-1R. In addition we show hydrogen bonding network stabilization on nGLP-1R in response to ligand binding, and validate direct binding events with the extracellular domain of the receptor for putative GLP-1R small molecule ligands.

  6. Influence of axial and peripheral ligands on the electronic structure of titanium phthalocyanines

    DEFF Research Database (Denmark)

    Pickup, David F.; García Lastra, Juan Maria; Rogero, Celia

    2013-01-01

    core-level binding energy was observed in the bidentate complex and compared to a calculated core-level stabilization. DFT predicts a change of the LUMO from the inner phthalocyanine ring to the Ti dxy orbital and a reversal of the high-lying dx2-y2 and d z2 orbitals. The N 1s edge was calculated using......-ray absorption spectroscopy and photoelectron spectroscopy were combined with density functional theory (DFT) and crystal-field multiplet calculations to characterize the Ti 3d and N 2p valence electrons that form the frontier orbitals. When a monodentate oxo axial ligand was replaced by a bidentate catechol...... ligand, the multiplet structure of the Ti 2p-to-3d transitions was found to change systematically. The most noticeable change was an additional transition into the low-lying 3dxy level, which is attributed to a reduction in local symmetry from 4-fold to 2-fold at the Ti center. An increase of the Ti 2p...

  7. EXAFS Studies of Some Copper(II) Mixed-Ligand Complexes

    International Nuclear Information System (INIS)

    Joshi, S. K.; Katare, R. K.; Shrivastava, B. D.

    2007-01-01

    X-ray K-absorption spectroscopic studies have been carried out on copper (II) mixed-ligand complexes with glutamic acid and aspartic acid as the primary ligands, where as water, pyridine, imidazole and benz-imidazole have been used as secondary ligands. Chemical shifts obtained from the X-ray absorption data have indicated that the glutamic acid complexes are more ionic as compared to their corresponding aspartic acid complexes having similar secondary ligands. Further, we have estimated the average metal-ligand bond distances from the from structure data. For the different complexes studied under the present investigation, the studies reveal that the bonding parameter α1 decreases with the increase in the percentage covalency of the metal-ligand bond. Thus, the bonding parameter α1 may be used for the estimation of percentage covalency of the metal-ligand bond in other similar complexes

  8. Interactions between alkaline earth cations and oxo ligands. DFT study of the affinity of the Mg²+ cation for phosphoryl ligands.

    Science.gov (United States)

    da Costa, Leonardo Moreira; de Mesquita Carneiro, José Walkimar; Paes, Lilian Weitzel Coelho

    2011-08-01

    DFT (B3LYP/6-31+G(d)) calculations of Mg(2+) affinities for a set of phosphoryl ligands were performed. Two types of ligands were studied: a set of trivalent [O = P(R)] and a set of pentavalent phosphoryl ligands [O = P(R)(3)] (R = H, F, Cl, Br, OH, OCH(3), CH(3), CN, NH(2) and NO(2)), with R either bound directly to the phosphorus atom or to the para position of a phenyl ring. The affinity of the Mg(2+) cation for the ligands was quantified by means of the enthalpy for the substitution of one water molecule in the [Mg(H(2)O)(6)](2+) complex for a ligand. The enthalpy of substitution was correlated with electronic and geometric parameters. Electron-donor groups increase the interaction between the cation and the ligand, while electron-acceptor groups decrease the interaction enthalpy.

  9. Tetrapyrroles as Endogenous TSPO Ligands in Eukaryotes and Prokaryotes: Comparisons with Synthetic Ligands

    Directory of Open Access Journals (Sweden)

    Leo Veenman

    2016-06-01

    Full Text Available The 18 kDa translocator protein (TSPO is highly 0conserved in eukaryotes and prokaryotes. Since its discovery in 1977, numerous studies established the TSPO’s importance for life essential functions. For these studies, synthetic TSPO ligands typically are applied. Tetrapyrroles present endogenous ligands for the TSPO. Tetrapyrroles are also evolutionarily conserved and regulate multiple functions. TSPO and tetrapyrroles regulate each other. In animals TSPO-tetrapyrrole interactions range from effects on embryonic development to metabolism, programmed cell death, response to stress, injury and disease, and even to life span extension. In animals TSPOs are primarily located in mitochondria. In plants TSPOs are also present in plastids, the nuclear fraction, the endoplasmic reticulum, and Golgi stacks. This may contribute to translocation of tetrapyrrole intermediates across organelles’ membranes. As in animals, plant TSPO binds heme and protoporphyrin IX. TSPO-tetrapyrrole interactions in plants appear to relate to development as well as stress conditions, including salt tolerance, abscisic acid-induced stress, reactive oxygen species homeostasis, and finally cell death regulation. In bacteria, TSPO is important for switching from aerobic to anaerobic metabolism, including the regulation of photosynthesis. As in mitochondria, in bacteria TSPO is located in the outer membrane. TSPO-tetrapyrrole interactions may be part of the establishment of the bacterial-eukaryote relationships, i.e., mitochondrial-eukaryote and plastid-plant endosymbiotic relationships.

  10. LiCABEDS II. Modeling of ligand selectivity for G-protein-coupled cannabinoid receptors.

    Science.gov (United States)

    Ma, Chao; Wang, Lirong; Yang, Peng; Myint, Kyaw Z; Xie, Xiang-Qun

    2013-01-28

    The cannabinoid receptor subtype 2 (CB2) is a promising therapeutic target for blood cancer, pain relief, osteoporosis, and immune system disease. The recent withdrawal of Rimonabant, which targets another closely related cannabinoid receptor (CB1), accentuates the importance of selectivity for the development of CB2 ligands in order to minimize their effects on the CB1 receptor. In our previous study, LiCABEDS (Ligand Classifier of Adaptively Boosting Ensemble Decision Stumps) was reported as a generic ligand classification algorithm for the prediction of categorical molecular properties. Here, we report extension of the application of LiCABEDS to the modeling of cannabinoid ligand selectivity with molecular fingerprints as descriptors. The performance of LiCABEDS was systematically compared with another popular classification algorithm, support vector machine (SVM), according to prediction precision and recall rate. In addition, the examination of LiCABEDS models revealed the difference in structure diversity of CB1 and CB2 selective ligands. The structure determination from data mining could be useful for the design of novel cannabinoid lead compounds. More importantly, the potential of LiCABEDS was demonstrated through successful identification of newly synthesized CB2 selective compounds.

  11. Semiconductor Quantum Dots with Photoresponsive Ligands.

    Science.gov (United States)

    Sansalone, Lorenzo; Tang, Sicheng; Zhang, Yang; Thapaliya, Ek Raj; Raymo, Françisco M; Garcia-Amorós, Jaume

    2016-10-01

    Photochromic or photocaged ligands can be anchored to the outer shell of semiconductor quantum dots in order to control the photophysical properties of these inorganic nanocrystals with optical stimulations. One of the two interconvertible states of the photoresponsive ligands can be designed to accept either an electron or energy from the excited quantum dots and quench their luminescence. Under these conditions, the reversible transformations of photochromic ligands or the irreversible cleavage of photocaged counterparts translates into the possibility to switch luminescence with external control. As an alternative to regulating the photophysics of a quantum dot via the photochemistry of its ligands, the photochemistry of the latter can be controlled by relying on the photophysics of the former. The transfer of excitation energy from a quantum dot to a photocaged ligand populates the excited state of the species adsorbed on the nanocrystal to induce a photochemical reaction. This mechanism, in conjunction with the large two-photon absorption cross section of quantum dots, can be exploited to release nitric oxide or to generate singlet oxygen under near-infrared irradiation. Thus, the combination of semiconductor quantum dots and photoresponsive ligands offers the opportunity to assemble nanostructured constructs with specific functions on the basis of electron or energy transfer processes. The photoswitchable luminescence and ability to photoinduce the release of reactive chemicals, associated with the resulting systems, can be particularly valuable in biomedical research and can, ultimately, lead to the realization of imaging probes for diagnostic applications as well as to therapeutic agents for the treatment of cancer.

  12. Ligand-controlled reactivity, selectivity, and mechanism of cationic ruthenium-catalyzed hydrosilylations of alkynes, ketones, and nitriles: a theoretical study.

    Science.gov (United States)

    Yang, Yun-Fang; Chung, Lung Wa; Zhang, Xinhao; Houk, K N; Wu, Yun-Dong

    2014-09-19

    Density functional theory calculations with the M06 functional have been performed on the reactivity, selectivity, and mechanism of hydrosilylations of alkynes, ketones, and nitriles catalyzed by cationic ruthenium complexes [CpRu(L)(MeCN)2](+), with L = P(i)Pr3 or MeCN. The hydrosilylation of alkynes with L = P(i)Pr3 involves an initial silyl migration mechanism to generate the anti-Markovnikov product, in contrast to the Markovnikov product obtained with L = MeCN. The bulky phosphine ligand directs the silyl group to migrate to Cβ of the alkyne. This explains the anti-Markovnikov selectivity of the catalyst with L = P(i)Pr3. By contrast, the silane additions to either ketone or nitrile proceed through an ionic SN2-Si outer-sphere mechanism, in which the substrate attacks the Si center. The P(i)Pr3 ligand facilitates the activation of the Si-H bond to furnish a η(2)-silane complex, whereas a η(1)-silane complex is formed for the MeCN ligand. This property of the phosphine ligand enables the catalytic hydrosilylation of ketones and nitriles in addition to that of alkynes.

  13. Photoluminescence of Se-related oxygen deficient center in ion-implanted silica films

    International Nuclear Information System (INIS)

    Zatsepin, A.F.; Buntov, E.A.; Pustovarov, V.A.; Fitting, H.-J.

    2013-01-01

    The results of low-temperature time-resolved photoluminescence (PL) investigation of thin SiO 2 films implanted with Se + ions are presented. The films demonstrate an intensive PL band in the violet spectral region, which is attributed to the triplet luminescence of a new variant of selenium-related oxygen deficient center (ODC). The main peculiarity of the defect energy structure is the inefficient direct optical excitation. Comparison with spectral characteristics of isoelectronic Si-, Ge- and SnODCs show that the difference in electronic properties of the new center is related to ion size factor. It was established that the dominating triplet PL excitation under VUV light irradiation is related to the energy transfer from SiO 2 excitons. A possible model of Se-related ODC is considered. -- Highlights: • The low-temperature photoluminescence of thin SiO 2 films implanted with Se + ions was studied. • The 3.4 eV PL band was attributed to triplet luminescence of Se-related ODC. • The peculiarity of SeODC electronic properties is related to ion size factor. • The dominating VUV excitation of triplet PL is related to energy transfer from SiO 2 excitons. • A possible model of Se-related ODC is considered

  14. Utilization of mixed ligands to construct diverse Ni(II)-coordination polymers based on terphenyl-2,2′,4,4′-tetracarboxylic acid and varied N-donor co-ligands

    International Nuclear Information System (INIS)

    Wang, Chao; Zhao, Jun; Xia, Liang; Wu, Xue-Qian; Wang, Jian-Fang; Dong, Wen-Wen; Wu, Ya-Pan

    2016-01-01

    Three new coordination polymers, namely, {[Ni(H 2 L)(bix)(H 2 O) 2 ]·2h 2 O} n (1), {[Ni(HL)(Hdpa)(H 2 O) 2 ]·H 2 O} n (2), {[Ni(L) 0.5 (bpp)(H 2 O)]·H 2 O} n (3) (H 4 L=terphenyl-2,2′,4,4′-tetracarboxylic acid; bix=1,4-bis(imidazol-1-ylmethyl)benzene; dpa =4,4′-dipyridylamine; bpp=1,3-bis(4-pyridyl)propane), based on rigid H 4 L ligand and different N-donor co-ligands, have been synthesized under hydrothermal conditions. Compound 1 features a 3D 4-connected 6 6 -dia-type framework with H 4 L ligand adopts a μ 2 -bridging mode with two symmetry-related carboxylate groups in μ 1 -η 1 :η 0 monodentate mode. Compound 2 displays a 1D [Ni(HL)(Hdpa)] n ribbon chains motif, in which the H 4 L ligand adopts a μ 2 -bridging mode with two carboxylate groups in μ 1 -η 1 :η 1 and μ 1 -η 1 :η 0 monodentate modes, while 3 possesses a (4,4)-connected 3D frameworks with bbf topology, with H 4 L ligand displays a μ 4 -bridging coordination mode. The H 4 L ligand displays not only different deprotonated forms but also diverse coordination modes and conformations. The structural diversities among 1–3 have been carefully discussed, and the roles of N-donor co-ligands in the self-assembly of coordination polymers have been well documented. - Graphical abstract: Three nickel coordination polymers with different architectures based on mixed ligand system were synthesized and structurally characterized. Topology analyses indicate that 1 shows the 4-connected 6 6 -dia net, 1D ribbon chains for 2 and 3D (4,4)-connected bbf network for 3. Display Omitted - Highlights: • Three Ni-based coordination polymers with distinct features have been prepared. • Compound 1 features a 3D 4-connected 66-dia-type framework, 2 displays a 1D [Ni(HL)(Hdpa)] n ribbon chains motif, while 3 possesses a (4,4)-connected 3D frameworks with bbf topology. • The “mixed ligand assembled” strategy is significant potential for network design.

  15. Discovering protein-ligand chalcogen bonding in the protein data bank using endocyclic sulfur-containing heterocycles as ligand search subsets.

    Science.gov (United States)

    Mitchell, Miguel O

    2017-09-24

    The chalcogen bond, the noncovalent, electrostatic attraction between covalently bonded atoms in group 16 and Lewis bases, is present in protein-ligand interactions based on X-ray structures deposited in the Protein Data Bank (PDB). Discovering protein-ligand chalcogen bonding in the PDB employed a strategy that focused on searching the database for protein complexes of five-membered, heterocyclic ligands containing endocyclic sulfur with endo electron-withdrawing groups (isothiazoles; thiazoles; 1,2,3-, 1,2.4-, 1,2,5-, 1,3,4-thiadiazoles) and thiophenes with exo electron-withdrawing groups, e.g., 2-chloro, 2-bromo, 2-amino, 2-alkylthio. Out of 930 ligands investigated, 33 or 3.5% have protein-ligand S---O interactions of which 31 are chalcogen bonds and two appear to be S---HO hydrogen bonds. The bond angles for some of the chalcogen bonds found in the PDB are less than 90°, and an electrostatic model is proposed to explain this phenomenon.

  16. Synthesis and characterization of two new zinc(II) coordination polymers with bidentate flexible ligands: Formation of a 2D structure with (44.62)-sql topology

    Science.gov (United States)

    Lalegani, Arash; Khaledi Sardashti, Mohammad; Gajda, Roman; Woźniak, Krzysztof

    2017-12-01

    Zinc(II) coordination polymers [Zn(bip)2(NCS)2]n (1) and [Zn(μ-bbd)(N3)2]n (2) were synthesized by using the neutral flexible bidentate N-donor ligands 1,4-bis(3,5-dimethylpyrazolyl)butane (bbd) and 1,3-bis(imidazolyl)propane (bip), mono-anionic NCS- or N3-ligand and zinc(II) chloride salts. The results of the X-ray analyses demonstrate that in the structure of 1, the zinc(II) ion is located on an inversion center and exhibits an ZnN6 octahedral arrangement while, in the structure of 2, the zinc(II) ion adopts an ZnN4 tetrahedral geometry. In the polymer 1, the NCS groups are terminally N-bonded to the metal center and the each bip with anti-gauche conformation acts as bridging connecting four zinc(II) ions to form a two-dimensional network with a sql [point symbol (44.62)] topology while, in the polymer 1, the N3 groups are terminally bonded to the metal center and each bbd with anti-anti-anti conformation acts as bridging ligand connecting two zinc(II) ions to form a one-dimensional zig-zag chain. Coordination compounds 1 and 2 have been characterized by infrared spectroscopy, elemental analyses and single-crystal X-ray diffraction. Thermal analyses of polymers were also presented.

  17. Bibliometric analysis of poison center-related research published in peer-review journals.

    Science.gov (United States)

    Forrester, M B

    2016-07-01

    Poison centers advance knowledge in the field of toxicology through publication in peer-review journals. This investigation describes the pattern of poison center-related publications. Cases were poison center-related research published in peer-review journals during 1995-2014. These were identified through searching the PubMed database, reviewing the tables of contents of selected toxicology journals, and reviewing abstracts of various national and international meetings. The following variables for each publication were identified: year of publication, journal, type of publication (meeting abstract vs. other, i.e. full article or letter to the editor), and the country(ies) of the poison center(s) included in the research. Of the 3147 total publications, 62.1% were meeting abstracts. There were 263 publications in 1995-1999, 536 in 2000-2004, 999 in 2005-2009, and 1349 in 2010-2014. The publications were in 234 different journals. The journals in which the highest number of research was published were Clinical Toxicology (69.7%), Journal of Medical Toxicology (2.2%), and Veterinary and Human Toxicology (2.1%). The research was reported from 62 different countries. The countries with the highest number of publications were the United States (67.9%), United Kingdom (6.5%), Germany (3.9%), France (2.5%), and Italy (2.4%). The number of publications increased greatly over the 20 years. Although the publications were in a large number of journals, a high proportion of the publications were in one journal. While the research came from a large number of countries, the preponderance came from the United States. © The Author(s) 2015.

  18. A tandem regression-outlier analysis of a ligand cellular system for key structural modifications around ligand binding.

    Science.gov (United States)

    Lin, Ying-Ting

    2013-04-30

    A tandem technique of hard equipment is often used for the chemical analysis of a single cell to first isolate and then detect the wanted identities. The first part is the separation of wanted chemicals from the bulk of a cell; the second part is the actual detection of the important identities. To identify the key structural modifications around ligand binding, the present study aims to develop a counterpart of tandem technique for cheminformatics. A statistical regression and its outliers act as a computational technique for separation. A PPARγ (peroxisome proliferator-activated receptor gamma) agonist cellular system was subjected to such an investigation. Results show that this tandem regression-outlier analysis, or the prioritization of the context equations tagged with features of the outliers, is an effective regression technique of cheminformatics to detect key structural modifications, as well as their tendency of impact to ligand binding. The key structural modifications around ligand binding are effectively extracted or characterized out of cellular reactions. This is because molecular binding is the paramount factor in such ligand cellular system and key structural modifications around ligand binding are expected to create outliers. Therefore, such outliers can be captured by this tandem regression-outlier analysis.

  19. The relative frequency of common neuromuscular diagnoses in a reference center

    OpenAIRE

    Cotta, Ana; Paim, Júlia Filardi; Carvalho, Elmano; da-Cunha-Júnior, Antonio Lopes; Navarro, Monica M.; Valicek, Jaquelin; Menezes, Miriam Melo; Nunes, Simone Vilela; Xavier-Neto, Rafael; Baptista Junior, Sidney; Lima, Luciano Romero; Takata, Reinaldo Issao; Vargas, Antonio Pedro

    2017-01-01

    ABSTRACT The diagnostic procedure in neuromuscular patients is complex. Knowledge of the relative frequency of neuromuscular diseases within the investigated population is important to allow the neurologist to perform the most appropriate diagnostic tests. Objective: To report the relative frequency of common neuromuscular diagnoses in a reference center. Methods: A 17-year chart review of patients with suspicion of myopathy. Results: Among 3,412 examinations, 1,603 (46.98%) yielded confir...

  20. Structural studies of P-type ATPase–ligand complexes using an X-ray free-electron laser

    Directory of Open Access Journals (Sweden)

    Maike Bublitz

    2015-07-01

    Full Text Available Membrane proteins are key players in biological systems, mediating signalling events and the specific transport of e.g. ions and metabolites. Consequently, membrane proteins are targeted by a large number of currently approved drugs. Understanding their functions and molecular mechanisms is greatly dependent on structural information, not least on complexes with functionally or medically important ligands. Structure determination, however, is hampered by the difficulty of obtaining well diffracting, macroscopic crystals. Here, the feasibility of X-ray free-electron-laser-based serial femtosecond crystallography (SFX for the structure determination of membrane protein–ligand complexes using microcrystals of various native-source and recombinant P-type ATPase complexes is demonstrated. The data reveal the binding sites of a variety of ligands, including lipids and inhibitors such as the hallmark P-type ATPase inhibitor orthovanadate. By analyzing the resolution dependence of ligand densities and overall model qualities, SFX data quality metrics as well as suitable refinement procedures are discussed. Even at relatively low resolution and multiplicity, the identification of ligands can be demonstrated. This makes SFX a useful tool for ligand screening and thus for unravelling the molecular mechanisms of biologically active proteins.

  1. Structural studies of P-type ATPase–ligand complexes using an X-ray free-electron laser

    Energy Technology Data Exchange (ETDEWEB)

    Bublitz, Maike; Nass, Karol; Drachmann, Nikolaj D.; Markvardsen, Anders J.; Gutmann, Matthias J.; Barends, Thomas R. M.; Mattle, Daniel; Shoeman, Robert L.; Doak, R. Bruce; Boutet, Sébastien; Messerschmidt, Marc; Seibert, Marvin M.; Williams, Garth J.; Foucar, Lutz; Reinhard, Linda; Sitsel, Oleg; Gregersen, Jonas L.; Clausen, Johannes D.; Boesen, Thomas; Gotfryd, Kamil; Wang, Kai-Tuo; Olesen, Claus; Møller, Jesper V.; Nissen, Poul; Schlichting, Ilme

    2015-06-11

    Membrane proteins are key players in biological systems, mediating signalling events and the specific transport ofe.g.ions and metabolites. Consequently, membrane proteins are targeted by a large number of currently approved drugs. Understanding their functions and molecular mechanisms is greatly dependent on structural information, not least on complexes with functionally or medically important ligands. Structure determination, however, is hampered by the difficulty of obtaining well diffracting, macroscopic crystals. Here, the feasibility of X-ray free-electron-laser-based serial femtosecond crystallography (SFX) for the structure determination of membrane protein–ligand complexes using microcrystals of various native-source and recombinant P-type ATPase complexes is demonstrated. The data reveal the binding sites of a variety of ligands, including lipids and inhibitors such as the hallmark P-type ATPase inhibitor orthovanadate. By analyzing the resolution dependence of ligand densities and overall model qualities, SFX data quality metrics as well as suitable refinement procedures are discussed. Even at relatively low resolution and multiplicity, the identification of ligands can be demonstrated. This makes SFX a useful tool for ligand screening and thus for unravelling the molecular mechanisms of biologically active proteins.

  2. -Pincer Ligand Family through Ligand Post-Modification

    KAUST Repository

    Huang, Mei-Hui; Hu, Jinsong; Huang, Kuo-Wei

    2017-01-01

    A series of air-stable nickel complexes containing triazine-based PN3P-pincer ligands were synthesized and fully characterized. Complex 3 contains a de-aromatized central triazine ring from the deprotonation of one of the N–H arms. With a post-modification strategy, the Me-PN3P*NiCl complex (3) could be converted into a new class of diimine–traizine PN3P-pincer nickel complexes.

  3. -Pincer Ligand Family through Ligand Post-Modification

    KAUST Repository

    Huang, Mei-Hui

    2017-10-02

    A series of air-stable nickel complexes containing triazine-based PN3P-pincer ligands were synthesized and fully characterized. Complex 3 contains a de-aromatized central triazine ring from the deprotonation of one of the N–H arms. With a post-modification strategy, the Me-PN3P*NiCl complex (3) could be converted into a new class of diimine–traizine PN3P-pincer nickel complexes.

  4. Database of ligand-induced domain movements in enzymes

    Directory of Open Access Journals (Sweden)

    Hayward Steven

    2009-03-01

    Full Text Available Abstract Background Conformational change induced by the binding of a substrate or coenzyme is a poorly understood stage in the process of enzyme catalysed reactions. For enzymes that exhibit a domain movement, the conformational change can be clearly characterized and therefore the opportunity exists to gain an understanding of the mechanisms involved. The development of the non-redundant database of protein domain movements contains examples of ligand-induced domain movements in enzymes, but this valuable data has remained unexploited. Description The domain movements in the non-redundant database of protein domain movements are those found by applying the DynDom program to pairs of crystallographic structures contained in Protein Data Bank files. For each pair of structures cross-checking ligands in their Protein Data Bank files with the KEGG-LIGAND database and using methods that search for ligands that contact the enzyme in one conformation but not the other, the non-redundant database of protein domain movements was refined down to a set of 203 enzymes where a domain movement is apparently triggered by the binding of a functional ligand. For these cases, ligand binding information, including hydrogen bonds and salt-bridges between the ligand and specific residues on the enzyme is presented in the context of dynamical information such as the regions that form the dynamic domains, the hinge bending residues, and the hinge axes. Conclusion The presentation at a single website of data on interactions between a ligand and specific residues on the enzyme alongside data on the movement that these interactions induce, should lead to new insights into the mechanisms of these enzymes in particular, and help in trying to understand the general process of ligand-induced domain closure in enzymes. The website can be found at: http://www.cmp.uea.ac.uk/dyndom/enzymeList.do

  5. The affinity plutonium(IV) for nitrogen donor ligands

    International Nuclear Information System (INIS)

    Jarvis, N.V.; Hancock, R.D.

    1994-01-01

    Established ligand design principles are used to predict the solution chemistry of Pu(IV) with nitrogen donor ligands which do not contain carboxylate donors. pK a 's of the nitrogen donors are lowered by addition of hydroxyalkyl groups causing Pu(IV) to have a greater affinity for these ligands than for hydroxide. Potentiometric studies using the ligands N,N,N'N',N''-pentakis(2-hydroxypropyl)-1,4,7-triazaheptane; N,N,N',N',N''-pentakis(2-hydroxyethyl)-1,4,7-triazaheptane; N,N,N',N',N'-tetrakis(2-hydroxyethyl)-1,2-diaminoethane; N,N,N',N'-tetrakis(2-hydroxyethyl)-trans-1,2-diaminocyclohexane; 1,4,8,11-tetrakis(2-hydroxyethyl)-1,4,8,11-tetraazacyclotetradecane and N,N-bis(2-hydroxyethyl)glycine with Pu(IV) showed that Pu(IV) has a considerable aqueous solution chemistry with these ligands. Data were processed by the ESTA library of programs and stability constants for all the systems are reported. Implications for selective ligand design for Pu(IV) are discussed. (orig.)

  6. Predicting Nanocrystal Shape through Consideration of Surface-Ligand Interactions

    KAUST Repository

    Bealing, Clive R.

    2012-03-27

    Density functional calculations for the binding energy of oleic acid-based ligands on Pb-rich {100} and {111} facets of PbSe nanocrystals determine the surface energies as a function of ligand coverage. Oleic acid is expected to bind to the nanocrystal surface in the form of lead oleate. The Wulff construction predicts the thermodynamic equilibrium shape of the PbSe nanocrystals. The equilibrium shape is a function of the ligand surface coverage, which can be controlled by changing the concentration of oleic acid during synthesis. The different binding energy of the ligand on the {100} and {111} facets results in different equilibrium ligand coverages on the facets, and a transition in the equilibrium shape from octahedral to cubic is predicted when increasing the ligand concentration during synthesis. © 2012 American Chemical Society.

  7. Mixed ligand chelates of rare earths in aqueous solution

    International Nuclear Information System (INIS)

    Lakhani, S.U.; Thakur, G.S.; Sangal, S.P.

    1981-01-01

    Mixed ligand chelates of the 1:1 trivalent lanthanoids-EDTA, HEDTA and NTA chelates-1, 2-Dihydroxybenzene (Pyrocatechol) have been investigated at 35degC and 0.2 M ionic strength maintained by NaC10 4 . The formation of mixed ligand chelates has been found in all cases. The formation of mixed ligand chelates with EDTA shows the coordination number of lanthanoids to be eight, while the mixed ligand chelates with HEDTA and NTA shows the coordination number to be seven and six respectively. The stability constants of mixed ligand chelates are smaller than the binary complexes. The order of stability constants with respect to primary ligands follows the order NTA>HEDTA>EDTA. With respect to metal ions the stability constants increases with the decrease in ionic radii such as Gd< Er< Yb. (author)

  8. Human NKG2D-ligands: cell biology strategies to ensure immune recognition

    Directory of Open Access Journals (Sweden)

    Lola eFernández-Messina

    2012-09-01

    Full Text Available Immune recognition mediated by the activating receptor NKG2D plays an important role for the elimination of stressed cells, including tumours and virus-infected cells. On the other hand, the ligands for NKG2D can also be shed into the sera of cancer patients where they weaken the immune response by downmodulating the receptor on effector cells, mainly NK and T cells. Although both families of NKG2D-ligands, MICA/B and ULBPs, are related to MHC molecules and their expression is increased after stress, many differences are observed in terms of their biochemical properties and cell trafficking. In this paper, we summarise the variety of NKG2D-ligands and propose that selection pressure has driven evolution of diversity in their trafficking and shedding, but not receptor binding affinity. However, it is also possible to identify functional properties common to individual ULBP molecules and MICA/B alleles, but not generally conserved within the MIC or ULBP families. These characteristics likely represent examples of convergent evolution for efficient immune recognition, but are also attractive targets for pathogen immune evasion strategies. Categorization of NKG2D-ligands according to their biological features, rather than their genetic family, may help to achieve a better understanding of NKG2D-ligand association with disease.

  9. Importance of the pharmacological profile of the bound ligand in enrichment on nuclear receptors: toward the use of experimentally validated decoy ligands.

    Science.gov (United States)

    Lagarde, Nathalie; Zagury, Jean-François; Montes, Matthieu

    2014-10-27

    The evaluation of virtual ligand screening methods is of major importance to ensure their reliability. Taking into account the agonist/antagonist pharmacological profile should improve the quality of the benchmarking data sets since ligand binding can induce conformational changes in the nuclear receptor structure and such changes may vary according to the agonist/antagonist ligand profile. We indeed found that splitting the agonist and antagonist ligands into two separate data sets for a given nuclear receptor target significantly enhances the quality of the evaluation. The pharmacological profile of the ligand bound in the binding site of the target structure was also found to be an additional critical parameter. We also illustrate that active compound data sets for a given pharmacological activity can be used as a set of experimentally validated decoy ligands for another pharmacological activity to ensure a reliable and challenging evaluation of virtual screening methods.

  10. Study of substitution reactions of ligands in VO2+ complexes in toluene solutions by ESR method

    International Nuclear Information System (INIS)

    Lundkvist, R.; Panfilov, A.T.; Kalinichenko, N.B.; Marov, I.N.; AN SSSR, Moscow. Inst. Geokhimii i Analiticheskoj Khimii)

    1976-01-01

    Kinetics and equilibrium of stepwise substitution of ligands have been investigated at different temperatures for the complexes of oxovanadium (4) with salicylaldoxime, 8-oxyquinoline, acetylacetone, benzoylacetone, and tenoyltrifluoroacetone. The relative complexability of these ligands in toluene has been studied. The parameters of spin-Hamiltonian of EPR spectra of the VO 2+ complexes have been determined. The equilibrium constants, the rate constants, and activation energy have been found for the substitution reactions of ligands in the complexes VOA 2 : VOA 2 +HB=VOAB+HA; VOAB+HB=VOB 2 +HA, where HA and HB are the ligands with different donor atoms. The mixed complexes have been detected of the general formula VOAB, where HA is salicylaldoxime or 8-oxyquinoline and HB is β-diketone

  11. Targeting bladder tumor cells in voided urine of Chinese patients with FITC-CSNRDARRC peptide ligand

    Directory of Open Access Journals (Sweden)

    Jia XY

    2012-05-01

    Full Text Available Xing-You Jia1, Qi Yu2, Zhe-Hui Zhang3, Xiao-Feng Yang11School of the First Clinical Hospital, Shanxi Medical University, Taiyuan, Shanxi, China; 2Department of Information Management, Shanxi Medical University, Taiyuan, Shanxi, China; 3Research Center for Philosophy of Science and Technology, Shanxi University, Taiyuan, Shanxi, ChinaObjective: To study the practicality of the FITC-CSNRDARRC peptide ligand (containing the Cys–Ser–Asn–Arg–Asp–Ala–Arg–Arg–Cys nonapeptide in diagnosing and monitoring bladder tumors.Materials and methods: Between March 2011 and September 2011, 80 consecutive patients with radiographic abnormalities, localizing hematuria, other symptoms, or signs were studied using the FITC-CSNRDARRC ligand, urinary cytology (UC, and fluorescence in situ hybridization (FISH. The sensitivity and specificity of these three technologies were determined and compared. Cystoscopy and tissue biopsy were taken as the “gold standards” for bladder tumor diagnosis in this study.Results: Twenty-nine out of 80 patients were diagnosed with a bladder tumor via histopathological examination. The FITC-CSNRDARRC ligand was positive in 23 out of 29 bladder tumor patients and produced false negatives in six (20.69% patients. The UC was positive in six out of 29 bladder tumor patients and produced false negatives in 23 (79.31% patients. The FISH was positive in 21 out of 29 bladder tumor patients and produced false negatives in eight (27.59% patients. The overall sensitivity as verified by the FITC-CSNRDARRC ligand was much higher than in UC (79.31% versus 20.69%, P < 0.001 and was slightly higher than in FISH (79.31% versus 72.41%, P = 0.625. The sensitivity of FISH was significantly higher than that of UC (72.41% versus 20.69%, P < 0.001. Sensitivities of the FITC-CSNRDARRC ligand and UC by grade were 58.33% versus 8.3% for low-grade (LG tumors (P = 0.031 and 94.12% versus 29.41% for high-grade (HG tumors (P = 0.003, respectively

  12. Selective oxoanion separation using a tripodal ligand

    Energy Technology Data Exchange (ETDEWEB)

    Custelcean, Radu; Moyer, Bruce A.; Rajbanshi, Arbin

    2016-02-16

    The present invention relates to urea-functionalized crystalline capsules self-assembled by sodium or potassium cation coordination and by hydrogen-bonding water bridges to selectively encapsulate tetrahedral divalent oxoanions from highly competitive aqueous alkaline solutions and methods using this system for selective anion separations from industrial solutions. The method involves competitive crystallizations using a tripodal tris(urea) functionalized ligand and, in particular, provides a viable approach to sulfate separation from nuclear wastes.

  13. Expression of nociceptive ligands in canine osteosarcoma.

    Science.gov (United States)

    Shor, S; Fadl-Alla, B A; Pondenis, H C; Zhang, X; Wycislo, K L; Lezmi, S; Fan, T M

    2015-01-01

    Canine osteosarcoma (OS) is associated with localized pain as a result of tissue injury from tumor infiltration and peritumoral inflammation. Malignant bone pain is caused by stimulation of peripheral pain receptors, termed nociceptors, which reside in the localized tumor microenvironment, including the periosteal and intramedullary bone cavities. Several nociceptive ligands have been determined to participate directly or indirectly in generating bone pain associated with diverse skeletal abnormalities. Canine OS cells actively produce nociceptive ligands with the capacity to directly or indirectly activate peripheral pain receptors residing in the bone tumor microenvironment. Ten dogs with appendicular OS. Expression of nerve growth factor, endothelin-1, and microsomal prostaglandin E synthase-1 was characterized in OS cell lines and naturally occurring OS samples. In 10 dogs with OS, circulating concentrations of nociceptive ligands were quantified and correlated with subjective pain scores and tumor volume in patients treated with standardized palliative therapies. Canine OS cells express and secrete nerve growth factor, endothelin-1, and prostaglandin E2. Naturally occurring OS samples uniformly express nociceptive ligands. In a subset of OS-bearing dogs, circulating nociceptive ligand concentrations were detectable but failed to correlate with pain status. Localized foci of nerve terminal proliferation were identified in a minority of primary bone tumor samples. Canine OS cells express nociceptive ligands, potentially permitting active participation of OS cells in the generation of malignant bone pain. Specific inhibitors of nociceptive ligand signaling pathways might improve pain control in dogs with OS. Copyright © 2015 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of American College of Veterinary Internal Medicine.

  14. A Versatile Dinucleating Ligand Containing Sulfonamide Groups

    DEFF Research Database (Denmark)

    Sundberg, Jonas; Witt, Hannes; Cameron, Lisa

    2014-01-01

    ligand can be prepared in aqueous solutions using only divalent metal ions. Two of the copper(II) complexes, [Cu2(psmp)(OH)] and [Cu2(psmp)(OAc)2]-, demonstrate the anticipated 1:2 ligand/metal stoichiometry and show that the dimetallic binding site created for exogenous ligands possesses high inherent...... of antiferromagnetic coupling. This is corroborated computationally by broken-symmetry density functional theory, which for isotropic modeling of the coupling predicts an antiferromagnetic coupling strength of J = 70.5 cm-1....

  15. How do ligands influence the quantum yields of cyclometalated platinum(ii) complexes, a theoretical research study.

    Science.gov (United States)

    Yang, Baozhu; Huang, Shuang; Wang, Jianhao

    2017-08-30

    A series of cyclometalated platinum(ii) complexes have been investigated with the TDDFT method. These complexes have similar structures but distinct phosphorescence quantum yields. Theoretical calculations were carried out to explain the differences in quantum yields from the conjugation effect of the cyclometalated ligand, molecular rigidity and ligand-field strength of the monodentate ligand. The radiative decay rate constants (k r ) have been discussed with the oscillator strength (f n ), the strength of the spin-orbit coupling (SOC) interaction between the lowest energy triplet excited state (T 1 ) and singlet excited states (S n ), and the energy gaps between E(T 1 ) and E(S n ). To illustrate the nonradiative decay processes, the transition states (TS) between the triplet metal-centered state ( 3 MC) and T 1 states have been optimized. In addition, the minimum energy crossing points (MECPs) between 3 MC and the ground states (S 0 ) were optimized. Finally, the potential energy curves along the nonradiative decay pathways are simulated. To obtain a phosphorescent complex with a high quantum yield, the complex should retain molecular rigidity well in the S 1 and T 1 states, while showing significant structural distortion at the MECP structure.

  16. An Evaluation of Army Wellness Center Clients' Health-Related Outcomes.

    Science.gov (United States)

    Rivera, L Omar; Ford, Jessica Danielle; Hartzell, Meredith Marie; Hoover, Todd Allan

    2018-01-01

    To examine whether Army community members participating in a best-practice based workplace health promotion program (WHPP) experience goal-moderated improvements in health-related outcomes. Pretest/posttest outcome evaluation examining an autonomously participating client cohort over 1 year. Army Wellness Center facilities on 19 Army installations. Army community members sample (N = 5703), mostly Active Duty Soldiers (64%). Assessment of health risks with feedback, health assessments, health education classes, and health coaching sessions conducted by health educators at a recommended frequency of once a month for 3 to 12 months. Initial and follow-up outcome assessments of body mass index (BMI), body fat, cardiorespiratory fitness, blood pressure, and perceived stress. Mixed model linear regression testing for goal-moderated improvements in outcomes. Clients experienced significant improvements in body fat (-2% change), perceived stress (-6% to -12% change), cardiorespiratory fitness (+6% change), and blood pressure (-1% change) regardless of health-related goal. Only clients with a weight loss goal experienced BMI improvement (-1% change). Follow-up outcome assessment rates ranged from 44% (N = 2509) for BMI to 6% (N = 342) for perceived stress. Army Wellness Center clients with at least 1 follow-up outcome assessment experienced improvements in military readiness correlates and chronic disease risk factors. Evaluation design and follow-up-related limitations notwithstanding results suggest that best practices in WHPPs can effectively serve a globally distributed military force.

  17. A Heteroleptic Ferrous Complex with Mesoionic Bis(1,2,3-triazol-5-ylidene) Ligands: Taming the MLCT Excited State of Iron(II)

    DEFF Research Database (Denmark)

    Liu, Yizhu; Kjær, Kasper Skov; Fredin, Lisa A.

    2015-01-01

    based on sequentially furnishing the Fe-II center with the benchmark 2,2-bipyridine (bpy) ligand and the more strongly sigma-donating mesoionic ligand, 4,4-bis(1,2,3-triazol-5-ylidene) (btz). Complex1 was comprehensively characterized by electrochemistry, static and ultrafast spectroscopy, and quantum...... chemical calculations and compared to [Fe(bpy)(3)](PF6)(2) and (TBA)(2)[Fe(bpy)(CN)(4)]. Heteroleptic complex1 extends the absorption spectrum towards longer wavelengths compared to a previously synthesized homoleptic Fe-II NHC complex. The combination of the mesoionic nature of btz and the heteroleptic...

  18. Superior serum half life of albumin tagged TNF ligands

    International Nuclear Information System (INIS)

    Mueller, Nicole; Schneider, Britta; Pfizenmaier, Klaus; Wajant, Harald

    2010-01-01

    Due to their immune stimulating and apoptosis inducing properties, ligands of the TNF family attract increasing interest as therapeutic proteins. A general limitation of in vivo applications of recombinant soluble TNF ligands is their notoriously rapid clearance from circulation. To improve the serum half life of the TNF family members TNF, TWEAK and TRAIL, we genetically fused soluble variants of these molecules to human serum albumin (HSA). The serum albumin-TNF ligand fusion proteins were found to be of similar bioactivity as the corresponding HSA-less counterparts. Upon intravenous injection (i.v.), serum half life of HSA-TNF ligand fusion proteins, as determined by ELISA, was around 15 h as compared to approximately 1 h for all of the recombinant control TNF ligands without HSA domain. Moreover, serum samples collected 6 or 24 h after i.v. injection still contained high TNF ligand bioactivity, demonstrating that there is only limited degradation/inactivation of circulating HSA-TNF ligand fusion proteins in vivo. In a xenotransplantation model, significantly less of the HSA-TRAIL fusion protein compared to the respective control TRAIL protein was required to achieve inhibition of tumor growth indicating that the increased half life of HSA-TNF ligand fusion proteins translates into better therapeutic action in vivo. In conclusion, our data suggest that genetic fusion to serum albumin is a powerful and generally applicable mean to improve bioavailability and in vivo activity of TNF ligands.

  19. Quantitative chemogenomics: machine-learning models of protein-ligand interaction.

    Science.gov (United States)

    Andersson, Claes R; Gustafsson, Mats G; Strömbergsson, Helena

    2011-01-01

    Chemogenomics is an emerging interdisciplinary field that lies in the interface of biology, chemistry, and informatics. Most of the currently used drugs are small molecules that interact with proteins. Understanding protein-ligand interaction is therefore central to drug discovery and design. In the subfield of chemogenomics known as proteochemometrics, protein-ligand-interaction models are induced from data matrices that consist of both protein and ligand information along with some experimentally measured variable. The two general aims of this quantitative multi-structure-property-relationship modeling (QMSPR) approach are to exploit sparse/incomplete information sources and to obtain more general models covering larger parts of the protein-ligand space, than traditional approaches that focuses mainly on specific targets or ligands. The data matrices, usually obtained from multiple sparse/incomplete sources, typically contain series of proteins and ligands together with quantitative information about their interactions. A useful model should ideally be easy to interpret and generalize well to new unseen protein-ligand combinations. Resolving this requires sophisticated machine-learning methods for model induction, combined with adequate validation. This review is intended to provide a guide to methods and data sources suitable for this kind of protein-ligand-interaction modeling. An overview of the modeling process is presented including data collection, protein and ligand descriptor computation, data preprocessing, machine-learning-model induction and validation. Concerns and issues specific for each step in this kind of data-driven modeling will be discussed. © 2011 Bentham Science Publishers

  20. [Supercomputer investigation of the protein-ligand system low-energy minima].

    Science.gov (United States)

    Oferkin, I V; Sulimov, A V; Katkova, E V; Kutov, D K; Grigoriev, F V; Kondakova, O A; Sulimov, V B

    2015-01-01

    The accuracy of the protein-ligand binding energy calculations and ligand positioning is strongly influenced by the choice of the docking target function. This work demonstrates the evaluation of the five different target functions used in docking: functions based on MMFF94 force field and functions based on PM7 quantum-chemical method accounting or without accounting the implicit solvent model (PCM, COSMO or SGB). For these purposes the ligand positions corresponding to the minima of the target function and the experimentally known ligand positions in the protein active site (crystal ligand positions) were compared. Each function was examined on the same test-set of 16 protein-ligand complexes. The new parallelized docking program FLM based on Monte Carlo search algorithm was developed to perform the comprehensive low-energy minima search and to calculate the protein-ligand binding energy. This study demonstrates that the docking target function based on the MMFF94 force field can be used to detect the crystal or near crystal positions of the ligand by the finding the low-energy local minima spectrum of the target function. The importance of solvent accounting in the docking process for the accurate ligand positioning is also shown. The accuracy of the ligand positioning as well as the correlation between the calculated and experimentally determined protein-ligand binding energies are improved when the MMFF94 force field is substituted by the new PM7 method with implicit solvent accounting.

  1. Metal coordination by sterically hindered heterocyclic ligands, including 2-vinylpyridine, assessed by investigation of cobaloximes.

    Science.gov (United States)

    Siega, Patrizia; Randaccio, Lucio; Marzilli, Patricia A; Marzilli, Luigi G

    2006-04-17

    Structural and 1H NMR data have been obtained for cobaloximes with the bulkiest substituted pyridines reported so far. We have isolated in noncoordinating solvents the complexes CH3Co(DH)2L (methylcobaloxime, where DH = the monoanion of dimethylglyoxime) with L = sterically hindered N-donor ligands: quinoline, 4-CH3quinoline, 2,4-(CH3)2pyridine, and 2-R-pyridine (R = CH3, OCH3, CH2CH3, CH=CH2). We have found that the Co-N(ax) bond is very long in the structurally characterized complexes. In particular, CH3Co(DH)2(4-CH3quinoline) has a longer Co-N(ax) bond (2.193(3) A) than any reported for methylcobaloximes. The main cause of the long bonds is unambiguously identified as the steric bulk of L by the fairly linear relationship found for Co-N(ax) distance vs CCA (calculated cone angle, CCA, a computed measure of bulk) over an extensive series of methylcobaloximes. The linear relationship improves if L basicity (quantified by pKa) is taken into account. In anhydrous CDCl3 at 25 degrees C, all complexes except the 2-aminopyridine adduct exhibit 1H NMR spectra consistent with partial dissociation of L to form the methylcobaloxime dimer. 1H NMR experiments at -20 degrees C allowed us to assess qualitatively the relative binding ability of L as follows: 2,4-(CH3)2pyridine > 4-CH3quinoline approximately = quinoline approximately = 2-CH3pyridine > 2-CH3Opyridine > 2-CH3CH2pyridine > 2-CH2=CHpyridine. The broadness of the 1H NMR signals at 25 degrees C suggests a similar order for the ligand exchange rate. The lack of dissociation by 2-aminopyridine is attributed to an intramolecular hydrogen bond between the NH2 group and an oxime O atom. The weaker than expected binding of 2-vinylpyridine relative to the Co-N(ax) bond length is attributed to rotation of the 2-vinyl group required for this bulky ligand to bind to the metal center, a conclusion supported by pronounced changes in 2-vinylpyridine signals upon coordination.

  2. Statistical Estimation of the Protein-Ligand Binding Free Energy Based On Direct Protein-Ligand Interaction Obtained by Molecular Dynamics Simulation

    Directory of Open Access Journals (Sweden)

    Haruki Nakamura

    2012-09-01

    Full Text Available We have developed a method for estimating protein-ligand binding free energy (DG based on the direct protein-ligand interaction obtained by a molecular dynamics simulation. Using this method, we estimated the DG value statistically by the average values of the van der Waals and electrostatic interactions between each amino acid of the target protein and the ligand molecule. In addition, we introduced fluctuations in the accessible surface area (ASA and dihedral angles of the protein-ligand complex system as the entropy terms of the DG estimation. The present method included the fluctuation term of structural change of the protein and the effective dielectric constant. We applied this method to 34 protein-ligand complex structures. As a result, the correlation coefficient between the experimental and calculated DG values was 0.81, and the average error of DG was 1.2 kcal/mol with the use of the fixed parameters. These results were obtained from a 2 nsec molecular dynamics simulation.

  3. Digallane with redox-active diimine ligand: dualism of electron-transfer reactions.

    Science.gov (United States)

    Fedushkin, Igor L; Skatova, Alexandra A; Dodonov, Vladimir A; Chudakova, Valentina A; Bazyakina, Natalia L; Piskunov, Alexander V; Demeshko, Serhiy V; Fukin, Georgy K

    2014-05-19

    The reactivity of digallane (dpp-Bian)Ga-Ga(dpp-Bian) (1), which consists of redox-active ligand 1,2-bis[(2,6-diisopropylphenyl)imino]acenaphthene (dpp-Bian), has been studied. The reaction of 1 with I2 proceeds via one-electron oxidation of each of two dpp-Bian ligands to a radical-anionic state and affords complex (dpp-Bian)IGa-GaI(dpp-Bian) (2). Dissolution of complex 2 in pyridine (Py) gives monomeric compound (dpp-Bian)GaI(Py) (3) as a result of a solvent-induced intramolecular electron transfer from the metal-metal bond to the dpp-Bian ligands. Treatment of compound 3 with B(C6F5)3 leads to removal of pyridine and restores compound 2. The reaction of compound 1 with 3,6-di-tert-butyl-ortho-benzoquinone (3,6-Q) proceeds with oxidation of all the redox-active centers in 1 (the Ga-Ga bond and two dpp-Bian dianions) and results in mononuclear catecholate (dpp-Bian)Ga(Cat) (4) (Cat = [3,6-Q](2-)). Treatment of 4 with AgBF4 gives a mixture of [(dpp-Bian)2Ag][BF4] (5) and (dpp-Bian)GaF(Cat) (6), which both consist of neutral dpp-Bian ligands. The reduction of benzylideneacetone (BA) with 1 generates the BA radical-anions, which dimerize, affording (dpp-Bian)Ga-(BA-BA)-Ga(dpp-Bian) (7). In this case the Ga-Ga bond remains unchanged. Within 10 min at 95 °C in solution compound 7 undergoes transformation to paramagnetic complex (dpp-Bian)Ga(BA-BA) (8) and metal-free compound C36H40N2 (9). The latter is a product of intramolecular addition of the C-H bond of one of the iPr groups to the C═N bond in dpp-Bian. Diamagnetic compounds 3, 5, 6, and 9 have been characterized by NMR spectroscopy, and paramagnetic complexes 2, 4, 7, and 8 by ESR spectroscopy. Molecular structures of 2-7 and 9 have been established by single-crystal X-ray analysis.

  4. Tissue distribution of the death ligand TRAIL and its receptors

    NARCIS (Netherlands)

    Spierings, DC; de Vries, EG; Vellenga, E; van den Heuvel, FA; Koornstra, JJ; Wesseling, J; Hollema, H; de Jong, S

    Recombinant human (rh) TNF-related apoptosis-inducing ligand (TRAIL) harbors potential as an anticancer agent. RhTRAIL induces apoptosis via the TRAIL receptors TRAIL-R1 and TRAIL-R2 in tumors and is non-toxic to nonhuman primates. Because limited data are available about TRAIL receptor

  5. Ligand manipulation of charge transfer excited state relaxation and spin crossover in [Fe(2,2′-bipyridine2(CN2

    Directory of Open Access Journals (Sweden)

    Kasper S. Kjær

    2017-07-01

    Full Text Available We have used femtosecond resolution UV-visible and Kβ x-ray emission spectroscopy to characterize the electronic excited state dynamics of [Fe(bpy2(CN2], where bpy=2,2′-bipyridine, initiated by metal-to-ligand charge transfer (MLCT excitation. The excited-state absorption in the transient UV-visible spectra, associated with the 2,2′-bipyridine radical anion, provides a robust marker for the MLCT excited state, while the transient Kβ x-ray emission spectra provide a clear measure of intermediate and high spin metal-centered excited states. From these measurements, we conclude that the MLCT state of [Fe(bpy2(CN2] undergoes ultrafast spin crossover to a metal-centered quintet excited state through a short lived metal-centered triplet transient species. These measurements of [Fe(bpy2(CN2] complement prior measurement performed on [Fe(bpy3]2+ and [Fe(bpy(CN4]2− in dimethylsulfoxide solution and help complete the chemical series [Fe(bpyN(CN6–2N]2N-4, where N = 1–3. The measurements confirm that simple ligand modifications can significantly change the relaxation pathways and excited state lifetimes and support the further investigation of light harvesting and photocatalytic applications of 3d transition metal complexes.

  6. Factors related to the performance of Specialized Dental Care Centers

    Directory of Open Access Journals (Sweden)

    Flávia Christiane de Azevedo Machado

    2015-04-01

    Full Text Available The Specialized Dental Care Centers (SDCC have the mission to expand access to public medium complexity dental care and support the primary health care actions at this level of complexity. However, it is necessary to ensure the quality of services and to evaluate such services continuously to identify weaknesses and strengths that support the processes of leadership/management. Nevertheless, there is a dearth of studies on the assessment of oral health in specialized care that may indicate which factors should be investigated. Therefore, this integrated literature review sought to explore the plethora of publications on the evaluation of SDCC in the LILACS and MEDLINE data bases in October 2013 to identify factors possibly related to the performance of such health services. Thus, 13 references were included in this review pointing to forms of organization and management of work processes related to the creation of healthcare networks (operation of regulation centers and setting up of health consortiums. They include the contextual characteristics of the places where SDCCs are located (population size, Family Health Strategy coverage, Municipal Human Development Index, governance, governing capacity were factors that influenced the SDCCs performance.

  7. The operator technique in the theory of the rare earth ion interaction with ligand nuclei

    International Nuclear Information System (INIS)

    Anikeenok, O.A.; Eremin, M.V.; Khutsishvili, O.G.

    1986-01-01

    The tensor structure of the operator of rare earth ion interaction with nuclei of close ligands conditioned by virtual processes of charge transport is established. It is taken into account that virtual processes of electron transport from the ligand can take place to the non-filled 4f-, void 5d- and 6s- and preliminarily excited 5p-shells of the rare earth ion. Effects of 4f- and 5d-state mixing by the odd crystal field are considered for the first time. In contrast to the usual multipole-dipole interaction the given one is characterized by anomalously greater significance of highest multipole momenta of the rare earth ion and in the common case it does not have axial symmetry. The theory is compared with data on double electron-nuclear resonance and radiofrequency discrete saturation, taking CaF 2 :Ce 3+ impurity centers as an example

  8. Simple Ligand-Receptor Interaction Descriptor (SILIRID) for alignment-free binding site comparison.

    Science.gov (United States)

    Chupakhin, Vladimir; Marcou, Gilles; Gaspar, Helena; Varnek, Alexandre

    2014-06-01

    We describe SILIRID (Simple Ligand-Receptor Interaction Descriptor), a novel fixed size descriptor characterizing protein-ligand interactions. SILIRID can be obtained from the binary interaction fingerprints (IFPs) by summing up the bits corresponding to identical amino acids. This results in a vector of 168 integer numbers corresponding to the product of the number of entries (20 amino acids and one cofactor) and 8 interaction types per amino acid (hydrophobic, aromatic face to face, aromatic edge to face, H-bond donated by the protein, H-bond donated by the ligand, ionic bond with protein cation and protein anion, and interaction with metal ion). Efficiency of SILIRID to distinguish different protein binding sites has been examined in similarity search in sc-PDB database, a druggable portion of the Protein Data Bank, using various protein-ligand complexes as queries. The performance of retrieval of structurally and evolutionary related classes of proteins was comparable to that of state-of-the-art approaches (ROC AUC ≈ 0.91). SILIRID can efficiently be used to visualize chemogenomic space covered by sc-PDB using Generative Topographic Mapping (GTM): sc-PDB SILIRID data form clusters corresponding to different protein types.

  9. Reduction reactions of water soluble cyano-cobalt(III)-porphyrins: Metal versus ligand centered processes

    International Nuclear Information System (INIS)

    Mosseri, S.; Neta, P.; Harriman, A.; Hambright, P.

    1990-01-01

    Reduction reactions of dicyano-cobalt(III)-porphyrins [potential in vivo cyanide scavenger drugs] were studied by radiolytic and electrochemical methods using the water soluble tetrakis(4-sulfonatophenyl)porphyrin (TPPS) and tetrakis(N-methyl-4-pyridyl)porphyrin (TMPyP). For [(CN)2CoIIITPPS]-, reduction occurs stepwise to the CoII, CoI, and finally to the phlorin anion. This behavior is similar to that of the cobalt porphyrins in the absence of cyanide, except that the cyanide ligand shifts the reduction potentials to much more negative values. On the other hand, under radiolytic conditions, [(CN)2CoIIITMPyP]- is reduced on the porphyrin macrocycle by one electron to give the CoIII pi-radical anion, which disproportionates into the initial complex and the two-electron ring reduced CoIII phlorin. The radical anion is also formed by intramolecular electron transfer subsequent to the reaction of CoIITMPyP and cyanide. The results are compared with the chemistry of Vitamin B-12

  10. Multiple pathways of sigma(1) receptor ligand uptakes into primary cultured neuronal cells.

    Science.gov (United States)

    Yamamoto, H; Karasawa, J; Sagi, N; Takahashi, S; Horikomi, K; Okuyama, S; Nukada, T; Sora, I; Yamamoto, T

    2001-08-03

    addition, pretreatment of cells with a calmodulin antagonist, N-(6-aminohexyl)-5-chloro-1-naphthalene sulfonamide (W-7), a myosin light chain kinase inhibitor, 1-(5-chloronaphthalene-1-sulfonyl)homopiperazine (ML-9), or microsomal Ca(2+)-ATPase inhibitors resulted in a reduction of the amount of sigma receptor ligand uptake. These findings suggest that the Ca(2+) pump on the endoplasmic reticulum and/or calmodulin-related events might be involved in the regulation of the uptake of sigma receptor ligands into primary neuronal cells.

  11. Cellular trafficking of quantum dot-ligand bioconjugates and their induction of changes in normal routing of unconjugated ligands

    DEFF Research Database (Denmark)

    Tekle, Christina; van Deurs, Bo; Sandvig, Kirsten

    2008-01-01

    Can quantum dots (Qdots) act as relevant intracellular probes to investigate routing of ligands in live cells? The intracellular trafficking of Qdots that were coupled to the plant toxin ricin, Shiga toxin, or the ligand transferrin (Tf) was studied by confocal fluorescence microscopy. The Tf...

  12. Predicting Efficient Antenna Ligands for Tb(III) Emission

    Energy Technology Data Exchange (ETDEWEB)

    Samuel, Amanda P.S.; Xu, Jide; Raymond, Kenneth

    2008-10-06

    A series of highly luminescent Tb(III) complexes of para-substituted 2-hydroxyisophthalamide ligands (5LI-IAM-X) has been prepared (X = H, CH{sub 3}, (C=O)NHCH{sub 3}, SO{sub 3}{sup -}, NO{sub 2}, OCH{sub 3}, F, Cl, Br) to probe the effect of substituting the isophthalamide ring on ligand and Tb(III) emission in order to establish a method for predicting the effects of chromophore modification on Tb(III) luminescence. The energies of the ligand singlet and triplet excited states are found to increase linearly with the {pi}-withdrawing ability of the substituent. The experimental results are supported by time-dependent density functional theory (TD-DFT) calculations performed on model systems, which predict ligand singlet and triplet energies within {approx}5% of the experimental values. The quantum yield ({Phi}) values of the Tb(III) complex increases with the triplet energy of the ligand, which is in part due to the decreased non-radiative deactivation caused by thermal repopulation of the triplet. Together, the experimental and theoretical results serve as a predictive tool that can be used to guide the synthesis of ligands used to sensitize lanthanide luminescence.

  13. Utilization of mixed ligands to construct diverse Ni(II)-coordination polymers based on terphenyl-2,2′,4,4′-tetracarboxylic acid and varied N-donor co-ligands

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Chao [College of Materials and Chemical Engineering, Key Laboratory of Inorganic Nonmetallic Crystalline and Energy Conversion Materials, Hubei Provincial Collaborative Innovation Center for New Energy Microgrid, China Three Gorges University, Yichang 443002 (China); Zhao, Jun, E-mail: junzhao08@126.com [College of Materials and Chemical Engineering, Key Laboratory of Inorganic Nonmetallic Crystalline and Energy Conversion Materials, Hubei Provincial Collaborative Innovation Center for New Energy Microgrid, China Three Gorges University, Yichang 443002 (China); State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian 35002 (China); Xia, Liang [College of Materials and Chemical Engineering, Key Laboratory of Inorganic Nonmetallic Crystalline and Energy Conversion Materials, Hubei Provincial Collaborative Innovation Center for New Energy Microgrid, China Three Gorges University, Yichang 443002 (China); State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian 35002 (China); Wu, Xue-Qian; Wang, Jian-Fang; Dong, Wen-Wen; Wu, Ya-Pan [College of Materials and Chemical Engineering, Key Laboratory of Inorganic Nonmetallic Crystalline and Energy Conversion Materials, Hubei Provincial Collaborative Innovation Center for New Energy Microgrid, China Three Gorges University, Yichang 443002 (China)

    2016-06-15

    Three new coordination polymers, namely, {[Ni(H_2L)(bix)(H_2O)_2]·2h_2O}{sub n} (1), {[Ni(HL)(Hdpa)(H_2O)_2]·H_2O}{sub n} (2), {[Ni(L)_0_._5(bpp)(H_2O)]·H_2O}{sub n} (3) (H{sub 4}L=terphenyl-2,2′,4,4′-tetracarboxylic acid; bix=1,4-bis(imidazol-1-ylmethyl)benzene; dpa =4,4′-dipyridylamine; bpp=1,3-bis(4-pyridyl)propane), based on rigid H{sub 4}L ligand and different N-donor co-ligands, have been synthesized under hydrothermal conditions. Compound 1 features a 3D 4-connected 6{sup 6}-dia-type framework with H{sub 4}L ligand adopts a μ{sub 2}-bridging mode with two symmetry-related carboxylate groups in μ{sub 1}-η{sup 1}:η{sup 0} monodentate mode. Compound 2 displays a 1D [Ni(HL)(Hdpa)]{sub n} ribbon chains motif, in which the H{sub 4}L ligand adopts a μ{sub 2}-bridging mode with two carboxylate groups in μ{sub 1}-η{sup 1}:η{sup 1} and μ{sub 1}-η{sup 1}:η{sup 0} monodentate modes, while 3 possesses a (4,4)-connected 3D frameworks with bbf topology, with H{sub 4}L ligand displays a μ{sub 4}-bridging coordination mode. The H{sub 4}L ligand displays not only different deprotonated forms but also diverse coordination modes and conformations. The structural diversities among 1–3 have been carefully discussed, and the roles of N-donor co-ligands in the self-assembly of coordination polymers have been well documented. - Graphical abstract: Three nickel coordination polymers with different architectures based on mixed ligand system were synthesized and structurally characterized. Topology analyses indicate that 1 shows the 4-connected 6{sup 6}-dia net, 1D ribbon chains for 2 and 3D (4,4)-connected bbf network for 3. Display Omitted - Highlights: • Three Ni-based coordination polymers with distinct features have been prepared. • Compound 1 features a 3D 4-connected 66-dia-type framework, 2 displays a 1D [Ni(HL)(Hdpa)]{sub n} ribbon chains motif, while 3 possesses a (4,4)-connected 3D frameworks with bbf topology. • The “mixed ligand assembled

  14. Supramolecular architectures constructed using angular bipyridyl ligands

    International Nuclear Information System (INIS)

    Barnett, Sarah Ann

    2003-01-01

    This work details the synthesis and characterization of a series of coordination frameworks that are formed using bidentate angular N-donor ligands. Pyrimidine was reacted with metal(ll) nitrate salts. Reactions using Cd(NO 3 ) 2 receive particular focus and the analogous reactions using the linear ligand, pyrazine, were studied for comparison. In all cases, two-dimensional coordination networks were prepared. Structural diversity is observed for the Cd(ll) centres including metal-nitrate bridging. In contrast, first row transition metal nitrates form isostructural one-dimensional chains with only the bridging N-donor ligands generating polymeric propagation. The angular ligand, 2,4-bis(4-pyridyl)-1,3,5-triazine (dpt), was reacted with Cd(NO 3 ) 2 and Zn(NO 3 ) 2 . Whereas Zn(NO 3 ) 2 compounds exhibit solvent mediated polymorphism, a range of structures were obtained for the reactions with Cd(NO 3 ) 2 , including the first example of a doubly parallel interpenetrated 4.8 2 net. 4,7-phenanthroline, was reacted with various metal(ll) nitrates as well as cobalt(ll) and copper(ll) halides. The ability of 4,7-phenanthroline to act as both a N-donor ligand and a hydrogen bond acceptor has been discussed. Reactions of CuSCN with pyrimidine yield an unusual three-dimensional structure in which polymeric propagation is not a result of ligand bridging. The reaction of CuSCN with dpt yielded structural supramolecular isomers. (author)

  15. Bone morphogenetic proteins regulate osteoprotegerin and its ligands in human vascular smooth muscle cells

    DEFF Research Database (Denmark)

    Knudsen, Kirsten Quyen Nguyen; Olesen, Ping; Ledet, Thomas

    2007-01-01

    The bone-related protein osteoprotegerin (OPG) may be involved in the development of vascular calcifications, especially in diabetes, where it has been found in increased amounts in the arterial wall. Experimental studies suggest that members of the TGF-superfamily are involved in the transformat......The bone-related protein osteoprotegerin (OPG) may be involved in the development of vascular calcifications, especially in diabetes, where it has been found in increased amounts in the arterial wall. Experimental studies suggest that members of the TGF-superfamily are involved...... in the transformation of human vascular smooth muscle cells (HVSMC) to osteoblast-like cells. In this study, we evaluated the effect of BMP-2, BMP-7 and transforming growth factor beta (TGF-beta1) on the secretion and mRNA expression of OPG and its ligands receptor activator of nuclear factor-kappabeta ligand (RANKL......) and TNF-related apoptosis-inducing ligand (TRAIL) in HVSMC. All three growth factors decreased OPG protein production significantly; these results were paralleled by reduced OPG mRNA expression. TRAIL mRNA levels were also decreased. RANKL mRNA expression declined when treated with TGF-beta1 but were...

  16. Dynamic ligand-based pharmacophore modeling and virtual ...

    Indian Academy of Sciences (India)

    Five ligand-based pharmacophore models were generated from 40 different .... the Phase module of the Schrodinger program.35 Each model consisted of six types of ... ligand preparation included the OPLS_2005 force field and to retain the ...

  17. Evolution of ligand specificity in vertebrate corticosteroid receptors

    Directory of Open Access Journals (Sweden)

    Deitcher David L

    2011-01-01

    Full Text Available Abstract Background Corticosteroid receptors include mineralocorticoid (MR and glucocorticoid (GR receptors. Teleost fishes have a single MR and duplicate GRs that show variable sensitivities to mineralocorticoids and glucocorticoids. How these receptors compare functionally to tetrapod MR and GR, and the evolutionary significance of maintaining two GRs, remains unclear. Results We used up to seven steroids (including aldosterone, cortisol and 11-deoxycorticosterone [DOC] to compare the ligand specificity of the ligand binding domains of corticosteroid receptors between a mammal (Mus musculus and the midshipman fish (Porichthys notatus, a teleost model for steroid regulation of neural and behavioral plasticity. Variation in mineralocorticoid sensitivity was considered in a broader phylogenetic context by examining the aldosterone sensitivity of MR and GRs from the distantly related daffodil cichlid (Neolamprologus pulcher, another teleost model for neurobehavioral plasticity. Both teleost species had a single MR and duplicate GRs. All MRs were sensitive to DOC, consistent with the hypothesis that DOC was the initial ligand of the ancestral MR. Variation in GR steroid-specificity corresponds to nine identified amino acid residue substitutions rather than phylogenetic relationships based on receptor sequences. Conclusion The mineralocorticoid sensitivity of duplicate GRs in teleosts is highly labile in the context of their evolutionary phylogeny, a property that likely led to neo-functionalization and maintenance of two GRs.

  18. Identification of VDR Antagonists among Nuclear Receptor Ligands Using Virtual Screening

    Directory of Open Access Journals (Sweden)

    Kelly Teske

    2014-04-01

    Full Text Available Herein, we described the development of two virtual screens to identify new vitamin D receptor (VDR antagonists among nuclear receptor (NR ligands. Therefore, a database of 14330 nuclear receptor ligands and their NR affinities was assembled using the online available “Binding Database.” Two different virtual screens were carried out in conjunction with a reported VDR crystal structure applying a stringent and less stringent pharmacophore model to filter docked NR ligand conformations. The pharmacophore models were based on the spatial orientation of the hydroxyl functionalities of VDR's natural ligands 1,25(OH2D3 and 25(OH2D3. The first virtual screen identified 32 NR ligands with a calculated free energy of VDR binding of more than -6.0 kJ/mol. All but nordihydroguaiaretic acid (NDGA are VDR ligands, which inhibited the interaction between VDR and coactivator peptide SRC2-3 with an IC50 value of 15.8 μM. The second screen identified 162 NR ligands with a calculated free energy of VDR binding of more than -6.0 kJ/mol. More than half of these ligands were developed to bind VDR followed by ERα/β ligands (26%, TRα/β ligands (7%, and LxRα/β ligands (7%. The binding between VDR and ERα ligand H6036 as well as TRα/β ligand triiodothyronine and a homoserine analog thereof was confirmed by fluorescence polarization.

  19. Water oxidation catalyzed by mononuclear ruthenium complexes with a 2,2'-bipyridine-6,6'-dicarboxylate (bda) ligand: how ligand environment influences the catalytic behavior.

    Science.gov (United States)

    Staehle, Robert; Tong, Lianpeng; Wang, Lei; Duan, Lele; Fischer, Andreas; Ahlquist, Mårten S G; Sun, Licheng; Rau, Sven

    2014-02-03

    A new water oxidation catalyst [Ru(III)(bda)(mmi)(OH2)](CF3SO3) (2, H2bda = 2,2'-bipyridine-6,6'-dicarboxylic acid; mmi = 1,3-dimethylimidazolium-2-ylidene) containing an axial N-heterocyclic carbene ligand and one aqua ligand was synthesized and fully characterized. The kinetics of catalytic water oxidation by 2 were measured using stopped-flow technique, and key intermediates in the catalytic cycle were probed by density functional theory calculations. While analogous Ru-bda water oxidation catalysts [Ru(bda)L2] (L = pyridyl ligands) are supposed to catalyze water oxidation through a bimolecular coupling pathway, our study points out that 2, surprisingly, undergoes a single-site water nucleophilic attack (acid-base) pathway. The diversion of catalytic mechanisms is mainly ascribed to the different ligand environments, from nonaqua ligands to an aqua ligand. Findings in this work provide some critical proof for our previous hypothesis about how alternation of ancillary ligands of water oxidation catalysts influences their catalytic efficiency.

  20. Systematic study of ligand structures of metal oxide EUV nanoparticle photoresists

    KAUST Repository

    Jiang, Jing

    2015-03-19

    Ligand stabilized metal oxide nanoparticle resists are promising candidates for EUV lithography due to their high sensitivity for high-resolution patterning and high etching resistance. As ligand exchange is responsible for the patterning mechanism, we systematically studied the influence of ligand structures of metal oxide EUV nanoparticles on their sensitivity and dissolution behavior. ZrO2 nanoparticles were protected with various aromatic ligands with electron withdrawing and electron donating groups. These nanoparticles have lower sensitivity compared to those with aliphatic ligands suggesting the structures of these ligands is more important than their pka on resist sensitivity. The influence of ligand structure was further studied by comparing the nanoparticles’ solubility for a single type ligand to mixtures of ligands. The mixture of nanoparticles showed improved pattern quality. © (2015) COPYRIGHT Society of Photo-Optical Instrumentation Engineers (SPIE). Downloading of the abstract is permitted for personal use only.

  1. LIBRA: LIgand Binding site Recognition Application.

    Science.gov (United States)

    Hung, Le Viet; Caprari, Silvia; Bizai, Massimiliano; Toti, Daniele; Polticelli, Fabio

    2015-12-15

    In recent years, structural genomics and ab initio molecular modeling activities are leading to the availability of a large number of structural models of proteins whose biochemical function is not known. The aim of this study was the development of a novel software tool that, given a protein's structural model, predicts the presence and identity of active sites and/or ligand binding sites. The algorithm implemented by ligand binding site recognition application (LIBRA) is based on a graph theory approach to find the largest subset of similar residues between an input protein and a collection of known functional sites. The algorithm makes use of two predefined databases for active sites and ligand binding sites, respectively, derived from the Catalytic Site Atlas and the Protein Data Bank. Tests indicate that LIBRA is able to identify the correct binding/active site in 90% of the cases analyzed, 90% of which feature the identified site as ranking first. As far as ligand binding site recognition is concerned, LIBRA outperforms other structure-based ligand binding sites detection tools with which it has been compared. The application, developed in Java SE 7 with a Swing GUI embedding a JMol applet, can be run on any OS equipped with a suitable Java Virtual Machine (JVM), and is available at the following URL: http://www.computationalbiology.it/software/LIBRAv1.zip. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  2. A response calculus for immobilized T cell receptor ligands

    DEFF Research Database (Denmark)

    Andersen, P S; Menné, C; Mariuzza, R A

    2001-01-01

    determine the level of T cell activation. When fitted to T cell responses against purified ligands immobilized on plastic surfaces, the 2D-affinity model adequately simulated changes in cellular activation as a result of varying ligand affinity and ligand density. These observations further demonstrated...

  3. Architecture effects on multivalent interactions by polypeptide-based multivalent ligands

    Science.gov (United States)

    Liu, Shuang

    Multivalent interactions are characterized by the simultaneous binding between multiple ligands and multiple binding sites, either in solutions or at interfaces. In biological systems, most multivalent interactions occur between protein receptors and carbohydrate ligands through hydrogen-bonding and hydrophobic interactions. Compared with weak affinity binding between one ligand and one binding site, i.e. monovalent interaction, multivalent interactioins provide greater avidity and specificity, and therefore play unique roles in a broad range of biological activities. Moreover, the studies of multivalent interactions are also essential for producing effective inhibitors and effectors of biological processes that could have important therapeutic applications. Synthetic multivalent ligands have been designed to mimic the biological functions of natural multivalent interactions, and various types of scaffolds have been used to display multiple ligands, including small molecules, linear polymers, dendrimers, nanoparticle surfaces, monolayer surfaces and liposomes. Studies have shown that multivalent interactions can be highly affected by various architectural parameters of these multivalent ligands, including ligand identities, valencies, spacing, ligand densities, nature of linker arms, scaffold length and scaffold conformation. Most of these multivalent ligands are chemically synthesized and have limitations of controlling over sequence and conformation, which is a barrier for mimicking ordered and controlled natural biological systems. Therefore, multivalent ligands with precisely controlled architecture are required for improved structure-function relationship studies. Protein engineering methods with subsequent chemical coupling of ligands provide significant advantages of controlling over backbone conformation and functional group placement, and therefore have been used to synthesize recombinant protein-based materials with desired properties similar to natural

  4. Non-equivalence of Wnt and R-spondin ligands during Lgr5+ intestinal stem-cell self-renewal.

    Science.gov (United States)

    Yan, Kelley S; Janda, Claudia Y; Chang, Junlei; Zheng, Grace X Y; Larkin, Kathryn A; Luca, Vincent C; Chia, Luis A; Mah, Amanda T; Han, Arnold; Terry, Jessica M; Ootani, Akifumi; Roelf, Kelly; Lee, Mark; Yuan, Jenny; Li, Xiao; Bolen, Christopher R; Wilhelmy, Julie; Davies, Paige S; Ueno, Hiroo; von Furstenberg, Richard J; Belgrader, Phillip; Ziraldo, Solongo B; Ordonez, Heather; Henning, Susan J; Wong, Melissa H; Snyder, Michael P; Weissman, Irving L; Hsueh, Aaron J; Mikkelsen, Tarjei S; Garcia, K Christopher; Kuo, Calvin J

    2017-05-11

    The canonical Wnt/β-catenin signalling pathway governs diverse developmental, homeostatic and pathological processes. Palmitoylated Wnt ligands engage cell-surface frizzled (FZD) receptors and LRP5 and LRP6 co-receptors, enabling β-catenin nuclear translocation and TCF/LEF-dependent gene transactivation. Mutations in Wnt downstream signalling components have revealed diverse functions thought to be carried out by Wnt ligands themselves. However, redundancy between the 19 mammalian Wnt proteins and 10 FZD receptors and Wnt hydrophobicity have made it difficult to attribute these functions directly to Wnt ligands. For example, individual mutations in Wnt ligands have not revealed homeostatic phenotypes in the intestinal epithelium-an archetypal canonical, Wnt pathway-dependent, rapidly self-renewing tissue, the regeneration of which is fueled by proliferative crypt Lgr5 + intestinal stem cells (ISCs). R-spondin ligands (RSPO1-RSPO4) engage distinct LGR4-LGR6, RNF43 and ZNRF3 receptor classes, markedly potentiate canonical Wnt/β-catenin signalling, and induce intestinal organoid growth in vitro and Lgr5 + ISCs in vivo. However, the interchangeability, functional cooperation and relative contributions of Wnt versus RSPO ligands to in vivo canonical Wnt signalling and ISC biology remain unknown. Here we identify the functional roles of Wnt and RSPO ligands in the intestinal crypt stem-cell niche. We show that the default fate of Lgr5 + ISCs is to differentiate, unless both RSPO and Wnt ligands are present. However, gain-of-function studies using RSPO ligands and a new non-lipidated Wnt analogue reveal that these ligands have qualitatively distinct, non-interchangeable roles in ISCs. Wnt proteins are unable to induce Lgr5 + ISC self-renewal, but instead confer a basal competency by maintaining RSPO receptor expression that enables RSPO ligands to actively drive and specify the extent of stem-cell expansion. This functionally non-equivalent yet cooperative interaction

  5. AMPA receptor ligands

    DEFF Research Database (Denmark)

    Strømgaard, Kristian; Mellor, Ian

    2004-01-01

    Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPAR), subtype of the ionotropic glutamate receptors (IGRs), mediate fast synaptic transmission in the central nervous system (CNS), and are involved in many neurological disorders, as well as being a key player in the f......Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPAR), subtype of the ionotropic glutamate receptors (IGRs), mediate fast synaptic transmission in the central nervous system (CNS), and are involved in many neurological disorders, as well as being a key player...... in the formation of memory. Hence, ligands affecting AMPARs are highly important for the study of the structure and function of this receptor, and in this regard polyamine-based ligands, particularly polyamine toxins, are unique as they selectively block Ca2+ -permeable AMPARs. Indeed, endogenous intracellular...

  6. Creation of near-infrared emitting optical center related to nickel–silicon impurity complex in nanodiamond grains

    International Nuclear Information System (INIS)

    Tóth, S.; Himics, L.; Koós, M.

    2016-01-01

    Nanodiamond grains having intensive light emission in the near-infrared region even at room temperature carry an important application potential. Advantages of light emitting optical centers formed in nanodiamond grains are the emission concentrated into a narrow band and that they are mostly single photon emitter. Transition metal related impurity centers formed in nanodiamond grains exhibit these favorable properties. In this work we report on the creation of Ni–Si impurity related complex defect center in nanodiamond grains under microwave plasma assisted chemical vapor deposition (MW CVD) growth process. This complex center accounts for the previously undocumented fluorescence system with zero phonon line (ZPL) emission at 865 nm (1.433 eV) and band width of 1.5 nm (2.4 meV) at room temperature. By varying deposition conditions the Ni–Si impurity related complex defect center was formed in nanodiamond grains of 80–200 nm average sizes. Some variation of ZPL peak position and line width have been detected in nanodiamond grains prepared at different conditions, as well as in numerous nanodiamond grains prepared at the same conditions. The variations of local stress field may explain the spread of ZPL spectral parameters.

  7. Creation of near-infrared emitting optical center related to nickel–silicon impurity complex in nanodiamond grains

    Energy Technology Data Exchange (ETDEWEB)

    Tóth, S., E-mail: toth.sara@wigner.mta.hu; Himics, L.; Koós, M.

    2016-08-15

    Nanodiamond grains having intensive light emission in the near-infrared region even at room temperature carry an important application potential. Advantages of light emitting optical centers formed in nanodiamond grains are the emission concentrated into a narrow band and that they are mostly single photon emitter. Transition metal related impurity centers formed in nanodiamond grains exhibit these favorable properties. In this work we report on the creation of Ni–Si impurity related complex defect center in nanodiamond grains under microwave plasma assisted chemical vapor deposition (MW CVD) growth process. This complex center accounts for the previously undocumented fluorescence system with zero phonon line (ZPL) emission at 865 nm (1.433 eV) and band width of 1.5 nm (2.4 meV) at room temperature. By varying deposition conditions the Ni–Si impurity related complex defect center was formed in nanodiamond grains of 80–200 nm average sizes. Some variation of ZPL peak position and line width have been detected in nanodiamond grains prepared at different conditions, as well as in numerous nanodiamond grains prepared at the same conditions. The variations of local stress field may explain the spread of ZPL spectral parameters.

  8. Cloud computing for protein-ligand binding site comparison.

    Science.gov (United States)

    Hung, Che-Lun; Hua, Guan-Jie

    2013-01-01

    The proteome-wide analysis of protein-ligand binding sites and their interactions with ligands is important in structure-based drug design and in understanding ligand cross reactivity and toxicity. The well-known and commonly used software, SMAP, has been designed for 3D ligand binding site comparison and similarity searching of a structural proteome. SMAP can also predict drug side effects and reassign existing drugs to new indications. However, the computing scale of SMAP is limited. We have developed a high availability, high performance system that expands the comparison scale of SMAP. This cloud computing service, called Cloud-PLBS, combines the SMAP and Hadoop frameworks and is deployed on a virtual cloud computing platform. To handle the vast amount of experimental data on protein-ligand binding site pairs, Cloud-PLBS exploits the MapReduce paradigm as a management and parallelizing tool. Cloud-PLBS provides a web portal and scalability through which biologists can address a wide range of computer-intensive questions in biology and drug discovery.

  9. Pd-bound functionalized mesoporous silica as active catalyst for Suzuki coupling reaction: Effect of OAcˉ, PPh3 and Clˉ ligands on catalytic activity

    Science.gov (United States)

    Das, Trisha; Uyama, Hiroshi; Nandi, Mahasweta

    2018-04-01

    Three new palladium catalysts, PdCat-I, PdCat-II and PdCat-III, immobilized over heterogeneous silica support have been synthesized using different ligands attached to the palladium precursor. The ligands that have been used in this study are acetate, triphenylphosphine and chloride in PdCat-I, PdCat-II and PdCat-III, respectively. The ligands have different effect on stability of the compounds and impart different oxidation states to the metal center. The materials have been characterized by powder X-ray diffraction, nitrogen adsorption-desorption studies, transmission electron microscopy, thermal analysis, and different spectroscopic techniques. The Pd-content of the samples have been determined by ICP-AES analysis. The materials have been used as catalysts for Suzuki coupling reaction of aryl halides with phenylboronic acid under mild conditions. A comparative study has been carried out to ascertain the effect of the nature of different ligands on the outcome of the catalytic reactions. Products have been identified and estimated by 1H NMR and gas chromatography. The results show that the best yields are obtained with the catalyst containing triphenylphosphine as the ligand in methanol. Such type of work to study the effect of ligand on Suzuki coupling reaction over functionalized mesoporous silica heterogeneous catalysts have not been carried out so far.

  10. Soluble Prokaryotic Expression and Purification of Bioactive Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand.

    Science.gov (United States)

    Do, Bich Hang; Nguyen, Minh Tan; Song, Jung-A; Park, Sangsu; Yoo, Jiwon; Jang, Jaepyeong; Lee, Sunju; So, Seoungjun; Yoon, Yejin; Kim, Inki; Lee, Kyungjin; Jang, Yeon Jin; Choe, Han

    2017-12-28

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is considered as an antitumor agent owing to its ability to induce apoptosis of cancer cells without imparting toxicity toward most normal cells. TRAIL is produced in poor yield because of its insoluble expression in the cytoplasm of E. coli . In this study, we achieved soluble expression of TRAIL by fusing maltose-binding protein (MBP), b'a' domain of protein disulfide isomerase (PDIb'a'), or protein disulfide isomerase at the N-terminus of TRAIL. The TRAIL was purified using subsequent immobilized metal affinity chromatography and amylose-binding chromatography, with the tag removal using tobacco etch virus protease. Approximately 4.5 mg of pure TRAIL was produced from 125 ml flask culture with a purification yield of 71.6%. The endotoxin level of the final product was 0.4 EU/μg, as measured by the Limulus amebocyte lysate endotoxin assay. The purified TRAIL was validated and shown to cause apoptosis of HeLa cells with an EC₅₀ and Hill coefficient of 0.6 ± 0.03 nM and 2.41 ± 0.15, respectively. The high level of apoptosis in HeLa cells following administration of purified TRAIL indicates the significance and novelty of this method for producing high-grade and high-yield TRAIL.

  11. Extreme sequence divergence but conserved ligand-binding specificity in Streptococcus pyogenes M protein.

    Directory of Open Access Journals (Sweden)

    2006-05-01

    Full Text Available Many pathogenic microorganisms evade host immunity through extensive sequence variability in a protein region targeted by protective antibodies. In spite of the sequence variability, a variable region commonly retains an important ligand-binding function, reflected in the presence of a highly conserved sequence motif. Here, we analyze the limits of sequence divergence in a ligand-binding region by characterizing the hypervariable region (HVR of Streptococcus pyogenes M protein. Our studies were focused on HVRs that bind the human complement regulator C4b-binding protein (C4BP, a ligand that confers phagocytosis resistance. A previous comparison of C4BP-binding HVRs identified residue identities that could be part of a binding motif, but the extended analysis reported here shows that no residue identities remain when additional C4BP-binding HVRs are included. Characterization of the HVR in the M22 protein indicated that two relatively conserved Leu residues are essential for C4BP binding, but these residues are probably core residues in a coiled-coil, implying that they do not directly contribute to binding. In contrast, substitution of either of two relatively conserved Glu residues, predicted to be solvent-exposed, had no effect on C4BP binding, although each of these changes had a major effect on the antigenic properties of the HVR. Together, these findings show that HVRs of M proteins have an extraordinary capacity for sequence divergence and antigenic variability while retaining a specific ligand-binding function.

  12. Sampling protein motion and solvent effect during ligand binding

    Science.gov (United States)

    Limongelli, Vittorio; Marinelli, Luciana; Cosconati, Sandro; La Motta, Concettina; Sartini, Stefania; Mugnaini, Laura; Da Settimo, Federico; Novellino, Ettore; Parrinello, Michele

    2012-01-01

    An exhaustive description of the molecular recognition mechanism between a ligand and its biological target is of great value because it provides the opportunity for an exogenous control of the related process. Very often this aim can be pursued using high resolution structures of the complex in combination with inexpensive computational protocols such as docking algorithms. Unfortunately, in many other cases a number of factors, like protein flexibility or solvent effects, increase the degree of complexity of ligand/protein interaction and these standard techniques are no longer sufficient to describe the binding event. We have experienced and tested these limits in the present study in which we have developed and revealed the mechanism of binding of a new series of potent inhibitors of Adenosine Deaminase. We have first performed a large number of docking calculations, which unfortunately failed to yield reliable results due to the dynamical character of the enzyme and the complex role of the solvent. Thus, we have stepped up the computational strategy using a protocol based on metadynamics. Our approach has allowed dealing with protein motion and solvation during ligand binding and finally identifying the lowest energy binding modes of the most potent compound of the series, 4-decyl-pyrazolo[1,5-a]pyrimidin-7-one. PMID:22238423

  13. Identification of individual protein-ligand NOEs in the limit of intermediate exchange

    International Nuclear Information System (INIS)

    Reibarkh, Mikhail; Malia, Thomas J.; Hopkins, Brian T.; Wagner, Gerhard

    2006-01-01

    Interactions of proteins with small molecules or other macromolecules play key roles in many biological processes and in drug action, and NMR is an excellent tool for their structural characterization. Frequently, however, line broadening due to intermediate exchange completely eliminates the signals needed for measuring specific intermolecular NOEs. This limits the use of NMR for detailed structural studies in such kinetic situations. Here we show that an optimally chosen excess of ligand over protein can reduce the extent of line broadening for both the ligand and the protein. This makes observation of ligand resonances possible but reduces the size of the measurable NOEs due to the residual line broadening and the non-stoichiometric concentrations. Because the solubility of small molecule drug leads are often limited to high micromolar concentrations, protein concentrations are restricted to even lower values in the low micromolar range. At these non-stoichiometric concentrations and in the presence of significant residual line broadening, conventional NOESY experiments very often are not sensitive enough to observe intermolecular NOEs since the signals inverted by the NOESY preparation pulse sequence relax prior to significant NOE build up. Thus, we employ methods related to driven NOE spectroscopy to investigate protein-ligand interactions in the intermediate exchange regime. In this approach, individual protein resonances are selectively irradiated for up to five seconds to build up measurable NOEs at the ligand resonances. To enable saturation of individual protein resonances we prepare deuterated protein samples selectively protonated at a few sites so that the 1D 1 H spectrum of the protein is resolved well enough to permit irradiation of individual protein signals, which do not overlap with the ligand spectrum. This approach is suitable for measuring a sufficiently large number of protein-ligand NOEs that allow calculation of initial complex structures

  14. Interaction between alkaline earth cations and oxo-ligands. DFT study of the affinity of the Ca2+ cation for carbonyl ligands.

    Science.gov (United States)

    da Costa, Leonardo Moreira; Carneiro, José Walkimar de Mesquita; Romeiro, Gilberto Alves; Paes, Lilian Weitzel Coelho

    2011-02-01

    The affinity of the Ca(2+) ion for a set of substituted carbonyl ligands was analyzed with both the DFT (B3LYP/6-31+G(d)) and semi-empirical (PM6) methods. Two types of ligands were studied: a set of monosubstituted [O=CH(R)] and a set of disubstituted ligands [O=C(R)(2)] (R=H, F, Cl, Br, OH, OCH(3), CH(3), CN, NH(2) and NO(2)), with R either directly bound to the carbonyl carbon atom or to the para position of a phenyl ring. The interaction energy was calculated to quantify the affinity of the Ca(2+) cation for the ligands. Geometric and electronic parameters were correlated with the intensity of the metal-ligand interaction. The electronic nature of the substituent is the main parameter that determines the interaction energy. Donor groups make the interaction energy more negative (stabilizing the complex formed), while acceptor groups make the interaction energy less negative (destabilizing the complex formed).

  15. A one-dimensional polymeric cobalt(III–potassium complex with 18-crown-6, cyanide and porphyrinate ligands

    Directory of Open Access Journals (Sweden)

    Yassine Belghith

    2014-03-01

    Full Text Available The reaction of CoII(TpivPP {TpivPP is the dianion of 5,10,15,20-tetrakis[2-(2,2-dimethylpropanamidophenyl]porphyrin} with an excess of KCN salts and an excess of the 18-crown-6 in chlorobenzene leads to the polymeric title compound catena-poly[[dicyanido-2κ2C-(1,4,7,10,13,16-hexaoxacyclooctadecane-1κ6O{μ3-(2α,2β-5,10,15,20-tetrakis[2-(2,2-dimethylpropanamidophenyl]porphyrinato-1κO5:2κ4N,N′,N′′,N′′′:1′κO15}cobalt(IIIpotassium] dihydrate], {[CoK(CN2(C12H24O6(C64H64N8O4]·2H2O}n. The CoIII ion lies on an inversion center, and the asymmetric unit contains one half of a [CoIII(2α,2β-TpivPP(CN2]− ion complex and one half of a [K(18-C-6]+ counter-ion (18-C-6 is 1,4,7,10,13,16-hexaoxacyclooctadecane, where the KI ion lies on an inversion center. The CoIII ion is hexacoordinated by two C-bonded axial cyanide ligands and the four pyrrole N atoms of the porphyrin ligand. The KI ion is chelated by the six O atoms of the 18-crown-6 molecule and is further coordinated by two O atoms of pivalamido groups of the porphyrin ligands, leading to the formation of polymeric chains running along [011]. In the crystal, the polymeric chains and the lattice water molecules are linked by N—H...O and O—H...N hydrogen bonds, as well as weak C—H...O, O—H...π and C—H...π interactions into a three-dimensional supramolecular architecture.

  16. Thermodynamic studies of the complexation of plutonium(IV) by linear and macrocyclic poly-amino-carboxylate ligands

    International Nuclear Information System (INIS)

    Burgat, Romain

    2007-01-01

    In the framework of a collaboration between the CEA (Commissariat a l Energie Atomique) of Valduc and the ICMUB (Institut de Chimie Moleculaire de l Universite de Bourgogne), a study platform of the structural and physico-chemical properties of the radioelements U, Pu and Am complexes has been implemented. The plutonium(IV) complexation has been studied in a molar nitrate medium. The affinity of three linear poly-amino-carboxylates (EDTA, CDTA and DTPA) towards plutonium(IV) has then been estimated. For the three ligands, the formation constants of the monoleptic complexes Pu(EDTA), Pu(CDTA) and [Pu(DTPA)] - have been determined in a (H,K)NO 3 1 M medium and then extrapolated at a zero ionic force with the specific interactions theory (SIT). For the three complexes, mono-hydroxylated monoleptic species have been observed. With the EDTA and the CDTA, protonated dileptic complexes of a general formula [Pu(L) 2 H h ] (4-h)- have been revealed too. Nevertheless, the steric hindrance around the metallic center is too important to allow to a second molecule of DTPA to coordinate the Pu 4+ cation. The exclusive formation of the species [Pu(DTPA)] - and [Pu(DTPA)(OH)] 2- has been confirmed by capillary electrophoresis (EC-ICP-MS). On account of the preliminary results obtained during the titration of the cyclame tetraacetic product (TETRA) in presence of plutonium(IV), the adding of a competitive ligand such as EDTA has been considered for the study of the complexation of this radioelement by macrocyclic ligands. At last, the affinity of different macrocyclic ligands containing either four amide functions (TETAMMe 2 and TETAMMEt 2 ) or carboxylate groups (TETA, DOTPr and TETPr) towards lanthanides(III) has been estimated too. Although the complexation reaction be fast with the two first ligands, these complexes are less stable than those formed with the carboxylic macrocycles. (O.M.)

  17. Structural, luminescence and biological studies of trivalent lanthanide complexes with N,N Prime -bis(2-hydroxynaphthylmethylidene)-1,3-propanediamine Schiff base ligand

    Energy Technology Data Exchange (ETDEWEB)

    Taha, Ziyad A., E-mail: tahaz33@just.edu.jo [Department of Applied Chemistry, Faculty of Arts and Sciences, Jordan University of Science and Technology, P.O. Box 3030, Irbid 22110 (Jordan); Ajlouni, Abdulaziz M. [Department of Applied Chemistry, Faculty of Arts and Sciences, Jordan University of Science and Technology, P.O. Box 3030, Irbid 22110 (Jordan); Al Momani, Waleed [Department of Allied Medical Sciences, Al Balqa Applied University (Jordan)

    2012-11-15

    New eight lanthanide metal complexes were prepared. These complexes were characterized by elemental analysis, molar conductivity measurements, spectral analysis ({sup 1}H NMR, FT-IR, UV-vis), luminescence and thermal gravimetric analysis. All Ln(III) complexes were 1:1 electrolytes as established by their molar conductivities. The microanalysis and spectroscopic analysis revealed eight-coordinated environments around lanthanide ions with two nitrate ligands behaving in a bidentate manner. The other four positions were found to be occupied with tetradentate L{sub III} ligand. Tb-L{sub III} and Sm-L{sub III} complexes exhibited characteristic luminescence emissions of the central metal ions and this was attributed to efficient energy transfer from the ligand to the metal center. The L{sub III} and Ln-L{sub III} complexes showed antibacterial activity against a number of pathogenic bacteria. - Highlights: Black-Right-Pointing-Pointer Ln(III) ion adopts an eight-coordinate geometry. Black-Right-Pointing-Pointer Luminescence spectra of Sm-L{sub III} and Tb-L{sub III} complexes display the metal centered line emission. Black-Right-Pointing-Pointer Energy transfer process from L{sub III} to Sm in Sm-L{sub III} complex is more efficient than to Tb in Tb-L{sub III} complex. Black-Right-Pointing-Pointer Ln(III) complexes may serve as models for biologically important species.

  18. New synthetic routes toward enantiopure nitrogen donor ligands

    OpenAIRE

    Sala, Xavier; Rodríguez, Anna M.; Rodríguez, Montserrat; Romero, Isabel; Parella, Teodor; Zelewsky, Alexander von; Llobet, Antoni; Benet-Buchholz, Jordi

    2008-01-01

    New polypyridylic chiral ligands, having either C₃ or lower symmetry, have been prepared via a de novo construction of the pyridine nucleus by means of Kröhnke methodology in the key step. The chiral moieties of these ligands originate from the monoterpen chiral pool, namely (-)-α-pinene ((-)-14, (-)-15) and (-)-myrtenal ((-)-9, (-)-10). Extension of the above-mentioned asymmetric synthesis procedure to the preparation of enantiopure derivatives of some commonly used polypyridylic ligands has...

  19. Effects of PPARγ ligands on vascular tone.

    Science.gov (United States)

    Salomone, Salvatore; Drago, Filippo

    2012-06-01

    Peroxisome Proliferator-Activated Receptor γ (PPARγ), originally described as a transcription factor for genes of carbohydrate and lipid metabolism, has been more recently studied in the context of cardiovascular pathophysiology. Here, we review the available data on PPARγ ligands as modulator of vascular tone. PPARγ ligands include: thiazolidinediones (used in the treatment of type 2 diabetes mellitus), glitazars (bind and activate both PPARγ and PPARα), and other experimental drugs (still in development) that exploit the chemistry of thiazolidinediones as a scaffold for PPARγ-independent pharmacological properties. In this review, we examine both short (mostly from in vitro data)- and long (mostly from in vivo data)-term effects of PPARγ ligands that extend from PPARγ-independent vascular effects to PPARγ-dependent gene expression. Because endothelium is a master regulator of vascular tone, we have attempted to differentiate between endothelium-dependent and endothelium-independent effects of PPARγ ligands. Based on available data, we conclude that PPARγ ligands appear to influence vascular tone in different experimental paradigms, most often in terms of vasodilatation (potentially increasing blood flow to some tissues). These effects on vascular tone, although potentially beneficial, must be weighed against specific cardiovascular warnings that may apply to some drugs, such as rosiglitazone.

  20. Regulation mechanisms of the FLT3-ligand after irradiation

    International Nuclear Information System (INIS)

    Prat-Lepesant, M.

    2005-06-01

    The hematopoietic compartment is one of the most severely damaged after chemotherapy, radiotherapy or accidental irradiations. Whatever its origin, the resulting damage to the bone marrow remains difficult to evaluate. Thus, it would be of great interest to get a biological indicator of residual hematopoiesis in order to adapt the treatment to each clinical situation. Recent results indicated that the plasma Flt3 ligand concentration was increased in patients suffering from either acquired or induced aplasia, suggesting that Flt3 ligand might be useful as a biological indicator of bone marrow status. We thus followed in a mouse model as well as in several clinical situations the variations in plasma Flt3 ligand concentration, after either homogeneous or heterogeneous irradiations. These variations were correlated to the number of hematopoietic progenitors and to other parameters such as duration and depth of pancytopenia. The results indicated that the concentration of Flt3 ligand in the blood reflects the bone marrow status, and that the follow-up of plasma Flt3 ligand concentration could give predictive information about the bone marrow function and the duration and severity of pancytopenia and thrombocytopenia. Nevertheless, the clinical use of Flt3 ligand as a biological indicator of bone marrow damage require the knowledge of the mechanisms regulating the variations in plasma Flt3 ligand concentration. We thus developed a study in the mouse model. The results indicated that the variations in plasma Flt3 ligand variations were not solely due to a balance between its production by lymphoid cells and its consumption by hematopoietic cells. Moreover, we showed that T lymphocytes are not the main regulator of plasma Flt3 ligand concentration as previously suggested, and that other cell types, possibly including bone marrow stromal cells, might be strongly implicated. These results also suggest that the Flt3 ligand is a main systemic regulator of hematopoiesis

  1. Relation of major volcanic center concentration on Venus to global tectonic patterns

    Science.gov (United States)

    Crumpler, L. S.; Head, James W.; Aubele, Jayne C.

    1993-01-01

    Global analysis of Magellan image data indicates that a major concentration of volcanic centers covering about 40 percent of the surface of Venus occurs between the Beta, Atla, and Themis regions. Associated with this enhanced concentration are geological characteristics commonly interpreted as rifting and mantle upwelling. Interconnected low plains in an annulus around this concentration are characterized by crustal shortening and infrequent volcanic centers that may represent sites of mantle return flow and net downwelling. Together, these observations suggest the existence of relatively simple, large-scale patterns of mantle circulation similar to those associated with concentrations of intraplate volcanism on earth.

  2. Effects of Center Offset and Noise on Weak-Lensing Derived Concentration-Mass Relation of Dark Matter Halos

    Science.gov (United States)

    Du, Wei; Fan, Zuhui

    2014-04-01

    With the halo catalog from the Millennium Simulation, we analyze the weak-lensing measured density profiles for clusters of galaxies, paying attention to the determination of the concentration-mass (c-M) relation, which can be biased by the center offset, selection effect, and shape noise from intrinsic ellipticities of background galaxies. Several different methods of locating the center of a cluster from weak-lensing effects alone are explored. We find that, for intermediate redshift clusters, the highest peak from our newly proposed two-scale smoothing method applied to the reconstructed convergence field, first with a smoothing scale of 2' and then 0.'5, corresponds best to the true center. Assuming the parameterized Navarro-Frenk-White profile, we fit the reduced tangential shear signals around different centers identified by different methods. It is shown that, for the ensemble median values, a center offset larger than one scale radius rs can bias the derived mass and concentration significantly lower than the true values, especially for low-mass halos. However, the existence of noise can compensate for the offset effect and reduce the systematic bias, although the scatter of mass and concentration becomes considerably larger. Statistically, the bias effect of center offset on the c-M relation is insignificant if an appropriate center finding method is adopted. On the other hand, noise from intrinsic ellipticities can bias the c-M relation derived from a sample of weak-lensing analyzed clusters if a simple χ2 fitting method is used. To properly account for the scatter and covariance between c and M, we apply a Bayesian method to improve the statistical analysis of the c-M relation. It is shown that this new method allows us to derive the c-M relation with significantly reduced biases.

  3. Effects of center offset and noise on weak-lensing derived concentration-mass relation of dark matter halos

    International Nuclear Information System (INIS)

    Du, Wei; Fan, Zuhui

    2014-01-01

    With the halo catalog from the Millennium Simulation, we analyze the weak-lensing measured density profiles for clusters of galaxies, paying attention to the determination of the concentration-mass (c-M) relation, which can be biased by the center offset, selection effect, and shape noise from intrinsic ellipticities of background galaxies. Several different methods of locating the center of a cluster from weak-lensing effects alone are explored. We find that, for intermediate redshift clusters, the highest peak from our newly proposed two-scale smoothing method applied to the reconstructed convergence field, first with a smoothing scale of 2' and then 0.'5, corresponds best to the true center. Assuming the parameterized Navarro-Frenk-White profile, we fit the reduced tangential shear signals around different centers identified by different methods. It is shown that, for the ensemble median values, a center offset larger than one scale radius r s can bias the derived mass and concentration significantly lower than the true values, especially for low-mass halos. However, the existence of noise can compensate for the offset effect and reduce the systematic bias, although the scatter of mass and concentration becomes considerably larger. Statistically, the bias effect of center offset on the c-M relation is insignificant if an appropriate center finding method is adopted. On the other hand, noise from intrinsic ellipticities can bias the c-M relation derived from a sample of weak-lensing analyzed clusters if a simple χ 2 fitting method is used. To properly account for the scatter and covariance between c and M, we apply a Bayesian method to improve the statistical analysis of the c-M relation. It is shown that this new method allows us to derive the c-M relation with significantly reduced biases.

  4. Misuse of thermodynamics in the interpretation of isothermal titration calorimetry data for ligand binding to proteins.

    Science.gov (United States)

    Pethica, Brian A

    2015-03-01

    Isothermal titration calorimetry (ITC) has given a mass of data on the binding of small molecules to proteins and other biopolymers, with particular interest in drug binding to proteins chosen as therapeutic indicators. Interpretation of the enthalpy data usually follows an unsound protocol that uses thermodynamic relations in circumstances where they do not apply. Errors of interpretation include incomplete definitions of ligand binding and equilibrium constants and neglect of the non-ideality of the solutions under study, leading to unreliable estimates of standard free energies and entropies of binding. The mass of reported thermodynamic functions for ligand binding to proteins estimated from ITC enthalpies alone is consequently of uncertain thermodynamic significance and utility. ITC and related experiments to test the protocol assumptions are indicated. A thermodynamic procedure avoiding equilibrium constants or other reaction models and not requiring protein activities is given. The discussion draws attention to the fundamental but neglected relation between the thermodynamic activity and bioactivity of drugs and to the generally unknown thermodynamic status of ligand solutions, which for drugs relates directly to effective therapeutic dosimetry. Copyright © 2014 Elsevier Inc. All rights reserved.

  5. Redox Potentials of Ligands and Complexes – a DFT Approach

    African Journals Online (AJOL)

    NICO

    A review of the limited literature concerned with theoretical ways to predict experimentally measured redox potentials of ligands and ... electrode surface, over-potentials and high solvent resistance, ... A correlation coefficient of 0.969 in the linear relation with ... of E0' were performed in two steps, i.e. calculation of the free.

  6. Catalposide is a natural agonistic ligand of peroxisome proliferator-activated receptor-α

    International Nuclear Information System (INIS)

    Lee, Ji Hae; Jun, Hee-jin; Hoang, Minh-Hien; Jia, Yaoyao; Han, Xiang Hua; Lee, Dong-Ho; Lee, Hak-Ju; Hwang, Bang Yeon; Lee, Sung-Joon

    2012-01-01

    Highlights: ► Catalposide is a novel ligand for PPARα. ► Cell stimulated with catalposide improved fatty acid uptake, regulated target genes in fatty acid β-oxidation and synthesis. ► Catalposdie reduces hepatic triacylglycerides. ► Theses demonstrate catalposide could ameliorate hyperlipidemia and hepatic steatosis. -- Abstract: Peroxisome proliferator-activated receptor-alpha (PPARα) is a nuclear receptor that regulates the expression of genes related to cellular lipid uptake and oxidation. Thus, PPARα agonists may be important in the treatment of hypertriglyceridemia and hepatic steatosis. In this study, we demonstrated that catalposide is a novel natural PPARα agonist, identified from reporter gene assay-based activity screening with approximately 900 natural plant and seaweed extracts. Results of time-resolved fluorescence resonance energy transfer analyses suggested that the compound interacted directly with the ligand-binding domain of PPARα. Cultured hepatocytes stimulated with catalposide exhibited significantly reduced cellular triglyceride concentrations, by 21%, while cellular uptake of fatty acids was increased, by 70% (P < 0.05). Quantitative PCR analysis revealed that the increase in cellular fatty acid uptake was due to upregulation of fatty acid transporter protein-4 (+19% vs. the control) in cells stimulated with catalposide. Additionally, expression of genes related to fatty acid oxidation and high-density lipoprotein metabolism were upregulated, while that of genes related to fatty acid synthesis were suppressed. In conclusion, catalposide is hypolipidemic by activation of PPARα via a ligand-mediated mechanism that modulates the expression of in lipid metabolism genes in hepatocytes.

  7. Prediction of ligand effects in platinum-amyloid-β coordination.

    Science.gov (United States)

    Turner, Matthew; Deeth, Robert J; Platts, James A

    2017-08-01

    Ligand field molecular mechanics (LFMM) and semi-empirical Parametric Model 7 (PM7) methods are applied to a series of six Pt II -Ligand systems binding to the N-terminal domain of the amyloid-β (Aβ) peptide. Molecular dynamics using a combined LFMM/Assisted Model Building with Energy Refinement (AMBER) approach is used to explore the conformational freedom of the peptide fragment, and identifies favourable platinum binding modes and peptide conformations for each ligand investigated. Platinum coordination is found to depend on the nature of the ligand, providing evidence that binding mode may be controlled by suitable ligand design. Boltzmann populations at 310K indicate that each Pt-Aβ complex has a small number of thermodynamically accessible states. Ramachandran maps are constructed for the sampled Pt-Aβ conformations and secondary structural analysis of the obtained complex structures is performed and contrasted with the free peptide; coordination of these platinum complexes disrupts existing secondary structure in the Aβ peptide and promotes formation of ligand-specific turn-type secondary structure. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Structural Diversity of Metallosupramolecular Assemblies Based on the Bent Bridging Ligand 4,4′-Dithiodipyridine

    Directory of Open Access Journals (Sweden)

    Rüdiger W. Seidel

    2013-05-01

    Full Text Available 4,4′-Dithiodipyridine (dtdp, also termed 4,4′-dipyridyldisulfide, is a bridging ligand of the 4,4′-bipyridine type. The introduction of the disulfide moiety inevitably leads to a relatively rigid angular structure, which exhibits axial chirality. More than 90 metal complexes containing the dtdp ligand have been crystallographically characterised until now. This review focuses on the preparation and structural diversity of discrete and polymeric metallosupramolecular assemblies constructed from dtdp as bridging ligands. These encompass metallamacrocycles with M2L2 topology and coordination polymers with periodicity in one or two dimensions. One-dimensional coordination polymers represent the vast majority of the metallosupramolecular structures obtained from dtdp. These include repeated rhomboids, zigzag, helical and arched chains among other types. In this contribution, we make an attempt to provide a comprehensive account of the structural data that are currently available for metallosupramolecular assemblies based on the bent bridging ligand dtdp.

  9. Magnetic levitation as a platform for competitive protein-ligand binding assays.

    Science.gov (United States)

    Shapiro, Nathan D; Soh, Siowling; Mirica, Katherine A; Whitesides, George M

    2012-07-17

    This paper describes a method based on magnetic levitation (MagLev) that is capable of indirectly measuring the binding of unlabeled ligands to unlabeled protein. We demonstrate this method by measuring the affinity of unlabeled bovine carbonic anhydrase (BCA) for a variety of ligands (most of which are benzene sulfonamide derivatives). This method utilizes porous gel beads that are functionalized with a common aryl sulfonamide ligand. The beads are incubated with BCA and allowed to reach an equilibrium state in which the majority of the immobilized ligands are bound to BCA. Since the beads are less dense than the protein, protein binding to the bead increases the overall density of the bead. This change in density can be monitored using MagLev. Transferring the beads to a solution containing no protein creates a situation where net protein efflux from the bead is thermodynamically favorable. The rate at which protein leaves the bead for the solution can be calculated from the rate at which the levitation height of the bead changes. If another small molecule ligand of BCA is dissolved in the solution, the rate of protein efflux is accelerated significantly. This paper develops a reaction-diffusion (RD) model to explain both this observation, and the physical-organic chemistry that underlies it. Using this model, we calculate the dissociation constants of several unlabeled ligands from BCA, using plots of levitation height versus time. Notably, although this method requires no electricity, and only a single piece of inexpensive equipment, it can measure accurately the binding of unlabeled proteins to small molecules over a wide range of dissociation constants (K(d) values within the range from ~10 nM to 100 μM are measured easily). Assays performed using this method generally can be completed within a relatively short time period (20 min-2 h). A deficiency of this system is that it is not, in its present form, applicable to proteins with molecular weight greater

  10. A grand unified model for liganded gold clusters

    Science.gov (United States)

    Xu, Wen Wu; Zhu, Beien; Zeng, Xiao Cheng; Gao, Yi

    2016-12-01

    A grand unified model (GUM) is developed to achieve fundamental understanding of rich structures of all 71 liganded gold clusters reported to date. Inspired by the quark model by which composite particles (for example, protons and neutrons) are formed by combining three quarks (or flavours), here gold atoms are assigned three `flavours' (namely, bottom, middle and top) to represent three possible valence states. The `composite particles' in GUM are categorized into two groups: variants of triangular elementary block Au3(2e) and tetrahedral elementary block Au4(2e), all satisfying the duet rule (2e) of the valence shell, akin to the octet rule in general chemistry. The elementary blocks, when packed together, form the cores of liganded gold clusters. With the GUM, structures of 71 liganded gold clusters and their growth mechanism can be deciphered altogether. Although GUM is a predictive heuristic and may not be necessarily reflective of the actual electronic structure, several highly stable liganded gold clusters are predicted, thereby offering GUM-guided synthesis of liganded gold clusters by design.

  11. Determination, at equilibrium, of association constants of labelled or unlabelled ligands by a non-graphical method

    International Nuclear Information System (INIS)

    Goertz, G.; Longchampt, J.; Crepy, O.; Judas, O.; Jayle, M.-F.

    1976-01-01

    Determination, at equilibrium of association constants of labelled or unlabelled ligands by a non-graphical method are described. This work deals with the determination of association constants at equilibrium by a non-graphical method in binding systems containing one specific receptor. Equations have been derived from that originally described by Lea (Biochim. Biophys. Acta, 322, 68-74), the terms of which are obtained from the data of simple displacement curves of a bound radioactive ligand by unlabelled competitors identical or different in nature. By knowing the function relating the variations of the bound ligand (B) to the affinity constant (Ksub(i)) and the quantity (Msub(i)) of competitor for a given system, it is possible to calculate any of these parameters when the two others are measured. Thus, it becomes easy to compare the relative affinities of different receptors for the same ligand or that of one receptor for various labelled or unlabelled ligands. Furthermore, theoretical displacement curves can be drawn and compared to experimental data, only when knowing the affinity constant of a specific binding system in given conditions. These modes of calculation have been tested in a study of interactions between various steroids and a fraction of human serum proteins precipitated by ammonium sulfate (30-45%) and containing the sex hormone-binding globulin. Association constants thus obtained agree well with those reported in the literature and determined by graphical procedures

  12. Reversible Size Control of Silver Nanoclusters via Ligand-exchange

    KAUST Repository

    Bootharaju, Megalamane Siddaramappa

    2015-05-21

    The properties of atomically monodisperse noble metal nanoclusters (NCs) are intricately intertwined with their precise molecular formula. The vast majority of size-specific NC syntheses start from the reduction of the metal salt and thiol ligand mixture. Only in gold was it recently shown that ligand-exchange could induce the growth of NCs from one atomically precise species to another; a process of yet unknown reversibility. Here, we present a process for the ligand-exchange-induced growth of atomically precise silver NCs, in a biphasic liquid-liquid system, which is particularly of interest because of its complete reversibility and ability to occur at room temperature. We explore this phenomenon in-depth using Ag35(SG)18 [SG= glutathionate] and Ag44(4-FTP)30 [4-FTP= 4-fluorothiophenol] as model systems. We show that the ligand-exchange conversion of Ag35(SG)18 into Ag44(4-FTP)30 is rapid (< 5 min) and direct, while the reverse process proceeds slowly through intermediate cluster sizes. We adapt a recently developed theory of reverse Ostwald ripening to model the NCs’ interconvertibility. The model’s predictions are in good agreement with the experimental observations, and they highlight the importance of small changes in the ligand-metal binding energy in determining the final equilibrium NC size. Based on the insight provided by this model, we demonstrated experimentally that by varying the choice of ligands, ligand-exchange can be used to obtain different sized NCs. The findings in this work establish ligand-exchange as a versatile tool for tuning cluster sizes.

  13. Reversible Size Control of Silver Nanoclusters via Ligand-exchange

    KAUST Repository

    Bootharaju, Megalamane Siddaramappa; Burlakov, Victor M.; Besong, Tabot M.D.; Joshi, Chakra Prasad; AbdulHalim, L; Black, David; Whetten, Robert; Goriely, Alain; Bakr, Osman

    2015-01-01

    The properties of atomically monodisperse noble metal nanoclusters (NCs) are intricately intertwined with their precise molecular formula. The vast majority of size-specific NC syntheses start from the reduction of the metal salt and thiol ligand mixture. Only in gold was it recently shown that ligand-exchange could induce the growth of NCs from one atomically precise species to another; a process of yet unknown reversibility. Here, we present a process for the ligand-exchange-induced growth of atomically precise silver NCs, in a biphasic liquid-liquid system, which is particularly of interest because of its complete reversibility and ability to occur at room temperature. We explore this phenomenon in-depth using Ag35(SG)18 [SG= glutathionate] and Ag44(4-FTP)30 [4-FTP= 4-fluorothiophenol] as model systems. We show that the ligand-exchange conversion of Ag35(SG)18 into Ag44(4-FTP)30 is rapid (< 5 min) and direct, while the reverse process proceeds slowly through intermediate cluster sizes. We adapt a recently developed theory of reverse Ostwald ripening to model the NCs’ interconvertibility. The model’s predictions are in good agreement with the experimental observations, and they highlight the importance of small changes in the ligand-metal binding energy in determining the final equilibrium NC size. Based on the insight provided by this model, we demonstrated experimentally that by varying the choice of ligands, ligand-exchange can be used to obtain different sized NCs. The findings in this work establish ligand-exchange as a versatile tool for tuning cluster sizes.

  14. Glutamate receptor ligands

    DEFF Research Database (Denmark)

    Guldbrandt, Mette; Johansen, Tommy N; Frydenvang, Karla Andrea

    2002-01-01

    Homologation and substitution on the carbon backbone of (S)-glutamic acid [(S)-Glu, 1], as well as absolute stereochemistry, are structural parameters of key importance for the pharmacological profile of (S)-Glu receptor ligands. We describe a series of methyl-substituted 2-aminoadipic acid (AA...

  15. Steric Maps to Evaluate the Role of Steric Hindrance on the IPr NHC Ligand

    KAUST Repository

    Poater, Albert

    2013-06-01

    Density functional theory (DFT) calculations were used to predict and rationalize the effect of the modification of the structure of the prototype 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) (IPr) N-heterocyclic carbene (NHC) ligand. The modification consists in the substitution of the methyl groups of ortho isopropyl substituent with phenyl groups, and here we plan to describe how such significant changes effect the metal environment and therefore the related catalytic behaviour by simple steric maps. Bearing in mind that there is a significant structural difference between IPr and IPr* ligands, that translated in different reactivity for several olefin metathesis reactions, here by means of DFT we characterize where the NHC ligand plays a more active role and where it is a simple spectator, or at least its modification does not significantly change its catalytic role/performance. Furthermore, this communication endeavours to modify further the skeleton of the IPr NHC ligand. The optimization of these bulky new systems go to the limits of the DFT computational method.

  16. Structural characterization of natural nickel and copper binding ligands along the US GEOTRACES Eastern Pacific Zonal transect

    Directory of Open Access Journals (Sweden)

    Rene M Boiteau

    2016-11-01

    Full Text Available Organic ligands form strong complexes with many trace elements in seawater. Various metals can compete for the same ligand chelation sites, and the final speciation of bound metals is determined by relative binding affinities, concentrations of binding sites, uncomplexed metal concentrations, and association/dissociation kinetics. Different ligands have a wide range of metal affinities and specificities. However, the chemical composition of these ligands in the marine environment remains poorly constrained, which has hindered progress in modeling marine metal speciation. In this study, we detected and characterized natural ligands that bind copper (Cu and nickel (Ni in the eastern South Pacific Ocean with liquid chromatography tandem inductively coupled plasma mass spectrometry (LC-ICPMS, and high resolution electrospray ionization mass spectrometry (ESIMS. Dissolved Cu, Ni, and ligand concentrations were highest near the coast. Chromatographically unresolved polar compounds dominated ligands isolated near the coast by solid phase extraction. Offshore, metal and ligand concentrations decreased, but several new ligands appeared. One major ligand was detected that bound both Cu2+ and Ni2+. Based on accurate mass and fragmentation measurements, this compound has a molecular formula of C20H21N4O8S2 + M+ (M = metal isotope and contains several azole-like metal binding groups. Additional lipophilic Ni complexes were also present only in oligotrophic waters, with masses of 649, 698, and 712 m/z (corresponding to the 58Ni metal complex. Molecular formulae of C32H54N3O6S2Ni+ and C33H56N3O6S2Ni+ were determined for two of these compounds. Addition of Cu and Ni to the samples also revealed the presence of additional compounds that can bind both Ni and Cu. Although these specific compounds represent a small fraction of the total dissolved Cu and Ni pool, they highlight the compositional diversity and spatial heterogeneity of marine Ni and Cu ligands, as

  17. Automated identification of crystallographic ligands using sparse-density representations

    International Nuclear Information System (INIS)

    Carolan, C. G.; Lamzin, V. S.

    2014-01-01

    A novel procedure for identifying ligands in macromolecular crystallographic electron-density maps is introduced. Density clusters in such maps can be rapidly attributed to one of 82 different ligands in an automated manner. A novel procedure for the automatic identification of ligands in macromolecular crystallographic electron-density maps is introduced. It is based on the sparse parameterization of density clusters and the matching of the pseudo-atomic grids thus created to conformationally variant ligands using mathematical descriptors of molecular shape, size and topology. In large-scale tests on experimental data derived from the Protein Data Bank, the procedure could quickly identify the deposited ligand within the top-ranked compounds from a database of candidates. This indicates the suitability of the method for the identification of binding entities in fragment-based drug screening and in model completion in macromolecular structure determination

  18. CXCR4 Ligands : The Next Big Hit?

    NARCIS (Netherlands)

    Walenkamp, Annemiek M. E.; Lapa, Constantin; Herrmann, Ken; Wester, Hans-Juergen

    2017-01-01

    The G protein-coupled protein receptor C-X-C chemokine receptor 4 (CXCR4) is an attractive target for cancer diagnosis and treatment, as it is overexpressed in many solid and hematologic cancers. Binding of its ligand, C-X-C chemokine ligand 12 (CXCL12), results in receptor internalization and

  19. Polymerization catalysts containing electron-withdrawing amide ligands

    Science.gov (United States)

    Watkin, John G.; Click, Damon R.

    2002-01-01

    The present invention describes methods of making a series of amine-containing organic compounds which are used as ligands for group 3-10 and lanthanide metal compounds. The ligands have electron-withdrawing groups bonded to them. The metal compounds, when combined with a cocatalyst, are catalysts for the polymerization of olefins.

  20. Synthesis and study of new oxazoline-based ligands

    OpenAIRE

    Tilliet, Mélanie

    2008-01-01

    This thesis deals with the study of oxazoline-based ligands in metal-catalyzed asymmetric reactions. The first part describes the synthesis of six new bifunctinal pyridine-bis(oxazoline) ligands and their applications in asymmetric metal-catalysis. These ligands, in addition to a Lewis acid coordination site, are equipped with a Lewis basic part in the 4-position of the oxazoline rings. Dual activation by means of this system was probed in cyanide addition to aldehydes. The second part is con...

  1. Selectivity in ligand recognition of G-quadruplex loops.

    Science.gov (United States)

    Campbell, Nancy H; Patel, Manisha; Tofa, Amina B; Ghosh, Ragina; Parkinson, Gary N; Neidle, Stephen

    2009-03-03

    A series of disubstituted acridine ligands have been cocrystallized with a bimolecular DNA G-quadruplex. The ligands have a range of cyclic amino end groups of varying size. The crystal structures show that the diagonal loop in this quadruplex results in a large cavity for these groups, in contrast to the steric constraints imposed by propeller loops in human telomeric quadruplexes. We conclude that the nature of the loop has a significant influence on ligand selectivity for particular quadruplex folds.

  2. [Factors related to the life space of daycare center users].

    Science.gov (United States)

    Kawamura, Koki; Kato, Chikako; Kondo, Izumi

    2018-01-01

    We examined the factors related to life space and changes in the care level after one year in daycare center users. The participants were 83 older adults (age, > 65 years; mean age, 79.5±6.8 years) with MMSE scores of ≥20, who could walk independently, who needed support (1-2) or care (1), and who underwent rehabilitation at a daycare center. The life space was evaluated by the Life Space Assessment (LSA). The subjects' basic information (i.e., age, medical history.) was collected, and their physical function (i.e., grip strength, timed up and go test [TUG]), mental function (i.e., vitality, fear of falls), and social function (i.e., friends, hobbies, public transportation) were assessed to investigate the factors associated with their LSA scores. In addition, a follow-up survey was conducted on the care level at approximately one year later. A multiple regression analysis indicated that TUG scores (β=-0.33), hobbies (β=0.30), friends (β=0.29), public transportation (β=0.26), and grip strength (β=0.24) were related to the life space. Next, the participants were divided into LSA-high and LSA-low groups, and changes in the care level (improvement, maintenance, deterioration) at approximately one year after the initial assessment were examined using a chi-squared test. A significant difference was observed in the distribution of the groups (p=0.03). Multiple factors were related to the life space. Moreover, it is possible that improvements in the level of care may be achieved by improving the life space.

  3. Copper complexing ligands and organic matter characterization in the northern Adriatic Sea

    Science.gov (United States)

    Plavšić, Marta; Gašparović, Blaženka; Strmečki, Slađana; Vojvodić, Vjeročka; Tepić, Nataša

    2009-11-01

    The study on dissolved organic ligands capable to complex copper ions (L T), surface-active substances (SAS) and dissolved organic carbon (DOC) in the Northern Adriatic Sea station (ST 101) under the influence of Po River was conducted in period from 2006-2008. The acidity of surface-active organic material (Ac r) was followed as well. The results are compared to temperature and salinity distributions. On that way, the contribution of the different pools of ligands capable to complex Cu ions could be determined as well as the influence of aging and transformation of the organic matter. The L T values in the investigated period were in the range of 40-300 nmol l -1. The range of DOC values for surface and bottom samples were 0.84-1.87 mg l -1 and 0.80-1.30 mg l -1, respectively. Total SAS concentrations in the bottom layer were 0.045-0.098 mg l -1 in equiv. of Triton-X-100 while those in the surface layer were 0.050-0.143 mg l -1 in equiv. of Triton-X-100. The majority of organic ligands responsible for Cu binding in surface water originate from new phytoplankton production promoted by river borne nutrients. Older, transformed organic matter, possessing higher relative acidity, is the main contributor to the pool of organic ligands that bind copper in the bottom samples. It was estimated that ˜9% of DOC in surface samples and ˜12% of DOC in the bottom samples are present as ligands capable to complex copper ions.

  4. Effects of different ligands on epidermal growth factor receptor (EGFR) nuclear translocation

    International Nuclear Information System (INIS)

    Faria, Jerusa A.Q.A.; Andrade, Carolina de; Goes, Alfredo M.; Rodrigues, Michele A.; Gomes, Dawidson A.

    2016-01-01

    The epidermal growth factor receptor (EGFR) is activated through binding to specific ligands and generates signals for proliferation, differentiation, migration, and cell survival. Recent data show the role of nuclear EGFR in tumors. Although many EGFR ligands are upregulated in cancers, little is known about their effects on EGFR nuclear translocation. We have compared the effects of six EGFR ligands (EGF, HB-EGF, TGF-α, β-Cellulin, amphiregulin, and epiregulin) on nuclear translocation of EGFR, receptor phosphorylation, migration, and proliferation. Cell fractionation and confocal immunofluorescence detected EGFR in the nucleus after EGF, HB-EGF, TGF-α and β-Cellulin stimulation in a dose-dependent manner. In contrast, amphiregulin and epiregulin did not generate nuclear translocation of EGFR. EGF, HB-EGF, TGF-α and β-Cellulin showed correlations between a higher rate of wound closure and increased phosphorylation of residues in the carboxy-terminus of EGFR, compared to amphiregulin and epiregulin. The data indicate that EGFR is translocated to the nucleus after stimulation with EGF, HB-EGF, TGF-α and β-Cellulin, and that these ligands are related to increased phosphorylation of EGFR tyrosine residues, inducing migration of SkHep-1 cells. - Highlights: • EGF, HB-EGF, TGF-α, β-Cellulin are involved in the EGFR nuclear translocation. • Amphiregulin and epiregulin did not promote nuclear translocation of EGFR. • EGF, HB-EGF, TGF-α and β-Cellulin have a role in SkHep-1 cells migration. • EGFR ligands associated with better prognosis don't stimulate EGFR translocation.

  5. Effects of different ligands on epidermal growth factor receptor (EGFR) nuclear translocation

    Energy Technology Data Exchange (ETDEWEB)

    Faria, Jerusa A.Q.A.; Andrade, Carolina de; Goes, Alfredo M. [Department of Biochemistry and Immunology, Universidade Federal de Minas Gerais, Av. Antonio Carlos, 6627, Belo Horizonte, MG, 31270-901 (Brazil); Rodrigues, Michele A. [Department of Biochemistry and Immunology, Universidade Federal de Minas Gerais, Av. Antonio Carlos, 6627, Belo Horizonte, MG, 31270-901 (Brazil); Department of General Pathology, Universidade Federal de Minas Gerais, Av. Antonio Carlos, 6627, Belo Horizonte, MG, 31270-901 (Brazil); Gomes, Dawidson A., E-mail: dawidson@ufmg.br [Department of Biochemistry and Immunology, Universidade Federal de Minas Gerais, Av. Antonio Carlos, 6627, Belo Horizonte, MG, 31270-901 (Brazil)

    2016-09-09

    The epidermal growth factor receptor (EGFR) is activated through binding to specific ligands and generates signals for proliferation, differentiation, migration, and cell survival. Recent data show the role of nuclear EGFR in tumors. Although many EGFR ligands are upregulated in cancers, little is known about their effects on EGFR nuclear translocation. We have compared the effects of six EGFR ligands (EGF, HB-EGF, TGF-α, β-Cellulin, amphiregulin, and epiregulin) on nuclear translocation of EGFR, receptor phosphorylation, migration, and proliferation. Cell fractionation and confocal immunofluorescence detected EGFR in the nucleus after EGF, HB-EGF, TGF-α and β-Cellulin stimulation in a dose-dependent manner. In contrast, amphiregulin and epiregulin did not generate nuclear translocation of EGFR. EGF, HB-EGF, TGF-α and β-Cellulin showed correlations between a higher rate of wound closure and increased phosphorylation of residues in the carboxy-terminus of EGFR, compared to amphiregulin and epiregulin. The data indicate that EGFR is translocated to the nucleus after stimulation with EGF, HB-EGF, TGF-α and β-Cellulin, and that these ligands are related to increased phosphorylation of EGFR tyrosine residues, inducing migration of SkHep-1 cells. - Highlights: • EGF, HB-EGF, TGF-α, β-Cellulin are involved in the EGFR nuclear translocation. • Amphiregulin and epiregulin did not promote nuclear translocation of EGFR. • EGF, HB-EGF, TGF-α and β-Cellulin have a role in SkHep-1 cells migration. • EGFR ligands associated with better prognosis don't stimulate EGFR translocation.

  6. Ligand mobility modulates immunological synapse formation and T cell activation.

    Directory of Open Access Journals (Sweden)

    Chih-Jung Hsu

    Full Text Available T cell receptor (TCR engagement induces clustering and recruitment to the plasma membrane of many signaling molecules, including the protein tyrosine kinase zeta-chain associated protein of 70 kDa (ZAP70 and the adaptor SH2 domain-containing leukocyte protein of 76 kDa (SLP76. This molecular rearrangement results in formation of the immunological synapse (IS, a dynamic protein array that modulates T cell activation. The current study investigates the effects of apparent long-range ligand mobility on T cell signaling activity and IS formation. We formed stimulatory lipid bilayers on glass surfaces from binary lipid mixtures with varied composition, and characterized these surfaces with respect to diffusion coefficient and fluid connectivity. Stimulatory ligands coupled to these surfaces with similar density and orientation showed differences in their ability to activate T cells. On less mobile membranes, central supramolecular activation cluster (cSMAC formation was delayed and the overall accumulation of CD3ζ at the IS was reduced. Analysis of signaling microcluster (MC dynamics showed that ZAP70 MCs exhibited faster track velocity and longer trajectories as a function of increased ligand mobility, whereas movement of SLP76 MCs was relatively insensitive to this parameter. Actin retrograde flow was observed on all surfaces, but cell spreading and subsequent cytoskeletal contraction were more pronounced on mobile membranes. Finally, increased tyrosine phosphorylation and persistent elevation of intracellular Ca(2+ were observed in cells stimulated on fluid membranes. These results point to ligand mobility as an important parameter in modulating T cell responses.

  7. Organotellurium ligands – designing and complexation reactions

    Indian Academy of Sciences (India)

    Unknown

    membered rings it is negative and ~30 ppm only. Keywords. Organotellurium ligands; hybrid telluroether; platinum metal complexes; tellurium-125 NMR. 1. Introduction. Tellurium is the noblest metalloid which may act as a Lewis acid as well as Lewis base. The ligand chemistry of tellurium, which acts as a 'soft' donor, was ...

  8. Preparation, Spectroscopic Investigation and Biological Activity of New Mixed Ligand Chelates

    International Nuclear Information System (INIS)

    Alassbaly, F.S.; Ajaily, M.M.E.

    2014-01-01

    Preparation and investigation of new Co(II), Ni(II), Zn(II) and Cr(III) chelates with mixed ligands including Schiff base (L1) formed from the condensation of 4-dimethylaminobenzaldehyde with 2-aminophenol and anthranilic acid (L2) were studied. The obtained Schiff base and mixed ligand chelates were subjected to several physiochemical techniques, in terms of CHN elemental analyses, molar conductivity, magnetic moment measurements, infrared, proton nuclear magnetic resonance, electronic and mass spectra. The analytical data showed the formation of the Schiff base compound and the ratio of metal to ligands of the chelates are 1:1:1(M:L1:L2). The infrared spectral data exhibited that the used ligands behaving as bidentate ligands towards the metal ions. The proton nuclear magnetic resonance spectral data showed the signals of the active groups in the ligands which entered in chelation with Zn(II) metal ion. The electronic spectral results showed the existence of pie (phenyl ring) and n = pie (C=N) of the ligands and suggested the geometrical structures of the chelates. Meanwhile, the mass spectral data revealed the fragmentations of the Schiff base, anthranilic acid and their Ni(II) mixed ligand chelate has been preformed the only chelate conducted for justification. All the prepared mixed chelates were non-electrolyte in nature. The antibacterial activity of the Schiff base, anthranilic acid, metal salts and mixed ligand chelates were studied and found to be that mixed ligand chelates have the most biological activity in comparison to the free ligands and salts. (author)

  9. Free-energy relationships in ion channels activated by voltage and ligand

    Science.gov (United States)

    Chowdhury, Sandipan

    2013-01-01

    Many ion channels are modulated by multiple stimuli, which allow them to integrate a variety of cellular signals and precisely respond to physiological needs. Understanding how these different signaling pathways interact has been a challenge in part because of the complexity of underlying models. In this study, we analyzed the energetic relationships in polymodal ion channels using linkage principles. We first show that in proteins dually modulated by voltage and ligand, the net free-energy change can be obtained by measuring the charge-voltage (Q-V) relationship in zero ligand condition and the ligand binding curve at highly depolarizing membrane voltages. Next, we show that the voltage-dependent changes in ligand occupancy of the protein can be directly obtained by measuring the Q-V curves at multiple ligand concentrations. When a single reference ligand binding curve is available, this relationship allows us to reconstruct ligand binding curves at different voltages. More significantly, we establish that the shift of the Q-V curve between zero and saturating ligand concentration is a direct estimate of the interaction energy between the ligand- and voltage-dependent pathway. These free-energy relationships were tested by numerical simulations of a detailed gating model of the BK channel. Furthermore, as a proof of principle, we estimate the interaction energy between the ligand binding and voltage-dependent pathways for HCN2 channels whose ligand binding curves at various voltages are available. These emerging principles will be useful for high-throughput mutagenesis studies aimed at identifying interaction pathways between various regulatory domains in a polymodal ion channel. PMID:23250866

  10. Diimine triscarbonyl Re(I) of isomeric pyridyl-fulvene ligands: an electrochemical, spectroscopic, and computational investigation.

    Science.gov (United States)

    Chartrand, Daniel; Castro Ruiz, Carlos A; Hanan, Garry S

    2012-12-03

    The synthesis and characterization of a novel family of positively charged fac-[Re(bpy)(CO)(3)(L)]PF(6) (bpy = 2,2'-bipyridine) complexes are reported, where L is a pyridine functionalized in para or meta position with a fulvene moiety, namely, 4-fluoren-9-ylidenemethyl-pyridine (pFpy) and 3-fluoren-9-ylidenemethyl-pyridine (mFpy). The complexes were prepared in high yield (86%) by direct addition at room temperature of the corresponding pyridine to the tetrahydrofuran (THF) adduct fac-[Re(bpy)(CO)(3)(THF)][PF(6)] precursor. Both ligand and complex structures were fully characterized by a variety of techniques including X-ray crystallography. The complexes did not exhibit the expected triplet mixed metal-ligand-to-ligand charge transfer (MLLCT) emission, because of its deactivation by the non-emissive triplet excited state of fulvene. The absorption profile shows that the MLLCT is overshadowed by the fulvene centered π-π* transition of higher molar absorptivity as shown by time dependent density functional theory (TD-DFT) calculations. The position of the fulvene on the pyridyl ring has a large effect on this transition, the para position displaying a much higher absorption coefficient (21.3 × 10(3) M(-1) cm(-1)) at lower energy (364 nm) than the meta position (331 nm, 16.0 × 10(3) M(-1) cm(-1)).

  11. The use of random-effects models to identify health care center-related characteristics modifying the effect of antipsychotic drugs.

    Science.gov (United States)

    Nordon, Clementine; Battin, Constance; Verdoux, Helene; Haro, Josef Maria; Belger, Mark; Abenhaim, Lucien; van Staa, Tjeerd Pieter

    2017-01-01

    A case study was conducted, exploring methods to identify drugs effects modifiers, at a health care center level. Data were drawn from the Schizophrenia Outpatient Health Outcome cohort, including hierarchical information on 6641 patients, recruited from 899 health care centers from across ten European countries. Center-level characteristics included the following: psychiatrist's gender, age, length of practice experience, practice setting and type, countries' Healthcare System Efficiency score, and psychiatrist density in the country. Mixed multivariable linear regression models were used: 1) to estimate antipsychotic drugs' effectiveness (defined as the association between patients' outcome at 3 months - dependent variable, continuous - and antipsychotic drug initiation at baseline - drug A vs other antipsychotic drug); 2) to estimate the similarity between clustered data (using the intra-cluster correlation coefficient); and 3) to explore antipsychotic drug effects modification by center-related characteristics (using the addition of an interaction term). About 23% of the variance found for patients' outcome was explained by unmeasured confounding at a center level. Psychiatrists' practice experience was found to be associated with patient outcomes ( p =0.04) and modified the relative effect of "drug A" ( p <0.001), independent of center- or patient-related characteristics. Mixed models may be useful to explore how center-related characteristics modify drugs' effect estimates, but require numerous assumptions.

  12. Precipitation and growth of zinc sulfide nanoparticles in the presence of thiol-containing natural organic ligands.

    Science.gov (United States)

    Lau, Boris L T; Hsu-Kim, Heileen

    2008-10-01

    In sulfidic aquatic systems, metal sulfides can control the mobility and bioavailability of trace metal pollutants such as zinc, mercury, and silver. Nanoparticles of ZnS and other metal sulfides are known to exist in oxic and anoxic waters. However, the processes that lead to their persistence in the aquatic environment are relatively unknown. The objective of this study was to evaluate the importance of dissolved natural organics in stabilizing nanoparticulate ZnS that precipitates under environmentally relevant conditions. Precipitation and growth of ZnS particles were investigated in the presence of dissolved humic acid and low-molecular weight organic acids that are prevalent in sediment porewater. Dynamic light scattering was used to monitor the hydrodynamic diameter of particles precipitating in laboratory solutions. Zn speciation was also measured by filtering the ZnS solutions (precipitation experiments and not to the dissolved organic ligands. X-ray photoelectron spectroscopy and electron microscopy were used to confirm that amorphous particles containing Zn and S were precipitating in the suspensions. Observed growth rates of ZnS particles varied by orders of magnitude, depending on the type and concentration of organic ligand in solution. In the presence of humic acid and thiol-containing ligands (cysteine, glutathione, and thioglycolate), observed growth rates decreased by 1-3 orders of magnitude relative to controls without the ligands. In contrast, growth rates of the particles were consistently within 1 order of magnitude of the ligand-free control when oxygen- and amine-containing ligands (oxalate, serine, and glycolate) were present Furthermore, particle growth rates decreased with an increase in thiol concentration and increased with NaNO3 electrolyte concentration. These studies suggest that specific surface interactions with thiol-containing organics may be one factor that contributes to the persistence of naturally occurring and anthropogenic

  13. Identification and characterization of PPARα ligands in the hippocampus.

    Science.gov (United States)

    Roy, Avik; Kundu, Madhuchhanda; Jana, Malabendu; Mishra, Rama K; Yung, Yeni; Luan, Chi-Hao; Gonzalez, Frank J; Pahan, Kalipada

    2016-12-01

    Peroxisome proliferator-activated receptor-α (PPARα) regulates hepatic fatty acid catabolism and mediates the metabolic response to starvation. Recently we found that PPARα is constitutively activated in nuclei of hippocampal neurons and controls plasticity via direct transcriptional activation of CREB. Here we report the discovery of three endogenous PPARα ligands-3-hydroxy-(2,2)-dimethyl butyrate, hexadecanamide, and 9-octadecenamide-in mouse brain hippocampus. Mass spectrometric detection of these compounds in mouse hippocampal nuclear extracts, in silico interaction studies, time-resolved FRET analyses, and thermal shift assay results clearly indicated that these three compounds served as ligands of PPARα. Site-directed mutagenesis studies further revealed that PPARα Y464 and Y314 are involved in binding these hippocampal ligands. Moreover, these ligands activated PPARα and upregulated the synaptic function of hippocampal neurons. These results highlight the discovery of hippocampal ligands of PPARα capable of modulating synaptic functions.

  14. Using chemical shift perturbation to characterise ligand binding.

    Science.gov (United States)

    Williamson, Mike P

    2013-08-01

    Chemical shift perturbation (CSP, chemical shift mapping or complexation-induced changes in chemical shift, CIS) follows changes in the chemical shifts of a protein when a ligand is added, and uses these to determine the location of the binding site, the affinity of the ligand, and/or possibly the structure of the complex. A key factor in determining the appearance of spectra during a titration is the exchange rate between free and bound, or more specifically the off-rate koff. When koff is greater than the chemical shift difference between free and bound, which typically equates to an affinity Kd weaker than about 3μM, then exchange is fast on the chemical shift timescale. Under these circumstances, the observed shift is the population-weighted average of free and bound, which allows Kd to be determined from measurement of peak positions, provided the measurements are made appropriately. (1)H shifts are influenced to a large extent by through-space interactions, whereas (13)Cα and (13)Cβ shifts are influenced more by through-bond effects. (15)N and (13)C' shifts are influenced both by through-bond and by through-space (hydrogen bonding) interactions. For determining the location of a bound ligand on the basis of shift change, the most appropriate method is therefore usually to measure (15)N HSQC spectra, calculate the geometrical distance moved by the peak, weighting (15)N shifts by a factor of about 0.14 compared to (1)H shifts, and select those residues for which the weighted shift change is larger than the standard deviation of the shift for all residues. Other methods are discussed, in particular the measurement of (13)CH3 signals. Slow to intermediate exchange rates lead to line broadening, and make Kd values very difficult to obtain. There is no good way to distinguish changes in chemical shift due to direct binding of the ligand from changes in chemical shift due to allosteric change. Ligand binding at multiple sites can often be characterised, by

  15. Gas-phase complexes formed between amidoxime ligands and vanadium or iron investigated using electrospray ionization mass spectrometry.

    Science.gov (United States)

    Mustapha, Adetayo M; Pasilis, Sofie P

    2016-08-15

    Amidoxime-functionalized sorbents can be used to extract uranium from seawater. Iron(III) and vanadium(V) may compete with uranium for adsorption sites. We use 2,6-dihydroxyiminopiperidine (DHIP) and N(1) ,N(5) -dihydroxypentanediimidamide (DHPD) to model amidoxime functional groups and characterize the vanadium(V) and iron(III) complexes with these ligands. We also examine the effect of iron(III) and vanadium(V) on uranyl(VI) complexation by DHIP and DHPD. The experiments were carried out in positive ion mode using a quadrupole ion trap mass spectrometer equipped with an electrospray ionization source. The effect on the mass spectra of changes in ligand, metal:ligand mole ratio, and pH was examined. Iron(III) formed a 1:2 metal:ligand complex with DHIP at all metal:ligand mole ratios and pH values investigated; it formed both 1:2 and 1:3 metal:ligand complexes with DHPD. Vanadium(V) formed 1:1 and 1:2 metal:ligand complexes with DHIP. A 1:2 metal:ligand complex was formed with DHPD at all vanadium(V):DHPD mole ratios investigated. Changes in solution pH did not affect the ions observed. The relative binding affinities of the metal ions towards DHIP followed the order iron(III) > vanadium(V) > uranyl(VI). This study presents a first look at the gas-phase vanadium(V)- and iron(III)-DHIP and -DHPD complexes using electrospray ionization mass spectrometry. These metals form stronger complexes with amidoxime ligands than uranyl(VI), and will affect uranyl(VI) adsorption to amidoxime-based sorbents. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  16. In vitro evaluation of biodegradable microspheres with surface-bound ligands.

    Science.gov (United States)

    Keegan, Mark E; Royce, Sara M; Fahmy, Tarek; Saltzman, W Mark

    2006-02-21

    Protein ligands were conjugated to the surface of biodegradable microspheres. These microsphere-ligand conjugates were then used in two in vitro model systems to evaluate the effect of conjugated ligands on microsphere behavior. Microsphere retention in agarose columns was increased by ligands on the microsphere surface specific for receptors on the agarose matrix. In another experiment, conjugating the lectin Ulex europaeus agglutinin 1 to the microsphere surface increased microsphere adhesion to Caco-2 monolayers compared to control microspheres. This increase in microsphere adhesion was negated by co-administration of l-fucose, indicating that the increase in adhesion is due to specific interaction of the ligand with carbohydrate receptors on the cell surface. These results demonstrate that the ligands conjugated to the microspheres maintain their receptor binding activity and are present on the microsphere surface at a density sufficient to target the microspheres to both monolayers and three-dimensional matrices bearing complementary receptors.

  17. Geographic distribution of trauma centers and injury-related mortality in the United States.

    Science.gov (United States)

    Brown, Joshua B; Rosengart, Matthew R; Billiar, Timothy R; Peitzman, Andrew B; Sperry, Jason L

    2016-01-01

    Regionalized trauma care improves outcomes; however, access to care is not uniform across the United States. The objective was to evaluate whether geographic distribution of trauma centers correlates with injury mortality across state trauma systems. Level I or II trauma centers in the contiguous United States were mapped. State-level age-adjusted injury fatality rates per 100,000 people were obtained and evaluated for spatial autocorrelation. Nearest neighbor ratios (NNRs) were generated for each state. A NNR less than 1 indicates clustering, while a NNR greater than 1 indicates dispersion. NNRs were tested for difference from random geographic distribution. Fatality rates and NNRs were examined for correlation. Fatality rates were compared between states with trauma center clustering versus dispersion. Trauma center distribution and population density were evaluated. Spatial-lag regression determined the association between fatality rate and NNR, controlling for state-level demographics, population density, injury severity, trauma system resources, and socioeconomic factors. Fatality rates were spatially autocorrelated (Moran's I = 0.35, p center distribution. Fatality rate and NNR were correlated (ρ = 0.34, p = 0.03). Clustered states had a lower median injury fatality rate compared with dispersed states (56.9 [IQR, 46.5-58.9] vs. 64.9 [IQR, 52.5-77.1]; p = 0.04). Dispersed compared with clustered states had more counties without a trauma center that had higher population density than counties with a trauma center (5.7% vs. 1.2%, p distribution of trauma centers correlates with injury mortality, with more clustered state trauma centers associated with lower fatality rates. This may be a result of access relative to population density. These results may have implications for trauma system planning and require further study to investigate underlying mechanisms. Therapeutic/care management study, level IV.

  18. Dinuclear Cu(II) complexes of isomeric bis-(3-acetylacetonate)benzene ligands: synthesis, structure, and magnetic properties.

    Science.gov (United States)

    Rancan, Marzio; Dolmella, Alessandro; Seraglia, Roberta; Orlandi, Simonetta; Quici, Silvio; Sorace, Lorenzo; Gatteschi, Dante; Armelao, Lidia

    2012-05-07

    Highly versatile coordinating ligands are designed and synthesized with two β-diketonate groups linked at the carbon 3 through a phenyl ring. The rigid aromatic spacer is introduced in the molecules to orient the two acetylacetone units along different angles and coordination vectors. The resulting para, meta, and ortho bis-(3-acetylacetonate)benzene ligands show efficient chelating properties toward Cu(II) ions. In the presence of 2,2'-bipyridine, they promptly react and yield three dimers, 1, 2, and 3, with the bis-acetylacetonate unit in bridging position between two metal centers. X-ray single crystal diffraction shows that the compounds form supramolecular chains in the solid state because of intermolecular interactions. Each of the dinuclear complexes shows a magnetic behavior which is determined by the combination of structural parameters and spin polarization effects. Notably, the para derivative (1) displays a moderate antiferromagnetic coupling (J = -3.3 cm(-1)) along a remarkably long Cu···Cu distance (12.30 Å).

  19. Distinct Iron-binding Ligands in the Upper Water Column at Station ALOHA

    Science.gov (United States)

    Bundy, R.; Boiteau, R.; Repeta, D.

    2016-02-01

    The distribution and chemical properties of iron-binding organic ligands at station ALOHA were examined using a combination of solid phase extraction (SPE) followed by high pressure liquid chromatography-inductively coupled plasma mass spectrometry (HPLC-ICPMS). HPLC-ICPMS ligand measurements were complemented by competitive ligand exchange adsorptive cathodic stripping voltammetry (CLE-ACSV) analysis using salicylaldoxime as the added ligand. By HPLC-ICPMS, we find enhanced concentrations of distinct naturally-occurring polar iron-binding ligands present at the surface and in the chlorophyll maximum. Lower concentrations were found in the subsurface, where a suite of non-polar ligands was detected. Siderophores were present at the deepest depths sampled at station ALOHA, down to 400m. Incubation studies provided evidence for the production of iron-binding ligands associated with nutrient amended phytoplankton growth in surface waters, and as a result of microbial particle remineralization in the subsurface water column. Ligands classes identified via SPE were then compared to CLE-ACSV ligand measurements, as well as the conditional stability constants measured from model polar and non-polar siderophores, yielding insight to the sources of iron-binding ligands throughout the water column at station ALOHA.

  20. C-H functionalization: thoroughly tuning ligands at a metal ion, a chemist can greatly enhance catalyst's activity and selectivity.

    Science.gov (United States)

    Shul'pin, Georgiy B

    2013-09-28

    This brief essay consists of a few "exciting stories" devoted to relations within a metal-complex catalyst between a metal ion and a coordinated ligand. When, as in the case of a human couple, the rapport of the partners is cordial and a love cements these relations, a chemist finds an ideal married couple, in other words he obtains a catalyst of choice which allows him to functionalize C-H bonds very efficiently and selectively. Examples of such lucky marriages in the catalytic world of ions and ligands are discussed here. Activity of the catalyst is characterized by turnover number (TON) or turnover frequency (TOF) as well as by yield of a target product. Introducing a chelating N,N- or N,O-ligand to the catalyst molecule (this can be an iron or manganese derivative) sharply enhances its activity. However, the activity of vanadium derivatives (with additionally added to the solution pyrazinecarboxylic acid, PCA) as well as of various osmium complexes does not dramatically depend on the nature of ligands surrounding metal ions. Complexes of these metals are very efficient catalysts in oxidations with H2O2. Osmium derivatives are record-holders exhibiting extremely high TONs whereas vanadium complexes are on the second position. Finally, elegant examples of alkane functionalization on the ions of non-transition metals (aluminium, gallium etc.) are described when one ligand within the metal complex (namely, hydroperoxyl ligand HOO(-)) helps other ligand of this complex (H2O2 molecule coordinated to the metal) to disintegrate into two species, generating very reactive hydroxyl radical. Hydrogen peroxide molecule, even ligated to the metal ion, is perfectly stable without the assistance of the neighboring HOO(-) ligand. This ligand can be easily oxidized donating an electron to its partner ligand (H2O2). In an analogous case, when the central ion in the catalyst is a transition metal, this ion changing its oxidation state can donate an electron to the coordinated H2O2

  1. Synthesis of meta-substituted monodentate phosphinite ligands and ...

    Indian Academy of Sciences (India)

    SATEJ S DESHMUKH

    from organic synthesis, phosphinite ligands find appli- cations in a variety of ... thesis of meta-substituted phosphinite ligands is rarely reported.18 This is most ... 1.9 μm; mobile phase used, 90% methanol + 10% water +. 0.1% formic acid) ...

  2. Rule of five in 2015 and beyond: Target and ligand structural limitations, ligand chemistry structure and drug discovery project decisions.

    Science.gov (United States)

    Lipinski, Christopher A

    2016-06-01

    The rule of five (Ro5), based on physicochemical profiles of phase II drugs, is consistent with structural limitations in protein targets and the drug target ligands. Three of four parameters in Ro5 are fundamental to the structure of both target and drug binding sites. The chemical structure of the drug ligand depends on the ligand chemistry and design philosophy. Two extremes of chemical structure and design philosophy exist; ligands constructed in the medicinal chemistry synthesis laboratory without input from natural selection and natural product (NP) metabolites biosynthesized based on evolutionary selection. Exceptions to Ro5 are found mostly among NPs. Chemistry chameleon-like behavior of some NPs due to intra-molecular hydrogen bonding as exemplified by cyclosporine A is a strong contributor to NP Ro5 outliers. The fragment derived, drug Navitoclax is an example of the extensive expertise, resources, time and key decisions required for the rare discovery of a non-NP Ro5 outlier. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. Detection of site-specific binding and co-binding of ligands to macromolecules using 19F NMR

    International Nuclear Information System (INIS)

    Jenkins, B.G.

    1991-01-01

    Study of ligand-macromolecular interactions by 19 F nuclear magnetic resonance (NMR) spectroscopy affords many opportunities for obtaining molecular biochemical and pharmaceutical information. This is due to the absence of a background fluorine signal, as well as the relatively high sensitivity of 19 F NMR. Use of fluorine-labeled ligands enables one to probe not only binding and co-binding phenomena to macromolecules, but also can provide data on binding constants, stoichiometries, kinetics, and conformational properties of these complexes. Under conditions of slow exchange and macromolecule-induced chemical shifts, multiple 19 F NMR resonances can be observed for free and bound ligands. These shifted resonances are a direct correlate of the concentration of ligand bound in a specific state rather than the global concentrations of bound or free ligand which are usually determined using other techniques such as absorption spectroscopy or equilibrium dialysis. Examples of these interactions are demonstrated both from the literature and from interactions of 5-fluorotryptophan, 5-fluorosalicylic acid, flurbiprofen, and sulindac sulfide with human serum albumin. Other applications of 19 F NMR to study of these interactions in vivo, as well for receptor binding and metabolic tracing of fluorinated drugs and proteins are discussed

  4. Catalposide is a natural agonistic ligand of peroxisome proliferator-activated receptor-{alpha}

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Ji Hae; Jun, Hee-jin; Hoang, Minh-Hien; Jia, Yaoyao [Division of Food Bioscience and Technology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of); Department of Biotechnology, Graduate School of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of); Han, Xiang Hua [College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk 361-763 (Korea, Republic of); Lee, Dong-Ho [Department of Biotechnology, Graduate School of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of); Lee, Hak-Ju [Division of Green Business Management, Department of Forest Resources Utilization, Korean Forest Research Institute, Seoul 130-712 (Korea, Republic of); Hwang, Bang Yeon, E-mail: byhwang@chungbuk.ac.kr [College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk 361-763 (Korea, Republic of); Lee, Sung-Joon, E-mail: junelee@korea.ac.kr [Division of Food Bioscience and Technology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of); Department of Biotechnology, Graduate School of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of)

    2012-06-15

    Highlights: Black-Right-Pointing-Pointer Catalposide is a novel ligand for PPAR{alpha}. Black-Right-Pointing-Pointer Cell stimulated with catalposide improved fatty acid uptake, regulated target genes in fatty acid {beta}-oxidation and synthesis. Black-Right-Pointing-Pointer Catalposdie reduces hepatic triacylglycerides. Black-Right-Pointing-Pointer Theses demonstrate catalposide could ameliorate hyperlipidemia and hepatic steatosis. -- Abstract: Peroxisome proliferator-activated receptor-alpha (PPAR{alpha}) is a nuclear receptor that regulates the expression of genes related to cellular lipid uptake and oxidation. Thus, PPAR{alpha} agonists may be important in the treatment of hypertriglyceridemia and hepatic steatosis. In this study, we demonstrated that catalposide is a novel natural PPAR{alpha} agonist, identified from reporter gene assay-based activity screening with approximately 900 natural plant and seaweed extracts. Results of time-resolved fluorescence resonance energy transfer analyses suggested that the compound interacted directly with the ligand-binding domain of PPAR{alpha}. Cultured hepatocytes stimulated with catalposide exhibited significantly reduced cellular triglyceride concentrations, by 21%, while cellular uptake of fatty acids was increased, by 70% (P < 0.05). Quantitative PCR analysis revealed that the increase in cellular fatty acid uptake was due to upregulation of fatty acid transporter protein-4 (+19% vs. the control) in cells stimulated with catalposide. Additionally, expression of genes related to fatty acid oxidation and high-density lipoprotein metabolism were upregulated, while that of genes related to fatty acid synthesis were suppressed. In conclusion, catalposide is hypolipidemic by activation of PPAR{alpha} via a ligand-mediated mechanism that modulates the expression of in lipid metabolism genes in hepatocytes.

  5. Geographic Distribution of Trauma Centers and Injury Related Mortality in the United States

    Science.gov (United States)

    Brown, Joshua B.; Rosengart, Matthew R.; Billiar, Timothy R.; Peitzman, Andrew B.; Sperry, Jason L.

    2015-01-01

    Background Regionalized trauma care improves outcomes; however access to care is not uniform across the US. The objective was to evaluate whether geographic distribution of trauma centers correlates with injury mortality across state trauma systems. Methods Level I/II trauma centers in the contiguous US were mapped. State-level age-adjusted injury fatality rates/100,000people were obtained and evaluated for spatial autocorrelation. Nearest neighbor ratios (NNR) were generated for each state. A NNR1 indicates dispersion. NNR were tested for difference from random geographic distribution. Fatality rates and NNR were examined for correlation. Fatality rates were compared between states with trauma center clustering versus dispersion. Trauma center distribution and population density were evaluated. Spatial-lag regression determined the association between fatality rate and NNR, controlling for state-level demographics, population density, injury severity, trauma system resources, and socioeconomic factors. Results Fatality rates were spatially autocorrelated (Moran's I=0.35, pcenter distribution. Fatality rate and NNR were correlated (ρ=0.34, p=0.03). Clustered states had a lower median injury fatality rate compared to dispersed states (56.9 [IQR 46.5–58.9] versus 64.9 [IQR 52.5–77.1], p=0.04). Dispersed compared to clustered states had more counties without a trauma center that had higher population density than counties with a trauma center (5.7% versus 1.2%, pdistribution of trauma centers correlates with injury mortality, with more clustered state trauma centers associated with lower fatality rates. This may be a result of access relative to population density. These results may have implications for trauma system planning and requires further study to investigate underlying mechanisms PMID:26517780

  6. Gas adsorption and gas mixture separations using mixed-ligand MOF material

    Science.gov (United States)

    Hupp, Joseph T [Northfield, IL; Mulfort, Karen L [Chicago, IL; Snurr, Randall Q [Evanston, IL; Bae, Youn-Sang [Evanston, IL

    2011-01-04

    A method of separating a mixture of carbon dioxiode and hydrocarbon gas using a mixed-ligand, metal-organic framework (MOF) material having metal ions coordinated to carboxylate ligands and pyridyl ligands.

  7. In Silico target fishing: addressing a "Big Data" problem by ligand-based similarity rankings with data fusion.

    Science.gov (United States)

    Liu, Xian; Xu, Yuan; Li, Shanshan; Wang, Yulan; Peng, Jianlong; Luo, Cheng; Luo, Xiaomin; Zheng, Mingyue; Chen, Kaixian; Jiang, Hualiang

    2014-01-01

    Ligand-based in silico target fishing can be used to identify the potential interacting target of bioactive ligands, which is useful for understanding the polypharmacology and safety profile of existing drugs. The underlying principle of the approach is that known bioactive ligands can be used as reference to predict the targets for a new compound. We tested a pipeline enabling large-scale target fishing and drug repositioning, based on simple fingerprint similarity rankings with data fusion. A large library containing 533 drug relevant targets with 179,807 active ligands was compiled, where each target was defined by its ligand set. For a given query molecule, its target profile is generated by similarity searching against the ligand sets assigned to each target, for which individual searches utilizing multiple reference structures are then fused into a single ranking list representing the potential target interaction profile of the query compound. The proposed approach was validated by 10-fold cross validation and two external tests using data from DrugBank and Therapeutic Target Database (TTD). The use of the approach was further demonstrated with some examples concerning the drug repositioning and drug side-effects prediction. The promising results suggest that the proposed method is useful for not only finding promiscuous drugs for their new usages, but also predicting some important toxic liabilities. With the rapid increasing volume and diversity of data concerning drug related targets and their ligands, the simple ligand-based target fishing approach would play an important role in assisting future drug design and discovery.

  8. Automatic generation of bioinformatics tools for predicting protein-ligand binding sites.

    Science.gov (United States)

    Komiyama, Yusuke; Banno, Masaki; Ueki, Kokoro; Saad, Gul; Shimizu, Kentaro

    2016-03-15

    Predictive tools that model protein-ligand binding on demand are needed to promote ligand research in an innovative drug-design environment. However, it takes considerable time and effort to develop predictive tools that can be applied to individual ligands. An automated production pipeline that can rapidly and efficiently develop user-friendly protein-ligand binding predictive tools would be useful. We developed a system for automatically generating protein-ligand binding predictions. Implementation of this system in a pipeline of Semantic Web technique-based web tools will allow users to specify a ligand and receive the tool within 0.5-1 day. We demonstrated high prediction accuracy for three machine learning algorithms and eight ligands. The source code and web application are freely available for download at http://utprot.net They are implemented in Python and supported on Linux. shimizu@bi.a.u-tokyo.ac.jp Supplementary data are available at Bioinformatics online. © The Author 2015. Published by Oxford University Press.

  9. Partitioning-separation of metal ions using heterocyclic ligands

    International Nuclear Information System (INIS)

    Hudson, M.J.; Drew, M.G.B.; Iveson, P.B.; Russell, M.L.

    2001-01-01

    Some guidelines are proposed for the effective design of heterocyclic ligands for partitioning because there is no doubt that the correct design of a molecular extractant is required for the effective separation of metal ions such as actinides(III) from lanthanides(III). Heterocyclic ligands with aromatic ring systems have a rich chemistry, which is only now becoming sufficiently well understood in relation to the partitioning process. The synthesis, characterisation and structures of some chosen molecules will be introduced in order to illustrate some important features. For example, the molecule N-carboxy-butyl-2-amino-4,6-di (2-pyridyl)-1,3,5-triazine (BADPTZ), which is an effective solvent extraction reagent for actinides and lanthanides, has been synthesised, characterised and its interaction with lanthanide ions studied. The interesting and important features of this molecule will be compared with those of other heterocyclic molecules such as 2,6-bis(5-butyl-1,2,4-triazole-3-yl) pyridine (DBTZP), which is a candidate molecule for the commercial separation of actinides and lanthanide elements. (author)

  10. Photolytic degradation of methylmercury enhanced by binding to natural organic ligands

    Science.gov (United States)

    Zhang, Tong; Hsu-Kim, Heileen

    2010-07-01

    Methylmercury is a neurotoxin that accumulates in food webs and poses a significant risk to human health. In natural water bodies, methylmercury concentrations remain low due to the degradation of methylmercury into inorganic mercury by sunlight, a process known as photodecomposition. Rates of photodecomposition are relatively rapid in freshwater lakes, and slow in marine waters, but the cause of this difference is not clear. Here, we carry out incubation experiments with artificial freshwater and seawater samples to examine the mechanisms regulating methylmercury photodecomposition. We show that singlet oxygen-a highly reactive form of dissolved oxygen generated by sunlight falling on dissolved organic matter-drives photodecomposition. However, in our experiments the rate of methylmercury degradation depends on the type of methylmercury-binding ligand present in the water. Relatively fast degradation rates (similar to observations in freshwater lakes) were detected when methylmercury species were bound to sulphur-containing ligands such as glutathione and mercaptoacetate. In contrast, methylmercury-chloride complexes, which are the dominant form of methylmercury in marine systems, did not degrade as easily. Our results could help to explain why methylmercury photodecomposition rates are relatively rapid in freshwater lakes and slow in marine waters.

  11. Novel chalcone-based fluorescent human histamine H3 receptor ligands as pharmacological tools

    Directory of Open Access Journals (Sweden)

    Holger eStark

    2012-03-01

    Full Text Available Novel fluorescent chalcone-based ligands at human histamine H3 receptors (hH3R have been designed, synthesized and characterized. Compounds described are non-imidazole analogues of ciproxifan with a tetralone motif. Tetralones as chemical precursors and related fluorescent chalcones exhibit affinities at hH3R in the same concentration range like that of the reference antagonist ciproxifan (hH3R pKi value of 7.2. Fluorescence characterization of our novel ligands shows emission maxima about 570 nm for yellow fluorescent chalcones and ≥600 nm for the red fluorescent derivatives. Interferences to cellular autofluorescence could be excluded. All synthesized chalcone compounds could be taken to visualize hH3R proteins in stably transfected HEK-293 cells using confocal laser scanning fluorescence microscopy. These novel fluorescent ligands possess high potential to be used as pharmacological tools for hH3R visualization in different tissues.

  12. Radiation sensitization by an iodine-labelled DNA ligand

    Energy Technology Data Exchange (ETDEWEB)

    Martin, R F; Murray, V; D' Cunha, G; Pardee, M; Haigh, A; Hodgson, G S [Peter MacCallum Cancer Inst., Melbourne (Australia); Kampouris, E; Kelly, D P [Melbourne Univ., Parkville (Australia)

    1990-05-01

    An iodinated DNA ligand, iodoHoechst 33258, which binds in the minor groove of DNA, enhances DNA strand breakage and cell killing by UV-A irradiation. The sites of UV-induced strand breaks reflect the known sequence specificity of the ligand. (author).

  13. Nurses’ Bedsore-Related Knowledge in Sanandaj Educational Healthcare Centers

    Directory of Open Access Journals (Sweden)

    Shadiyeh Kanani

    2017-10-01

    Full Text Available Background and Purpose A bed sore is a major problem in hospitalized patients, which can cost a lot for the patients, families, hospitals, health care institutions, and the community as a whole. On the other hand, one of the duties of the nursing staff is the care of the patient’s skin to prevent the formation of an ulcer. In addition, they are also responsible for providing the necessary measures to prevent the onset of pressure ulcers in the hospital. This critical role of nurses itself requires improving their knowledge regarding compression ulcers. The aim of this study was to determine the knowledge level of nurses in Sanandaj sanitary care centers, which was done in 2014 for bedsores. Methods This cross-sectional study was conducted in 2014 on 390 nurses from Sanandaj health centers that were selected by the census. Data were collected using the Piperfahr questionnaire. Data analysis was done using the SPSS software and necessary tests. Results The rate of correct answers related to the onset of bedsore with the highest frequency being 77.7% in the range of “good”, the bedsore evaluation with the frequency of 48.7% in the range of “average, and that of the bedsore-related knowledge with the highest correct answers of 94.6% in the range of “good”. There was a significant relationship (P 0.05. Conclusions The results showed that, with the highest frequency of correct answers (86.2%, the nursing knowledge is in an average level. Therefore, their level of knowledge can be promoted by additional relevant learning. Furthermore, the level of knowledge can have a positive effect on the performance.

  14. Real-Time Ligand Binding Pocket Database Search Using Local Surface Descriptors

    Science.gov (United States)

    Chikhi, Rayan; Sael, Lee; Kihara, Daisuke

    2010-01-01

    Due to the increasing number of structures of unknown function accumulated by ongoing structural genomics projects, there is an urgent need for computational methods for characterizing protein tertiary structures. As functions of many of these proteins are not easily predicted by conventional sequence database searches, a legitimate strategy is to utilize structure information in function characterization. Of a particular interest is prediction of ligand binding to a protein, as ligand molecule recognition is a major part of molecular function of proteins. Predicting whether a ligand molecule binds a protein is a complex problem due to the physical nature of protein-ligand interactions and the flexibility of both binding sites and ligand molecules. However, geometric and physicochemical complementarity is observed between the ligand and its binding site in many cases. Therefore, ligand molecules which bind to a local surface site in a protein can be predicted by finding similar local pockets of known binding ligands in the structure database. Here, we present two representations of ligand binding pockets and utilize them for ligand binding prediction by pocket shape comparison. These representations are based on mapping of surface properties of binding pockets, which are compactly described either by the two dimensional pseudo-Zernike moments or the 3D Zernike descriptors. These compact representations allow a fast real-time pocket searching against a database. Thorough benchmark study employing two different datasets show that our representations are competitive with the other existing methods. Limitations and potentials of the shape-based methods as well as possible improvements are discussed. PMID:20455259

  15. A feasibility study of unconventional planar ligand spacers in chalcogenide nanocrystals.

    Science.gov (United States)

    Lukose, Binit; Clancy, Paulette

    2016-05-18

    The solar cell efficiency of chalcogenide nanocrystals (quantum dots) has been limited in the past by the insulation between neighboring quantum dots caused by intervening, often long-chain, aliphatic ligands. We have conducted a computationally based feasibility study to investigate the use of ultra-thin, planar, charge-conducting ligands as an alternative to traditional long passive ligands. Not only might these radically unconventional ligands decrease the mean distance between adjacent quantum dots, but, since they are charge-conducting, they have the potential to actively enhance charge migration. Our ab initio studies compare the binding energies, electronic energy gaps, and absorption characteristics for both conventional and unconventional ligands, such as phthalocyanines, porphyrins and coronene. This comparison identified these unconventional ligands with the exception of titanyl phthalocyanine, that bind to themselves more strongly than to the surface of the quantum dot, which is likely to be less desirable for enhancing charge transport. The distribution of finite energy levels of the bound system is sensitive to the ligand's binding site and the levels correspond to delocalized states. We also observed a trap state localized on a single Pb atom when a sulfur-containing phenyldithiocarbamate (PTC) ligand is attached to a slightly off-stoichiometric dot in a manner that the sulfur of the ligand completes stoichiometry of the bound system. Hence, this is indicative of the source of trap state when thio-based ligands are bound to chalcogenide nanocrystals. We also predict that titanyl phthalocyanine in a mix with chalcogenide dots of diameter ∼1.5 Å can form a donor-acceptor system.

  16. Cytotoxicity of an 125I-labelled DNA ligand

    International Nuclear Information System (INIS)

    Karagiannis, T.C.; Lobachevsky, P.N.; Martin, R.F.

    2000-01-01

    The subcellular distribution and cytotoxicity of a DNA-binding ligand [ 125 I]-Hoechst 33258 following incubation of K562 cells with the drug was investigated. The ability of a radical scavenger, dimethyl sulphoxide, to protect cells from the 125 I-decay induced cell death was also studied. Three different concentrations and specific activities of the drug were used to provide different ligand : DNA binding ratios. The results demonstrated a trend toward improved delivery of the ligand to the nucleus and to chromatin at higher ligand concentrations, with concomitant increased sensitivity to 125 I-decay induced cytotoxicity and decreased protection by dimethyl sulphoxide. This correlation of radiobiological parameters with subcellular drug distribution is consistent with the classical dogma that attributes cytotoxicity to DNA double-stranded breakage in the vicinity of the site of decay, where the high LET nature of the damage confers minimal sensitivity to radical scavenging

  17. Positron annihilation studies of bio-related N2S2-tetradentate ligands and their zinc complexes

    International Nuclear Information System (INIS)

    Shaban, S.Y.; Mahmoud, K.R.; Sharshar, T.

    2013-01-01

    In this study, a series of three N 2 S 2 -tetradentate ligands and their zinc complexes were investigated by positron annihilation lifetime spectroscopy. The measurements were performed at room temperature. The analysis of lifetime spectra of all samples yielded four lifetime components, except in one sample that yielded three components. The results showed that the formation probability and lifetime of ortho-positronium in this series are dependent on the structure.

  18. Identification and Biological Activity of Synthetic Macrophage Inducible C-Type Lectin Ligands

    Directory of Open Access Journals (Sweden)

    Chriselle D. Braganza

    2018-01-01

    Full Text Available The macrophage inducible C-type lectin (Mincle is a pattern recognition receptor able to recognize both damage-associated and pathogen-associated molecular patterns, and in this respect, there has been much interest in determining the scope of ligands that bind Mincle and how structural modifications to these ligands influence ensuing immune responses. In this review, we will present Mincle ligands of known chemical structure, with a focus on ligands that have been synthetically prepared, such as trehalose glycolipids, glycerol-based ligands, and 6-acylated glucose and mannose derivatives. The ability of the different classes of ligands to influence the innate, and consequently, the adaptive, immune response will be described, and where appropriate, structure–activity relationships within each class of Mincle ligands will be presented.

  19. Spectra of fluorinated rare earth β-diketonates with added ligands

    International Nuclear Information System (INIS)

    Khomenko, V.S.; Lozinskij, M.O.; Fialkov, Yu.A.; Rasshinina, T.A.; Krasovskaya, L.I.; AN Ukrainskoj SSR, Kiev. Inst. Organicheskoj Khimii)

    1984-01-01

    Different-ligand rare earth complexes are synthesized. Fluorated β-diketones, triethylphosphine oxide and trifluoracetic acid are used as active ligands. Mass-spectra of low and high resolution are taken at the energy of ionizing electrons of 70 eV, as well as luminescence spectra of complexes. Fragmentation ways of complexes decomposition under electron shock are studied. A series of changing the bound strength of additional ligands with europium in mixed complexes is determined. It is shown that the introduction of additional ligands can purposefully change physical and chemical properties of complexes

  20. Spectra of fluorinated rare earth. beta. -diketonates with added ligands

    Energy Technology Data Exchange (ETDEWEB)

    Khomenko, V.S.; Lozinskij, M.O.; Fialkov, Yu.A.; Rasshinina, T.A.; Krasovskaya, L.I. (AN Belorusskoj SSR, Minsk. Inst. Fiziki; AN Ukrainskoj SSR, Kiev. Inst. Organicheskoj Khimii)

    1984-01-01

    Different-ligand rare earth complexes are synthesized. Fluorated ..beta..-diketones, triethylphosphine oxide and trifluoracetic acid are used as active ligands. Mass-spectra of low and high resolution are taken at the energy of ionizing electrons of 70 eV, as well as luminescence spectra of complexes. Fragmentation ways of complexes decomposition under electron shock are studied. A series of changing the bound strength of additional ligands with europium in mixed complexes is determined. It is shown that the introduction of additional ligands can purposefully change physical and chemical properties of complexes.

  1. New Ru(II) complexes for dual photoreactivity: ligand exchange and (1)O2 generation.

    Science.gov (United States)

    Knoll, Jessica D; Albani, Bryan A; Turro, Claudia

    2015-08-18

    Uncovering the factors that govern the electronic structure of Ru(II)-polypyridyl complexes is critical in designing new compounds for desired photochemical reactions, and strategies to tune excited states for ligand dissociation and (1)O2 production are discussed herein. The generally accepted mechanism for photoinduced ligand dissociation proposes that population of the dissociative triplet ligand field ((3)LF) state proceeds through thermal population from the vibrationally cooled triplet metal-to-ligand charge transfer ((3)MLCT) state; however, temperature-dependent emission spectroscopy provides varied activation energies using the emission and ligand exchange quantum yields for [Ru(bpy)2(L)2](2+) (bpy = 2,2'-bipyridine; L = CH3CN or py). This suggests that population of the (3)LF state proceeds from the vibrationally excited (3)MLCT state. Because the quantum yield of ligand dissociation for nitriles is much more efficient than that for py, steric bulk was introduced into the ligand set to distort the pseudo-octahedral geometry and lower the energy of the (3)LF state. The py dissociation quantum yield with 500 nm irradiation in a series of [Ru(tpy)(NN)(py)](2+) complexes (tpy = 2,2':6',2″-terpyridine; NN = bpy, 6,6'-dimethyl-2,2'-bipyridine (Me2bpy), 2,2'-biquinoline (biq)) increases by 2-3 orders of magnitude with the sterically bulky Me2bpy and biq ligands relative to bpy. Ultrafast transient absorption spectroscopy reveals population of the (3)LF state within 3-7 ps when NN is bulky, and density functional theory calculations support stabilized (3)LF states. Dual activity via ligand dissociation and (1)O2 production can be achieved by careful selection of the ligand set to tune the excited-state dynamics. Incorporation of an extended π system in Ru(II) complexes such as [Ru(bpy)(dppn)(CH3CN)2](2+) (dppn = benzo[i]dipyrido[3,2-a:2',3'-c]phenazine) and [Ru(tpy)(Me2dppn)(py)](2+) (Me2dppn = 3,6-dimethylbenzo[i]dipyrido[3,2-a:2',3'-c]phenazine) introduces

  2. New Ru(II) Complexes for Dual Photoreactivity: Ligand Exchange and 1O2 Generation

    Science.gov (United States)

    Knoll, Jessica D.; Albani, Bryan A.; Turro, Claudia

    2016-01-01

    CONSPECTUS Uncovering the factors that govern the electronic structure of Ru(II)–polypyridyl complexes is critical in designing new compounds for desired photochemical reactions, and strategies to tune excited states for ligand dissociation and 1O2 production are discussed herein. The generally accepted mechanism for photoinduced ligand dissociation proposes that population of the dissociative triplet ligand field (3LF) state proceeds through thermal population from the vibrationally cooled triplet metal-to-ligand charge transfer (3MLCT) state; however, temperature-dependent emission spectroscopy provides varied activation energies using the emission and ligand exchange quantum yields for [Ru(bpy)2(L)2]2+ (bpy = 2,2′-bipyridine; L = CH3CN or py). This suggests that population of the 3LF state proceeds from the vibrationally excited 3MLCT state. Because the quantum yield of ligand dissociation for nitriles is much more efficient than that for py, steric bulk was introduced into the ligand set to distort the pseudo-octahedral geometry and lower the energy of the 3LF state. The py dissociation quantum yield with 500 nm irradiation in a series of [Ru(tpy)(NN)(py)]2+ complexes (tpy = 2,2′:6′,2″-terpyridine; NN = bpy, 6,6′-dimethyl-2,2′-bipyridine (Me2bpy), 2,2′-biquinoline (biq)) increases by 2–3 orders of magnitude with the sterically bulky Me2bpy and biq ligands relative to bpy. Ultrafast transient absorption spectroscopy reveals population of the 3LF state within 3–7 ps when NN is bulky, and density functional theory calculations support stabilized 3LF states. Dual activity via ligand dissociation and 1O2 production can be achieved by careful selection of the ligand set to tune the excited-state dynamics. Incorporation of an extended π system in Ru(II) complexes such as [Ru(bpy)(dppn)(CH3CN)2]2+ (dppn = benzo[i]dipyrido[3,2-a:2′,3′-c]phenazine) and [Ru(tpy)(Me2dppn)(py)]2+ (Me2dppn = 3,6-dimethylbenzo[i]dipyrido[3,2-a:2′,3

  3. Sampling and energy evaluation challenges in ligand binding protein design.

    Science.gov (United States)

    Dou, Jiayi; Doyle, Lindsey; Jr Greisen, Per; Schena, Alberto; Park, Hahnbeom; Johnsson, Kai; Stoddard, Barry L; Baker, David

    2017-12-01

    The steroid hormone 17α-hydroxylprogesterone (17-OHP) is a biomarker for congenital adrenal hyperplasia and hence there is considerable interest in development of sensors for this compound. We used computational protein design to generate protein models with binding sites for 17-OHP containing an extended, nonpolar, shape-complementary binding pocket for the four-ring core of the compound, and hydrogen bonding residues at the base of the pocket to interact with carbonyl and hydroxyl groups at the more polar end of the ligand. Eight of 16 designed proteins experimentally tested bind 17-OHP with micromolar affinity. A co-crystal structure of one of the designs revealed that 17-OHP is rotated 180° around a pseudo-two-fold axis in the compound and displays multiple binding modes within the pocket, while still interacting with all of the designed residues in the engineered site. Subsequent rounds of mutagenesis and binding selection improved the ligand affinity to nanomolar range, while appearing to constrain the ligand to a single bound conformation that maintains the same "flipped" orientation relative to the original design. We trace the discrepancy in the design calculations to two sources: first, a failure to model subtle backbone changes which alter the distribution of sidechain rotameric states and second, an underestimation of the energetic cost of desolvating the carbonyl and hydroxyl groups of the ligand. The difference between design model and crystal structure thus arises from both sampling limitations and energy function inaccuracies that are exacerbated by the near two-fold symmetry of the molecule. © 2017 The Authors Protein Science published by Wiley Periodicals, Inc. on behalf of The Protein Society.

  4. Monochloro non-bridged half-metallocene-type zirconium complexes containing phosphine oxide-(thio)phenolate chelating ligands as efficient ethylene polymerization catalysts.

    Science.gov (United States)

    Tang, Xiao-Yan; Wang, Yong-Xia; Liu, San-Rong; Liu, Jing-Yu; Li, Yue-Sheng

    2013-01-14

    A series of novel monochloro half-zirconocene complexes containing phosphine oxide-(thio)phenolate chelating ligands of the type, ClCp'Zr[X-2-R(1)-4-R(2)-6-(Ph(2)P=O)C(6)H(2)](2) (Cp' = C(5)H(5), 2a: X = O, R(1) = Ph, R(2) = H; 2b: X = O, R(1) = F, R(2) = H; 2c: X = O, R(1) = (t)Bu, R(2) = H; 2d: X = O, R(1) = R(2) = (t)Bu; 2e: X = O, R(1) = SiMe(3), R(2) = H; 2f: X = S, R(1) = SiMe(3), R(2) = H; Cp' = C(5)Me(5), 2g: X = O, R(1) = SiMe(3), R(2) = H), have been synthesized in high yields. These complexes were identified by (1)H {(13)C} NMR and elemental analyses. Structures for 2b, 2c and 2f were further confirmed by X-ray crystallography. Structural characterization of these complexes reveals crowded environments around the zirconium. Complexes 2b and 2c adopt six-coordinate, distorted octahedral geometry around the zirconium center, in which the equatorial positions are occupied by three oxygen atoms of two chelating phosphine oxide-bridged phenolate ligands and a chlorine atom. The cyclopentadienyl ring and one oxygen atom of the ligand are coordinated on the axial position. Complex 2f also folds a six-coordinate, distorted octahedral geometry around the Zr center, consisting of a Cp-Zr-O (in P=O) axis [177.16°] and a distorted plane of two sulfur atoms and one oxygen atom of two chelating phosphine oxide-bridged thiophenolate ligands as well as a chlorine atom. When activated by modified methylaluminoxane (MMAO), all the complexes exhibited high activities towards ethylene polymerization at high temperature (75 °C), giving high molecular weight polymers with unimodal molecular weight distribution. The formation of 14-electron, cationic metal alkyl species might come from the Zr-O (in phenol ring) bond cleavage based on the DFT calculations study.

  5. X irradiation combined with TNF alpha-related apoptosis-inducing ligand (TRAIL) reduces hypoxic regions of human gastric adenocarcinoma xenografts in SCID mice

    International Nuclear Information System (INIS)

    Takahashi, Momoko; Yasui, Hironobu; Ogura, Aki; Asanuma, Taketoshi; Inanami, Osamu; Kubota, Nobuo; Tsujitani, Michihiko; Kuwabara, Mikinori

    2008-01-01

    Our previous study showed that X irradiation induced the expression of death receptor DR5 on the cell surface in tumor cell lines under not only normoxia but also hypoxia. X irradiation combined with TNF α-related apoptosis-inducing ligand (TRAIL), which is the ligand of DR5, induced apoptosis in vitro (Takahashi et al., (2007) Journal of Radiation Research, 48: 461-468). In this report, we examined the in vivo antitumor efficacy of X irradiation combined with TRAIL treatment in tumor xenograft models derived from human gastric adenocarcinoma MKN45 and MKN28 cells in severe combined immunodeficiency (SCID) mice. X irradiation combined with TRAIL synergistically suppressed the tumor growth rates in the xenograft models derived from MKN45 and MKN28 cells, which have wild type Tp53 and mutated Tp53, respectively, indicating that the antitumor effects occurred in a Tp53-independent manner. Histological analysis showed that the combination of X irradiation and TRAIL induced caspase-3-dependent apoptotic cell death. Moreover, the immunohistochemical detection of hypoxic regions using the hypoxic marker pimonidazole revealed that caspase-3-dependent apoptosis occurred in the hypoxic regions in the tumors. These results indicated that X irradiation combined with TRAIL may be a useful treatment to reduce tumor growth in not only normoxic but also hypoxic regions. (author)

  6. New selective ligands for caesium. Application to Cs+/Na+ separation by nano-filtration-complexation in aqueous phase

    International Nuclear Information System (INIS)

    Pellet-Rostaing, S.; Chitry, F.; Lemaire, M.; Guy, A.; Foos, J.

    2000-01-01

    Separating traces of caesium from aqueous medium containing high sodium concentration is a harsh problem because caesium and sodium have a similar behaviour in aqueous medium. The aim of our study was to select a highly caesium-selective ligand in a nano-filtration-complexation process in order to achieve Cs + /Na + separation. This process involve a nano-filtration step combined with a preliminary complexation step. Caesium complexes are retained by the nano-filtration membrane whereas free sodium cations pass through it. We tried to find a relation between the ligands structure and their activity towards caesium-complexation. Among the synthesized receptors, Tetra-hydroxylated bis-crown-6 calix[4]arene was found to be the more caesium-selective ligand (S=β(Cs + )/β(Na+)=6600). Combined with a nano-filtration process, this ligand helped reaching 90% caesium retention in a highly concentrated aqueous medium ([NaNO 3 ] = 3 mol/L). (authors)

  7. Fullerenes as a new type of ligands for transition metals

    International Nuclear Information System (INIS)

    Sokolov, V.I.

    2007-01-01

    Fullerenes are considered as ligands in transition metal π-complexes. The following aspects are discussed: metals able to form π-complexes with fullerenes (Zr, V, Ta, Mo, W, Re, Ru, etc.); haptic numbers; homo- and hetero ligand complexes; ligand compatibility with fullerenes for different metals, including fullerenes with a disturbed structure of conjugation [ru

  8. Segmentation of age-related white matter changes in a clinical multi-center study

    DEFF Research Database (Denmark)

    Dyrby, Tim B.; Rostrup, E.; Baare, W.F.C.

    2008-01-01

    Age-related white matter changes (WMC) are thought to be a marker of vascular pathology, and have been associated with motor and cognitive deficits. In the present study, an optimized artificial neural network was used as an automatic segmentation method to produce probabilistic maps of WMC...... in a clinical multi-center study. The neural network uses information from T1- and T2-weighted and fluid attenuation inversion recovery (FLAIR) magnetic resonance (MR) scans, neighboring voxels and spatial location. Generalizability of the neural network was optimized by including the Optimal Brain Damage (OBD......) pruning method in the training stage. Six optimized neural networks were produced to investigate the impact of different input information on WMC segmentation. The automatic segmentation method was applied to MR scans of 362 non-demented elderly subjects from 11 centers in the European multi-center study...

  9. Forging the Basis for Developing Protein-Ligand Interaction Scoring Functions.

    Science.gov (United States)

    Liu, Zhihai; Su, Minyi; Han, Li; Liu, Jie; Yang, Qifan; Li, Yan; Wang, Renxiao

    2017-02-21

    In structure-based drug design, scoring functions are widely used for fast evaluation of protein-ligand interactions. They are often applied in combination with molecular docking and de novo design methods. Since the early 1990s, a whole spectrum of protein-ligand interaction scoring functions have been developed. Regardless of their technical difference, scoring functions all need data sets combining protein-ligand complex structures and binding affinity data for parametrization and validation. However, data sets of this kind used to be rather limited in terms of size and quality. On the other hand, standard metrics for evaluating scoring function used to be ambiguous. Scoring functions are often tested in molecular docking or even virtual screening trials, which do not directly reflect the genuine quality of scoring functions. Collectively, these underlying obstacles have impeded the invention of more advanced scoring functions. In this Account, we describe our long-lasting efforts to overcome these obstacles, which involve two related projects. On the first project, we have created the PDBbind database. It is the first database that systematically annotates the protein-ligand complexes in the Protein Data Bank (PDB) with experimental binding data. This database has been updated annually since its first public release in 2004. The latest release (version 2016) provides binding data for 16 179 biomolecular complexes in PDB. Data sets provided by PDBbind have been applied to many computational and statistical studies on protein-ligand interaction and various subjects. In particular, it has become a major data resource for scoring function development. On the second project, we have established the Comparative Assessment of Scoring Functions (CASF) benchmark for scoring function evaluation. Our key idea is to decouple the "scoring" process from the "sampling" process, so scoring functions can be tested in a relatively pure context to reflect their quality. In our

  10. Synthesis, Structure and Electrochemistry of Tetranuclear Oxygen-Centered Copper(II) Clusters with Acetylacetone and Benz-pyrazole Hydrolyzed Derivatives as Ligand.

    Science.gov (United States)

    Vafazadeh, Rasoul; Willis, Anthony C

    2016-01-01

    Two copper(II) clusters Cu(4)OCl(6)(pyrazole)4, 1, and Cu(4)OBr(6)(Br-pyrazole)4, 2, have been synthesized by reacting acetylacetone and benzohydrazide (1:1 ratio) with CuX(2) (X = Cl for 1 and X= Br for 2) in methanol solutions. The structures of both clusters have been established by X-ray crystallography. The clusters contain four Cu, one O, six μ(2)-X atoms, and four pyrazole ligands. The pyrazoles was prepared in situ by the reaction of acetylacetone with benzohydrazide in methanol under reflux. In 2, the methine hydrogens of the pyrazole ligands have been replaced by bromine atoms. The four copper atoms encapsulate the central O atom in a tetrahedral arrangement. All copper atoms are five-coordinate and have similar coordination environments with slightly distorted trigonal bipyramidal geometry. The cyclic voltammogram of the clusters 1 and 2 show a one-electron quasi-reversible reduction wave in the region 0.485 to 0.731 V, and a one-electron quasi-reversible oxidation wave in the region 0.767 to 0.898 V. In 1, one irreversible oxidative response is observed on the positive of side of the voltammogram at 1.512 V and this can be assigned to Cu(II) to Cu(III) oxidation.

  11. A web server for analysis, comparison and prediction of protein ligand binding sites.

    Science.gov (United States)

    Singh, Harinder; Srivastava, Hemant Kumar; Raghava, Gajendra P S

    2016-03-25

    One of the major challenges in the field of system biology is to understand the interaction between a wide range of proteins and ligands. In the past, methods have been developed for predicting binding sites in a protein for a limited number of ligands. In order to address this problem, we developed a web server named 'LPIcom' to facilitate users in understanding protein-ligand interaction. Analysis, comparison and prediction modules are available in the "LPIcom' server to predict protein-ligand interacting residues for 824 ligands. Each ligand must have at least 30 protein binding sites in PDB. Analysis module of the server can identify residues preferred in interaction and binding motif for a given ligand; for example residues glycine, lysine and arginine are preferred in ATP binding sites. Comparison module of the server allows comparing protein-binding sites of multiple ligands to understand the similarity between ligands based on their binding site. This module indicates that ATP, ADP and GTP ligands are in the same cluster and thus their binding sites or interacting residues exhibit a high level of similarity. Propensity-based prediction module has been developed for predicting ligand-interacting residues in a protein for more than 800 ligands. In addition, a number of web-based tools have been integrated to facilitate users in creating web logo and two-sample between ligand interacting and non-interacting residues. In summary, this manuscript presents a web-server for analysis of ligand interacting residue. This server is available for public use from URL http://crdd.osdd.net/raghava/lpicom .

  12. Plutonium research and related activities at the Amarillo National Resource Center for Plutonium

    International Nuclear Information System (INIS)

    Hartley, R.S.; Beard, C.A.; Barnes, D.L.

    1998-01-01

    With the end of the Cold War, the US and Russia are reducing their nuclear weapons stockpiles. What to do with the materials from thousands of excess nuclear weapons is an important international challenge. How to handle the remaining US stockpile to ensure safe storage and reliability, in light of the aging support infrastructure, is an important national challenge. To help address these challenges and related issues, the Amarillo National Resource Center for Plutonium is working on behalf of the State of Texas with the US Department of Energy (DOE). The center directs three major programs that address the key aspects of the plutonium management issue: (1) the Communications, Education, Training and Community Involvement Program, which focuses on informing the public about plutonium and providing technical education at all levels; (2) the Environmental, Safety, and Health (ES and H) Program, which investigates the key ES and H impacts of activities related to the DOE weapons complex in Texas; and (3) the Nuclear and Other Materials Program, which is aimed at minimizing safety and proliferation risks by helping to develop and advocate safe stewardship, storage, and disposition of nuclear weapons materials. This paper provides an overview of the center's nuclear activities described in four broad categories of international activities, materials safety, plutonium storage, and plutonium disposition

  13. Identification of the iron-sulfur center of spinach ferredoxin-nitrite reductase as a tetranuclear center, and preliminary EPR studies of mechanism.

    Science.gov (United States)

    Lancaster, J R; Vega, J M; Kamin, H; Orme-Johnson, N R; Orme-Johnson, W H; Krueger, R J; Siegel, L M

    1979-02-25

    EPR spectroscopic and chemical analyses of spinach nitrite reductase show that the enzyme contains one reducible iron-sulfur center, and one site for binding either cyanide or nitrite, per siroheme. The heme is nearly all in the high spin ferric state in the enzyme as isolated. The extinction coefficient of the enzyme has been revised to E386 = 7.6 X 10(4) cm-1 (M heme)-1. The iron-sulfur center is reduced with difficulty by agents such as reduced methyl viologen (equilibrated with 1 atm of H2 at pH 7.7 in the presence of hydrogenase) or dithionite. Complexation of the enzyme with CO (a known ligand for nitrite reductase heme) markedly increases the reducibility of the iron-sulfur center. New chemical analyses and reinterpretation of previous data show that the enzyme contains 6 mol of iron and 4 mol of acid-labile S2-/mol of siroheme. The EPR spectrum of reduced nitrite reductase in 80% dimethyl sulfoxide establishes clearly that the enzyme contains a tetranuclear iron-sulfur (Fe4S4) center. The ferriheme and Fe4S4 centers are reduced at similar rates (k = 3 to 4 s-1) by dithionite. The dithionite-reduced Fe4S4 center is rapidly (k = 100 s-1) reoxidized by nitrite. These results indicate a role for the Fe4S4 center in catalysis.

  14. A Protein Data Bank survey reveals shortening of intermolecular hydrogen bonds in ligand-protein complexes when a halogenated ligand is an H-bond donor.

    Science.gov (United States)

    Poznański, Jarosław; Poznańska, Anna; Shugar, David

    2014-01-01

    Halogen bonding in ligand-protein complexes is currently widely exploited, e.g. in drug design or supramolecular chemistry. But little attention has been directed to other effects that may result from replacement of a hydrogen by a strongly electronegative halogen. Analysis of almost 30000 hydrogen bonds between protein and ligand demonstrates that the length of a hydrogen bond depends on the type of donor-acceptor pair. Interestingly, lengths of hydrogen bonds between a protein and a halogenated ligand are visibly shorter than those estimated for the same family of proteins in complexes with non-halogenated ligands. Taking into account the effect of halogenation on hydrogen bonding is thus important when evaluating structural and/or energetic parameters of ligand-protein complexes. All these observations are consistent with the concept that halogenation increases the acidity of the proximal amino/imino/hydroxyl groups and thus makes them better, i.e. stronger, H-bond donors.

  15. Ligand Binding Domain Protein in Tetracycline-Inducible Expression

    African Journals Online (AJOL)

    Purpose: To investigate tetracycline-inducible expression system for producing clinically usable, highquality liver X receptor ligand-binding domain recombinant protein. Methods: In this study, we have expressed and purified the recombinant liver X receptor β-ligand binding domain proteins in E. coli using a tetracycline ...

  16. Residue preference mapping of ligand fragments in the Protein Data Bank.

    Science.gov (United States)

    Wang, Lirong; Xie, Zhaojun; Wipf, Peter; Xie, Xiang-Qun

    2011-04-25

    The interaction between small molecules and proteins is one of the major concerns for structure-based drug design because the principles of protein-ligand interactions and molecular recognition are not thoroughly understood. Fortunately, the analysis of protein-ligand complexes in the Protein Data Bank (PDB) enables unprecedented possibilities for new insights. Herein, we applied molecule-fragmentation algorithms to split the ligands extracted from PDB crystal structures into small fragments. Subsequently, we have developed a ligand fragment and residue preference mapping (LigFrag-RPM) algorithm to map the profiles of the interactions between these fragments and the 20 proteinogenic amino acid residues. A total of 4032 fragments were generated from 71 798 PDB ligands by a ring cleavage (RC) algorithm. Among these ligand fragments, 315 unique fragments were characterized with the corresponding fragment-residue interaction profiles by counting residues close to these fragments. The interaction profiles revealed that these fragments have specific preferences for certain types of residues. The applications of these interaction profiles were also explored and evaluated in case studies, showing great potential for the study of protein-ligand interactions and drug design. Our studies demonstrated that the fragment-residue interaction profiles generated from the PDB ligand fragments can be used to detect whether these fragments are in their favorable or unfavorable environments. The algorithm for a ligand fragment and residue preference mapping (LigFrag-RPM) developed here also has the potential to guide lead chemistry modifications as well as binding residues predictions.

  17. A novel dinuclear Ru(II) complex having a bridging ligand of a rigid and extended structure. Incorporation of an anthraquinone unit and efficient emission quenching

    International Nuclear Information System (INIS)

    Mishra, L.; Choi, Chang-Shik; Araki, Koji

    1997-01-01

    Dinuclear Ru(II) complex having extended conjugation within the bridging ligand was prepared by coupling of the Ru(II) polypyridyl complex having a benzoyl-substituted phenazine unit with diaminoanthraquinone in one step, in which emission from the excited Ru(II) center was efficiently quenched through the anthraquinone unit. (author)

  18. Analysis of ligand-protein exchange by Clustering of Ligand Diffusion Coefficient Pairs (CoLD-CoP)

    Science.gov (United States)

    Snyder, David A.; Chantova, Mihaela; Chaudhry, Saadia

    2015-06-01

    NMR spectroscopy is a powerful tool in describing protein structures and protein activity for pharmaceutical and biochemical development. This study describes a method to determine weak binding ligands in biological systems by using hierarchic diffusion coefficient clustering of multidimensional data obtained with a 400 MHz Bruker NMR. Comparison of DOSY spectrums of ligands of the chemical library in the presence and absence of target proteins show translational diffusion rates for small molecules upon interaction with macromolecules. For weak binders such as compounds found in fragment libraries, changes in diffusion rates upon macromolecular binding are on the order of the precision of DOSY diffusion measurements, and identifying such subtle shifts in diffusion requires careful statistical analysis. The "CoLD-CoP" (Clustering of Ligand Diffusion Coefficient Pairs) method presented here uses SAHN clustering to identify protein-binders in a chemical library or even a not fully characterized metabolite mixture. We will show how DOSY NMR and the "CoLD-CoP" method complement each other in identifying the most suitable candidates for lysozyme and wheat germ acid phosphatase.

  19. Virtual Ligand Screening Using PL-PatchSurfer2, a Molecular Surface-Based Protein-Ligand Docking Method.

    Science.gov (United States)

    Shin, Woong-Hee; Kihara, Daisuke

    2018-01-01

    Virtual screening is a computational technique for predicting a potent binding compound for a receptor protein from a ligand library. It has been a widely used in the drug discovery field to reduce the efforts of medicinal chemists to find hit compounds by experiments.Here, we introduce our novel structure-based virtual screening program, PL-PatchSurfer, which uses molecular surface representation with the three-dimensional Zernike descriptors, which is an effective mathematical representation for identifying physicochemical complementarities between local surfaces of a target protein and a ligand. The advantage of the surface-patch description is its tolerance on a receptor and compound structure variation. PL-PatchSurfer2 achieves higher accuracy on apo form and computationally modeled receptor structures than conventional structure-based virtual screening programs. Thus, PL-PatchSurfer2 opens up an opportunity for targets that do not have their crystal structures. The program is provided as a stand-alone program at http://kiharalab.org/plps2 . We also provide files for two ligand libraries, ChEMBL and ZINC Drug-like.

  20. Synthesis of several tetraaza macrocyclic amine ligands and the biodistribution of their Tc-complexes

    International Nuclear Information System (INIS)

    Ketring, A.R.

    1982-01-01

    Several macrocyclic tetraaza ligands were synthesized and their /sup 99m/Tc-complexes prepared. The biological distribution of these complexes was examined to determine their possible utility as radiodiagnostic agents. The simplest of the macrocyclic tetraaza ligands studied, cyclam, forms a very stable cationic complex with Tc when pertechnetate is reduced with stannous ion in an aqueous solution of the ligand. When injected intravenously into mice Tc-cyclam was excreted predominantly by the urinary system. Derivatives of cyclam which were synthesized contained aromatic or aliphatic substituents and formed more lipophilic complexes with Tc. The complexes were formed in high yield as determined by paper chromatography, thin layer chromatography, electrophoresis and/or high performance liquid chromatography. Relative lipophilicities were determined for the complexes by octanol-to-water extractions. Animal studies using mice indicated there was an inverse relationship between the octanol-to-water extraction ratio and urinary excretion. Two of the complexes having relatively high octanol-to-water extraction ratios were significantly excreted by the hepatobiliary system with localization in the gall bladder. The complex having the highest octanol-to-water ratio was not excreted significantly by the hepatobiliary system, but cleared very slowly from the blood and localized in the liver, lungs, spleen and to some extent the heart. Derivatization of cyclam can be performed without greatly reducing its ability to complex Tc but greatly influencing the biological distribution of its Tc complex. This indicates that there is a potential for preparing radiodiagnostic agents using macrocyclic tetraaza ligands

  1. Colloidal-quantum-dot photovoltaics using atomic-ligand passivation

    KAUST Repository

    Tang, Jiang

    2011-09-18

    Colloidal-quantum-dot (CQD) optoelectronics offer a compelling combination of solution processing and spectral tunability through quantum size effects. So far, CQD solar cells have relied on the use of organic ligands to passivate the surface of the semiconductor nanoparticles. Although inorganic metal chalcogenide ligands have led to record electronic transport parameters in CQD films, no photovoltaic device has been reported based on such compounds. Here we establish an atomic ligand strategy that makes use of monovalent halide anions to enhance electronic transport and successfully passivate surface defects in PbS CQD films. Both time-resolved infrared spectroscopy and transient device characterization indicate that the scheme leads to a shallower trap state distribution than the best organic ligands. Solar cells fabricated following this strategy show up to 6% solar AM1.5G power-conversion efficiency. The CQD films are deposited at room temperature and under ambient atmosphere, rendering the process amenable to low-cost, roll-by-roll fabrication. © 2011 Macmillan Publishers Limited. All rights reserved.

  2. Ligand assisted cleavage of uranium oxo-clusters

    Energy Technology Data Exchange (ETDEWEB)

    Nocton, Gregory; Pecaut, Jacques; Mazzanti, Marinella [Laboratoire de Reconnaissance Ionique et Chimie de Coordination, Service de Chimie Inorganique et Biologique, UMR-E 3 CEA-UJF, CEA/DSM/INAC, CEA-Grenoble, 38054 Grenoble, Cedex 09 (France); Filinchuk, Yaroslav [Swiss Norwegian Beam Lines (SNBL) at the European Synchrotron Radiation Facility (ESRF), rue Jules Horowitz, 38043 Grenoble (France)

    2010-07-01

    Dibenzoylmethanate replaces the bridging triflate ligands in uranium triflate poly-oxo-clusters and cleaves the U{sub 12}O{sub 20} core yielding the new [U{sub 6}O{sub 4}(OH){sub 4}({eta}-dbm){sub 12}] dibenzoylmethanate (dbm{sup -}) cluster which slowly dissociates into a monomeric complex. This reactivity demonstrates the importance of bridging ligands in stabilizing uranium poly-oxo-clusters. (authors)

  3. Ligand-regulated peptide aptamers.

    Science.gov (United States)

    Miller, Russell A

    2009-01-01

    The peptide aptamer approach employs high-throughput selection to identify members of a randomized peptide library displayed from a scaffold protein by virtue of their interaction with a target molecule. Extending this approach, we have developed a peptide aptamer scaffold protein that can impart small-molecule control over the aptamer-target interaction. This ligand-regulated peptide (LiRP) scaffold, consisting of the protein domains FKBP12, FRB, and GST, binds to the cell-permeable small-molecule rapamycin and the binding of this molecule can prevent the interaction of the randomizable linker region connecting FKBP12 with FRB. Here we present a detailed protocol for the creation of a peptide aptamer plasmid library, selection of peptide aptamers using the LiRP scaffold in a yeast two-hybrid system, and the screening of those peptide aptamers for a ligand-regulated interaction.

  4. Essential role of conformational selection in ligand binding.

    Science.gov (United States)

    Vogt, Austin D; Pozzi, Nicola; Chen, Zhiwei; Di Cera, Enrico

    2014-02-01

    Two competing and mutually exclusive mechanisms of ligand recognition - conformational selection and induced fit - have dominated our interpretation of ligand binding in biological macromolecules for almost six decades. Conformational selection posits the pre-existence of multiple conformations of the macromolecule from which the ligand selects the optimal one. Induced fit, on the other hand, postulates the existence of conformational rearrangements of the original conformation into an optimal one that are induced by binding of the ligand. In the former case, conformational transitions precede the binding event; in the latter, conformational changes follow the binding step. Kineticists have used a facile criterion to distinguish between the two mechanisms based on the dependence of the rate of relaxation to equilibrium, kobs, on the ligand concentration, [L]. A value of kobs decreasing hyperbolically with [L] has been seen as diagnostic of conformational selection, while a value of kobs increasing hyperbolically with [L] has been considered diagnostic of induced fit. However, this simple conclusion is only valid under the rather unrealistic assumption of conformational transitions being much slower than binding and dissociation events. In general, induced fit only produces values of kobs that increase with [L] but conformational selection is more versatile and is associated with values of kobs that increase with, decrease with or are independent of [L]. The richer repertoire of kinetic properties of conformational selection applies to kinetic mechanisms with single or multiple saturable relaxations and explains the behavior of nearly all experimental systems reported in the literature thus far. Conformational selection is always sufficient and often necessary to account for the relaxation kinetics of ligand binding to a biological macromolecule and is therefore an essential component of any binding mechanism. On the other hand, induced fit is never necessary and

  5. Unexpected self-sorting self-assembly formation of a [4:4] sulfate:ligand cage from a preorganized tripodal urea ligand.

    Science.gov (United States)

    Pandurangan, Komala; Kitchen, Jonathan A; Blasco, Salvador; Boyle, Elaine M; Fitzpatrick, Bella; Feeney, Martin; Kruger, Paul E; Gunnlaugsson, Thorfinnur

    2015-04-07

    The design and synthesis of tripodal ligands 1-3 based upon the N-methyl-1,3,5-benzenetricarboxamide platform appended with three aryl urea arms is reported. This ligand platform gives rise to highly preorganized structures and is ideally suited for binding SO4 (2-) and H2 PO4 (-) ions through multiple hydrogen-bonding interactions. The solid-state crystal structures of 1-3 with SO4 (2-) show the encapsulation of a single anion within a cage structure, whereas the crystal structure of 1 with H2 PO4 (-) showed that two anions are encapsulated. We further demonstrate that ligand 4, based on the same platform but consisting of two bis-urea moieties and a single ammonium moiety, also recognizes SO4 (2-) to form a self-assembled capsule with [4:4] SO4 (2-) :4 stoichiometry in which the anions are clustered within a cavity formed by the four ligands. This is the first example of a self-sorting self-assembled capsule where four tetrahedrally arranged SO4 (2-) ions are embedded within a hydrophobic cavity. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. Steric and Stereochemical Modulation in Pyridyl- and Quinolyl-Containing Ligands

    Directory of Open Access Journals (Sweden)

    Zhaohua Dai

    2016-12-01

    Full Text Available Nitrogen-containing pyridine and quinoline are outstanding platforms on which excellent ionophores and sensors for metal ions can be built. Steric and stereochemical effects can be used to modulate the affinity and selectivity of such ligands toward different metal ions on the coordination chemistry front. On the signal transduction front, such effects can also be used to modulate optical responses of these ligands in metal sensing systems. In this review, steric modulation of achiral ligands and stereochemical modulation in chiral ligands, especially ionophores and sensors for zinc, copper, silver, and mercury, are examined using published structural and spectral data. Although it might be more challenging to construct chiral ligands than achiral ones, isotropic and anisotropic absorption signals from a single chiroptical fluorescent sensor provide not only detection but also differentiation of multiple analytes with high selectivity.

  7. Novel peptide ligand with high binding capacity for antibody purification

    DEFF Research Database (Denmark)

    Lund, L. N.; Gustavsson, P. E.; Michael, R.

    2012-01-01

    Small synthetic ligands for protein purification have become increasingly interesting with the growing need for cheap chromatographic materials for protein purification and especially for the purification of monoclonal antibodies (mAbs). Today, Protein A-based chromatographic resins are the most...... commonly used capture step in mAb down stream processing; however, the use of Protein A chromatography is less attractive due to toxic ligand leakage as well as high cost. Whether used as an alternative to the Protein A chromatographic media or as a subsequent polishing step, small synthetic peptide...... ligands have an advantage over biological ligands; they are cheaper to produce, ligand leakage by enzymatic degradation is either eliminated or significantly reduced, and they can in general better withstand cleaning in place (CIP) conditions such as 0.1 M NaOH. Here, we present a novel synthetic peptide...

  8. The affinity of the uranyl ion for nitrogen donor ligands

    International Nuclear Information System (INIS)

    Jarvis, N.V.; De Sousa, A.S.; Hancock, R.D.

    1992-01-01

    Established ligand design principles are used to predict the solution chemistry of UO 2 2+ with nitrogen donor ligands which do not contain carboxylate donors. pK a 's of the nitrogen donors are lowered by addition of hydroxylalkyl groups causing UO 2 2+ to have a greater affinity for these ligands than for hydroxide. Potentiometric studies using the ligands N,N,N',N',N''-pentakis(2-hydroxypropyl)-1,4,7-triazaheptane; N,N,N',N',N''-pentakis(2-hydroxyethyl)-1,4,7-triazaheptane; N,N,N',N'-tetrakis(2-hydroxypropyl)1,2-diaminoethane, N,N,N',N'-tetrakis(2-hydroxyethyl)-trans-1,2-diaminocyclohexane; 1,4,8,11-tetrakis(2-hydroxyethyl)-1,4,8,11-tetraazacyclotetradecane and N,N-bis(2-hydroxyethyl)glycine with UO 2 2+ showed that UO 2 2+ has a considerable aqueous solution chemistry with these ligands. (orig.)

  9. Magnetic Ligand Fishing as a Targeting Tool for HPLC-HRMS-SPE-NMR: α-Glucosidase Inhibitory Ligands and Alkylresorcinol Glycosides from Eugenia catharinae.

    Science.gov (United States)

    Wubshet, Sileshi G; Brighente, Inês M C; Moaddel, Ruin; Staerk, Dan

    2015-11-25

    A bioanalytical platform combining magnetic ligand fishing for α-glucosidase inhibition profiling and HPLC-HRMS-SPE-NMR for structural identification of α-glucosidase inhibitory ligands, both directly from crude plant extracts, is presented. Magnetic beads with N-terminus-coupled α-glucosidase were synthesized and characterized for their inherent catalytic activity. Ligand fishing with the immobilized enzyme was optimized using an artificial test mixture consisting of caffeine, ferulic acid, and luteolin before proof-of-concept with the crude extract of Eugenia catharinae. The combination of ligand fishing and HPLC-HRMS-SPE-NMR identified myricetin 3-O-α-L-rhamnopyranoside, myricetin, quercetin, and kaempferol as α-glucosidase inhibitory ligands in E. catharinae. Furthermore, HPLC-HRMS-SPE-NMR analysis led to identification of six new alkylresorcinol glycosides, i.e., 5-(2-oxopentyl)resorcinol 4-O-β-D-glucopyranoside, 5-propylresorcinol 4-O-β-D-glucopyranoside, 5-pentylresorcinol 4-O-[α-D-apiofuranosyl-(1→6)]-β-D-glucopyranoside, 5-pentylresorcinol 4-O-β-D-glucopyranoside, 4-hydroxy-3-O-methyl-5-pentylresorcinol 1-O-β-D-glucopyranoside, and 3-O-methyl-5-pentylresorcinol 1-O-[β-D-glucopyranosyl-(1→6)]-β-D-glucopyranoside.

  10. 3,4-Dimethyl diphenyldithiophosphate of mononuclear cobalt(II) with N-donor ligands: Synthesis, structural characterization, DFT and antibacterial studies

    Science.gov (United States)

    Kumar, Sandeep; Kour, Gurpreet; Schreckenbach, Georg; Andotra, Savit; Hundal, Geeta; Sharma, Vishal; Jaglan, Sundeep; Pandey, Sushil K.

    2017-08-01

    3,4-Dimethyl diphenyldithiophosphate of cobalt(II) with N-donor ligands [{(ArO)2PS2}2CoL2] [Ar = 3,4-(CH3)2C6H3 (1-3); L = C5H5N (1), 3,4-(CH3)2C5H3N (2) and 4-(C2H5)C5H4N (3)] have been synthesized and characterized by elemental analyses, infrared spectroscopy (IR), powder X-ray diffraction (PXRD) and single crystal X-ray analysis. Complex 1 crystallizes in the monoclinic space group P21/n whereas complexes 2 and 3 crystallize in the triclinic space group Pbar1. The crystal structures of complexes 1-3 reveal mononuclear units with the Co(II) center chelated in bidentate fashion by four S atoms of the two diphenyldithiophosphate ligands. The N atoms from two donor ligands are axially coordinated, leading to distorted octahedral geometry around Co(II). The complexes have been optimized using density functional theory (DFT), structural parameters have been calculated, and the energy gaps of the frontier orbitals (HOMO-LUMO) have been predicted. Mayer bond orders have also been calculated. Structural parameters from the crystallographic and DFT studies are in good agreement with each other. To explore the biological potential, complexes were evaluated for their antibacterial activity against three bacterial strains. The bacterial growth inhibition capacity of the ligand and complexes followed the order of 3 > 2 > 1 > L1.

  11. The influence of ligand field effects on the magnetic exchange of high-spin Co(II)-semiquinonate complexes.

    Science.gov (United States)

    Bencini, Alessandro; Beni, Alessandra; Costantino, Ferdinando; Dei, Andrea; Gatteschi, Dante; Sorace, Lorenzo

    2006-02-07

    [Co(Me(4)cyclam)(tropolonate)](PF(6)) was synthesised and structurally characterised. Its electronic and W-band EPR spectra have been analysed by means of the angular overlap calculation of the Spin Hamiltonian parameters that provided also a satisfactory reproduction of the temperature dependence of the magnetic susceptibility. The present results can be interpreted assuming a pseudo-octahedral character for the Co(II) center. This prompted us to reconsider the model formerly used for the analysis of the magnetic coupling between hs-Co(II) and the paramagnetic o-semiquinonate ligand in the corresponding derivatives [Co(Me(4)cyclam)(PhenSQ)](PF(6)) and [Co(Me(4)cyclam)(DTBSQ)](PF(6)). These results indicate that the effect of the magnetic coupling is active only below 50 K and that a more refined model of exchange coupling between Co(II) and semiquinonato ligands is needed to quantitatively analyze the magnetic behaviour of this class of systems.

  12. Force loading explains spatial sensing of ligands by cells

    Science.gov (United States)

    Oria, Roger; Wiegand, Tina; Escribano, Jorge; Elosegui-Artola, Alberto; Uriarte, Juan Jose; Moreno-Pulido, Cristian; Platzman, Ilia; Delcanale, Pietro; Albertazzi, Lorenzo; Navajas, Daniel; Trepat, Xavier; García-Aznar, José Manuel; Cavalcanti-Adam, Elisabetta Ada; Roca-Cusachs, Pere

    2017-12-01

    Cells can sense the density and distribution of extracellular matrix (ECM) molecules by means of individual integrin proteins and larger, integrin-containing adhesion complexes within the cell membrane. This spatial sensing drives cellular activity in a variety of normal and pathological contexts. Previous studies of cells on rigid glass surfaces have shown that spatial sensing of ECM ligands takes place at the nanometre scale, with integrin clustering and subsequent formation of focal adhesions impaired when single integrin-ligand bonds are separated by more than a few tens of nanometres. It has thus been suggested that a crosslinking ‘adaptor’ protein of this size might connect integrins to the actin cytoskeleton, acting as a molecular ruler that senses ligand spacing directly. Here, we develop gels whose rigidity and nanometre-scale distribution of ECM ligands can be controlled and altered. We find that increasing the spacing between ligands promotes the growth of focal adhesions on low-rigidity substrates, but leads to adhesion collapse on more-rigid substrates. Furthermore, disordering the ligand distribution drastically increases adhesion growth, but reduces the rigidity threshold for adhesion collapse. The growth and collapse of focal adhesions are mirrored by, respectively, the nuclear or cytosolic localization of the transcriptional regulator protein YAP. We explain these findings not through direct sensing of ligand spacing, but by using an expanded computational molecular-clutch model, in which individual integrin-ECM bonds—the molecular clutches—respond to force loading by recruiting extra integrins, up to a maximum value. This generates more clutches, redistributing the overall force among them, and reducing the force loading per clutch. At high rigidity and high ligand spacing, maximum recruitment is reached, preventing further force redistribution and leading to adhesion collapse. Measurements of cellular traction forces and actin flow speeds

  13. Rhodium, iridium and nickel complexes with a 1,3,5-triphenylbenzene tris-MIC ligand. Study of the electronic properties and catalytic activities

    Directory of Open Access Journals (Sweden)

    Carmen Mejuto

    2015-12-01

    Full Text Available The coordination versatility of a 1,3,5-triphenylbenzene-tris-mesoionic carbene ligand is illustrated by the preparation of complexes with three different metals: rhodium, iridium and nickel. The rhodium and iridium complexes contained the [MCl(COD] fragments, while the nickel compound contained [NiCpCl]. The preparation of the tris-MIC (MIC = mesoionic carbene complex with three [IrCl(CO2] fragments, allowed the estimation of the Tolman electronic parameter (TEP for the ligand, which was compared with the TEP value for a related 1,3,5-triphenylbenzene-tris-NHC ligand. The electronic properties of the tris-MIC ligand were studied by cyclic voltammetry measurements. In all cases, the tris-MIC ligand showed a stronger electron-donating character than the corresponding NHC-based ligands. The catalytic activity of the tri-rhodium complex was tested in the addition reaction of arylboronic acids to α,β-unsaturated ketones.

  14. Synthesis of mixed ligand europium complexes: Verification of predicted luminescence intensification

    International Nuclear Information System (INIS)

    Lima, Nathalia B.D.; Silva, Anderson I.S.; Gonçalves, Simone M.C.; Simas, Alfredo M.

    2016-01-01

    Mixed ligand europium complexes are predicted to be more luminescent than what would be expected from their corresponding repeating ligand compounds according to a conjecture recently advanced by our research group; a conjecture that has already been validated for strongly luminescent europium complexes. In this article, we seek to further verify the validity of this conjecture for complexes which are much more symmetric, and which thus display lower levels of luminescence. Accordingly, we synthesized complexes Eu(DBM) 3 (L) 2 , and all novel mixed ligand combinations Eu(DBM) 3 (L,L') with L and L' equal to DBSO, PTSO, and TPPO. The syntheses were carried out via displacement reactions from the starting complex Eu(DBM) 3 (H 2 O) 2 , passing through the intermediates Eu(DBM) 3 (L) 2 and finally, by displacement of L by L', arriving at Eu(DBM) 3 (L,L'). The ligands L obey the following order of displacement TPPO>PTSO>DBSO>H 2 O, which had been previously described by our group. In the present article, we further show that this displacement order could have been predicted by Sparkle/RM1 thermochemical calculations. Subsequently, we determined the radiative decay rates, A rad , for all six compounds by photophysical measurements. As expected, results show that the measured A rad values for all novel mixed ligand complexes are larger than the average of the A rad values for the corresponding repeating ligand coordination compounds. In conclusion, the present article does broaden the scope of our conjecture, which enunciates that an increase in the diversity of ligands around the europium ion tends to intensify the luminescence. - Highlights: • Mixed ligand europium complexes are predicted to be more luminescent than repeating ligand ones. • Radiative decay rates increase with structural coordination asymmetry. • The non-ionic ligands displacement order in substitution reactions is TPPO>PTSO>DBSO>H 2 O. • Sparkle/RM1 correctly predicts the

  15. Characterization of Colloidal Quantum Dot Ligand Exchange by X-ray Photoelectron Spectroscopy

    Science.gov (United States)

    Atewologun, Ayomide; Ge, Wangyao; Stiff-Roberts, Adrienne D.

    2013-05-01

    Colloidal quantum dots (CQDs) are chemically synthesized semiconductor nanoparticles with size-dependent wavelength tunability. Chemical synthesis of CQDs involves the attachment of long organic surface ligands to prevent aggregation; however, these ligands also impede charge transport. Therefore, it is beneficial to exchange longer surface ligands for shorter ones for optoelectronic devices. Typical characterization techniques used to analyze surface ligand exchange include Fourier-transform infrared spectroscopy, x-ray diffraction, transmission electron microscopy, and nuclear magnetic resonance spectroscopy, yet these techniques do not provide a simultaneously direct, quantitative, and sensitive method for evaluating surface ligands on CQDs. In contrast, x-ray photoelectron spectroscopy (XPS) can provide nanoscale sensitivity for quantitative analysis of CQD surface ligand exchange. A unique aspect of this work is that a fingerprint is identified for shorter surface ligands by resolving the regional XPS spectrum corresponding to different types of carbon bonds. In addition, a deposition technique known as resonant infrared matrix-assisted pulsed laser evaporation is used to improve the CQD film uniformity such that stronger XPS signals are obtained, enabling more accurate analysis of the ligand exchange process.

  16. Oxidation of ligand-protected aluminum clusters: An ab initio molecular dynamics study

    International Nuclear Information System (INIS)

    Alnemrat, Sufian; Hooper, Joseph P.

    2014-01-01

    We report Car-Parrinello molecular dynamics simulations of the oxidation of ligand-protected aluminum clusters that form a prototypical cluster-assembled material. These clusters contain a small aluminum core surrounded by a monolayer of organic ligand. The aromatic cyclopentadienyl ligands form a strong bond with surface Al atoms, giving rise to an organometallic cluster that crystallizes into a low-symmetry solid and is briefly stable in air before oxidizing. Our calculations of isolated aluminum/cyclopentadienyl clusters reacting with oxygen show minimal reaction between the ligand and O 2 molecules at simulation temperatures of 500 and 1000 K. In all cases, the reaction pathway involves O 2 diffusing through the ligand barrier, splitting into atomic oxygen upon contact with the aluminum, and forming an oxide cluster with aluminum/ligand bonds still largely intact. Loss of individual aluminum-ligand units, as expected from unimolecular decomposition calculations, is not observed except following significant oxidation. These calculations highlight the role of the ligand in providing a steric barrier against oxidizers and in maintaining the large aluminum surface area of the solid-state cluster material

  17. A Protein Data Bank survey reveals shortening of intermolecular hydrogen bonds in ligand-protein complexes when a halogenated ligand is an H-bond donor.

    Directory of Open Access Journals (Sweden)

    Jarosław Poznański

    Full Text Available Halogen bonding in ligand-protein complexes is currently widely exploited, e.g. in drug design or supramolecular chemistry. But little attention has been directed to other effects that may result from replacement of a hydrogen by a strongly electronegative halogen. Analysis of almost 30000 hydrogen bonds between protein and ligand demonstrates that the length of a hydrogen bond depends on the type of donor-acceptor pair. Interestingly, lengths of hydrogen bonds between a protein and a halogenated ligand are visibly shorter than those estimated for the same family of proteins in complexes with non-halogenated ligands. Taking into account the effect of halogenation on hydrogen bonding is thus important when evaluating structural and/or energetic parameters of ligand-protein complexes. All these observations are consistent with the concept that halogenation increases the acidity of the proximal amino/imino/hydroxyl groups and thus makes them better, i.e. stronger, H-bond donors.

  18. NKG2D and its ligands in cancer.

    Science.gov (United States)

    Dhar, Payal; Wu, Jennifer D

    2018-04-01

    NKG2D is an activating immune receptor expressed by NK and effector T cells. Induced expression of NKG2D ligand on tumor cell surface during oncogenic insults renders cancer cells susceptible to immune destruction. In advanced human cancers, tumor cells shed NKG2D ligand to produce an immune soluble form as a means of immune evasion. Soluble NKG2D ligands have been associated with poor clinical prognosis in cancer patients. Harnessing NKG2D pathway is considered a viable avenue in cancer immunotherapy over recent years. In this review, we will discuss the progress and perspectives. Copyright © 2018. Published by Elsevier Ltd.

  19. On the analysis and comparison of conformer-specific essential dynamics upon ligand binding to a protein

    International Nuclear Information System (INIS)

    Grosso, Marcos; Kalstein, Adrian; Parisi, Gustavo; Fernandez-Alberti, Sebastian; Roitberg, Adrian E.

    2015-01-01

    The native state of a protein consists of an equilibrium of conformational states on an energy landscape rather than existing as a single static state. The co-existence of conformers with different ligand-affinities in a dynamical equilibrium is the basis for the conformational selection model for ligand binding. In this context, the development of theoretical methods that allow us to analyze not only the structural changes but also changes in the fluctuation patterns between conformers will contribute to elucidate the differential properties acquired upon ligand binding. Molecular dynamics simulations can provide the required information to explore these features. Its use in combination with subsequent essential dynamics analysis allows separating large concerted conformational rearrangements from irrelevant fluctuations. We present a novel procedure to define the size and composition of essential dynamics subspaces associated with ligand-bound and ligand-free conformations. These definitions allow us to compare essential dynamics subspaces between different conformers. Our procedure attempts to emphasize the main similarities and differences between the different essential dynamics in an unbiased way. Essential dynamics subspaces associated to conformational transitions can also be analyzed. As a test case, we study the glutaminase interacting protein (GIP), composed of a single PDZ domain. Both GIP ligand-free state and glutaminase L peptide-bound states are analyzed. Our findings concerning the relative changes in the flexibility pattern upon binding are in good agreement with experimental Nuclear Magnetic Resonance data

  20. On the analysis and comparison of conformer-specific essential dynamics upon ligand binding to a protein

    Energy Technology Data Exchange (ETDEWEB)

    Grosso, Marcos; Kalstein, Adrian; Parisi, Gustavo; Fernandez-Alberti, Sebastian, E-mail: sfalberti@gmail.com [Universidad Nacional de Quilmes, Roque Saenz Peña 352, B1876BXD Bernal (Argentina); Roitberg, Adrian E. [Departments of Physics and Chemistry, University of Florida, Gainesville, Florida 32611 (United States)

    2015-06-28

    The native state of a protein consists of an equilibrium of conformational states on an energy landscape rather than existing as a single static state. The co-existence of conformers with different ligand-affinities in a dynamical equilibrium is the basis for the conformational selection model for ligand binding. In this context, the development of theoretical methods that allow us to analyze not only the structural changes but also changes in the fluctuation patterns between conformers will contribute to elucidate the differential properties acquired upon ligand binding. Molecular dynamics simulations can provide the required information to explore these features. Its use in combination with subsequent essential dynamics analysis allows separating large concerted conformational rearrangements from irrelevant fluctuations. We present a novel procedure to define the size and composition of essential dynamics subspaces associated with ligand-bound and ligand-free conformations. These definitions allow us to compare essential dynamics subspaces between different conformers. Our procedure attempts to emphasize the main similarities and differences between the different essential dynamics in an unbiased way. Essential dynamics subspaces associated to conformational transitions can also be analyzed. As a test case, we study the glutaminase interacting protein (GIP), composed of a single PDZ domain. Both GIP ligand-free state and glutaminase L peptide-bound states are analyzed. Our findings concerning the relative changes in the flexibility pattern upon binding are in good agreement with experimental Nuclear Magnetic Resonance data.

  1. Development of radioiodinated receptor ligands for cerebral single photon emission tomography

    International Nuclear Information System (INIS)

    Knapp, F.F. Jr.; McPherson, D.W.

    1992-01-01

    In the last decade the use of radiolabeled ligands for the imaging of cerebral receptors by emission computed tomography (ECT) has seen rapid growth. The opportunity to routinely perform cerebral single photon emission tomography (SPET) with iodine-123-labeled ligands depends on the availability of receptor ligands into which iodine can be introduced without decreasing the required high target receptor specificity. The use of iodine-123-labeled receptor-specific ligands also depends on the availability of high purity iodine-123 at reasonable costs and the necessary imaging instrumentation. In this paper, the development and current stage of evaluation of various iodine-123-labeled ligands for SPET imaging of dopaminergic, serotonergic and muscarinic acetylcholinergic receptor classes are discussed

  2. Ligand electronic parameters as a measure of the polarization of the C≡O bond in [M(CO)(x)L(y)]n complexes and of the relative stabilization of [M(CO)(x)L(y)](n/n+1) species.

    Science.gov (United States)

    Zobi, Fabio

    2010-11-15

    The electronic description of octahedral (fac-[M(CO)(3)L(3)](n), with M = Re, Ru, and Mn, and [Cr(CO)(5)L](n)), square-planar (cis-[Pt(CO)(2)L(2)](n)), and tetrahedral ([Ni(CO)(3)L](n)) carbonyl complexes (where L = monodentate ligand) was obtained via density functional theory and natural population analyses in order to understand what effects are probed in these species by vibrational spectroscopy and electrochemistry as a function of the ligand electronic parameter of the associated L. The analysis indicates that while ligand electronic parameters may be considered as a measure of the net donor power of the ligand, the net transfer of the electron density (or charge) does not occur from the ligand to the metal ion. In [M(CO)(x)L(y)](n) carbonyl species, the charge transfer occurs from the ligand L to the oxygen atom of the bound carbon monoxides. This charge transfer translates into changes of the polarization (or permanent dipole) and the covalency of the C≡O bonds, and it is this effect that is probed in IR spectroscopy. As the analysis shifts from IR radiations to electrochemical potentials, the parameters best describe the relative thermodynamic stability of the oxidized and reduced [M(CO)(x)L(y)](n/n+1) species. No relationship is found between the metal natural charge of the [M(CO)(x)L(y)](n) fragments analyzed and the parameters. Brief considerations are given on the possible design of CO-releasing molecules.

  3. Radioiodinated ligands for dopamine receptors

    International Nuclear Information System (INIS)

    Kung, H.F.

    1994-01-01

    The dopamine receptor system is important for normal brain function; it is also the apparent action site for various neuroleptic drugs for the treatment of schizophrenia and other metal disorders. In the past few years radioiodinated ligands for single photon emission tomography (SPECT) have been successfully developed and tested in humans: [ 123 I]TISCH for D1 dopamine receptors; [ 123 I]IBZM, epidepride, IBF and FIDA2, four iodobenzamide derivatives, for D2/D3 dopamine receptors. In addition, [ 123 I]β-CIT (RTI-55) and IPT, cocaine derivatives, for the dopamine reuptake site are potentially useful for diagnosis of loss of dopamine neurons. The first iodinated ligand, (R)trans-7-OH-PIPAT, for D3 dopamine receptors, was synthesized and characterized with cloned cell lines (Spodoptera frugiperda, Sf9) expressing the D2 and D3 dopamine receptors and with rat basal forebrain membrane preparations. Most of the known iodobenzamides displayed similar potency in binding to both D2 and D3 dopamine receptors expressed in the cell lines. Initial studies appear to suggest that by fine tuning the structures it may be possible to develop agents specific for D2 and D3 dopamine receptors. It is important to investigate D2/D3 selectivity for this series of potent ligands

  4. Intuitive Density Functional Theory-Based Energy Decomposition Analysis for Protein-Ligand Interactions.

    Science.gov (United States)

    Phipps, M J S; Fox, T; Tautermann, C S; Skylaris, C-K

    2017-04-11

    First-principles quantum mechanical calculations with methods such as density functional theory (DFT) allow the accurate calculation of interaction energies between molecules. These interaction energies can be dissected into chemically relevant components such as electrostatics, polarization, and charge transfer using energy decomposition analysis (EDA) approaches. Typically EDA has been used to study interactions between small molecules; however, it has great potential to be applied to large biomolecular assemblies such as protein-protein and protein-ligand interactions. We present an application of EDA calculations to the study of ligands that bind to the thrombin protein, using the ONETEP program for linear-scaling DFT calculations. Our approach goes beyond simply providing the components of the interaction energy; we are also able to provide visual representations of the changes in density that happen as a result of polarization and charge transfer, thus pinpointing the functional groups between the ligand and protein that participate in each kind of interaction. We also demonstrate with this approach that we can focus on studying parts (fragments) of ligands. The method is relatively insensitive to the protocol that is used to prepare the structures, and the results obtained are therefore robust. This is an application to a real protein drug target of a whole new capability where accurate DFT calculations can produce both energetic and visual descriptors of interactions. These descriptors can be used to provide insights for tailoring interactions, as needed for example in drug design.

  5. The relative importance of topography and RGD ligand density for endothelial cell adhesion.

    Directory of Open Access Journals (Sweden)

    Guillaume Le Saux

    Full Text Available The morphology and function of endothelial cells depends on the physical and chemical characteristics of the extracellular environment. Here, we designed silicon surfaces on which topographical features and surface densities of the integrin binding peptide arginine-glycine-aspartic acid (RGD could be independently controlled. We used these surfaces to investigate the relative importance of the surface chemistry of ligand presentation versus surface topography in endothelial cell adhesion. We compared cell adhesion, spreading and migration on surfaces with nano- to micro-scaled pyramids and average densities of 6×10(2-6×10(11 RGD/mm(2. We found that fewer cells adhered onto rough than flat surfaces and that the optimal average RGD density for cell adhesion was 6×10(5 RGD/mm(2 on flat surfaces and substrata with nano-scaled roughness. Only on surfaces with micro-scaled pyramids did the topography hinder cell migration and a lower average RGD density was optimal for adhesion. In contrast, cell spreading was greatest on surfaces with 6×10(8 RGD/mm(2 irrespectively of presence of feature and their size. In summary, our data suggest that the size of pyramids predominately control the number of endothelial cells that adhere to the substratum but the average RGD density governs the degree of cell spreading and length of focal adhesion within adherent cells. The data points towards a two-step model of cell adhesion: the initial contact of cells with a substratum may be guided by the topography while the engagement of cell surface receptors is predominately controlled by the surface chemistry.

  6. Characterization of chicken thrombocyte responses to Toll-like receptor ligands.

    Directory of Open Access Journals (Sweden)

    Michael St Paul

    Full Text Available Thrombocytes are the avian equivalent to mammalian platelets. In addition to their hemostatic effects, mammalian platelets rely in part on pattern recognition receptors, such as the Toll-like receptors (TLR, to detect the presence of pathogens and signal the release of certain cytokines. Ligands for TLRs include lipopolysaccharide (LPS, which is bound by TLR4, as well as unmethylated CpG DNA motifs, which are bound by TLR9 in mammals and TLR21 in chickens. Similar to mammalian platelets, avian thrombocytes have been shown to express TLR4 and secrete some pro-inflammatory cytokines in response to LPS treatment. However, the full extent of the contributions made by thrombocytes to host immunity has yet to be elucidated. Importantly, the mechanisms by which TLR stimulation may modulate thrombocyte effector functions have not been well characterized. As such, the objective of the present study was to gain further insight into the immunological role of thrombocytes by analyzing their responses to treatment with ligands for TLR4 and TLR21. To this end, we quantified the relative expression of several immune system genes at 1, 3, 8 and 18 hours post-treatment using real-time RT-PCR. Furthermore, production of nitric oxide and phagocytic activity of thrombocytes was measured after their activation with TLR ligands. We found that thrombocytes constitutively express transcripts for both pro- and anti-inflammatory cytokines, in addition to those associated with anti-viral responses and antigen presentation. Moreover, we found that both LPS and CpG oligodeoxynucleotides (ODN induced robust pro-inflammatory responses in thrombocytes, as characterized by more than 100 fold increase in interleukin (IL-1β, IL-6 and IL-8 transcripts, while only LPS enhanced nitric oxide production and phagocytic capabilities. Future studies may be aimed at examining the responses of thrombocytes to other TLR ligands.

  7. Redox non-innocent ligands: versatile new tools to control catalytic reactions

    NARCIS (Netherlands)

    Lyaskovskyy, V.; de Bruin, B.

    2012-01-01

    In this (tutorial overview) perspective we highlight the use of "redox non-innocent" ligands in catalysis. Two main types of reactivity in which the redox non-innocent ligand is involved can be specified: (A) The redox active ligand participates in the catalytic cycle only by accepting/donating

  8. Flow Cytometry-Based Bead-Binding Assay for Measuring Receptor Ligand Specificity

    NARCIS (Netherlands)

    Sprokholt, Joris K.; Hertoghs, Nina; Geijtenbeek, Teunis B. H.

    2016-01-01

    In this chapter we describe a fluorescent bead-binding assay, which is an efficient and feasible method to measure interaction between ligands and receptors on cells. In principle, any ligand can be coated on fluorescent beads either directly or via antibodies. Binding between ligand-coated beads

  9. Ligand-free, protein-bound technetium-99m. Evidence for tumour localisation

    International Nuclear Information System (INIS)

    Jakovljevic, A.C.; Pojer, P.M.

    1984-11-01

    An hypothesis that cations accumulate in tumours independent of ligand is tested. A preparation of technetium-99m known to be ligand-free (that is, the technetium is protein bound and no other ligand is injected) has been shown to accumulate in a T-cell lymphoma

  10. Synthesis, thermogravimetric study and crystal structure of an N-rich copper(II) compound with tren ligands and nitrate counter-anions

    Energy Technology Data Exchange (ETDEWEB)

    Pérez-Toro, Inmaculada; Domínguez-Martín, Alicia [Department of Inorganic Chemistry, Faculty of Pharmacy, University of Granada, 18071 Granada (Spain); Choquesillo-Lazarte, Duane [Laboratorio de Estudios Cristalográficos, IACT, CSIC-Universidad de Granada, Av. de las Palmeras 4, E-18100 Armilla, Granada (Spain); Vílchez-Rodríguez, Esther [Department of Inorganic Chemistry, Faculty of Pharmacy, University of Granada, 18071 Granada (Spain); Department of Inorganic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, 15782 Santiago de Compostela (Spain); Castiñeiras, Alfonso [Department of Inorganic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, 15782 Santiago de Compostela (Spain); Niclós-Gutiérrez, Juan, E-mail: jniclos@ugr.es [Department of Inorganic Chemistry, Faculty of Pharmacy, University of Granada, 18071 Granada (Spain)

    2014-10-10

    The N-rich salt [{Cu(tren)}{sub 3}(μ{sub 3}-tren)]{sub 2}(NO{sub 3}){sub 12}·3H{sub 2}O has been studied by XRD and by coupled TG and FT-IR spectroscopy of the evolved gases. After water loss, thermal decomposition of the nitrate ions and some tren ligands in the salt are overlapped. - Highlights: • A novel N-rich copper(II)-tren complex has been crystallized as a 3-hydrated nitrate salt. • Tren acts both as tripodal tetradentate and as μ{sub 3}-tren bridging ligand. • Copper(II) centers exhibit distorted trigonal bipyramidal coordination. • Coupled thermogravimetry and FT-IR spectra of evolved gases have been used. • Decomposition of nitrate anions and tren ligands occurs in an overlapped step. - Abstract: The compound [{Cu(tren)}{sub 3}(μ3-tren)]{sub 2}(NO{sub 3}){sub 12}·3H{sub 2}O has been synthesized, crystallized and characterized by single crystal X-ray diffraction, thermogravimetry (TG) coupled to FT-IR spectroscopy of the evolved gases, TG–differential scanning calorimetry (DSC) and electronic (diffuse reflectance) and FT-IR spectroscopies. The sample loses the crystallization water between room temperature and 200 °C. The decomposition of the salt begins with an overlapped decomposition of nitrate anions and some tren ligands where CO{sub 2}, H{sub 2}O, CO, NH{sub 3}, N{sub 2}O, NO and NO{sub 2} are evolved (205–235 °C). Then decomposition of additional tren ligands takes place (235–725 °C). Finally a non-pure CuO residue is obtained at 725 °C.

  11. Characteristic molecular vibrations of adenosine receptor ligands.

    Science.gov (United States)

    Chee, Hyun Keun; Yang, Jin-San; Joung, Je-Gun; Zhang, Byoung-Tak; Oh, S June

    2015-02-13

    Although the regulation of membrane receptor activation is known to be crucial for molecular signal transduction, the molecular mechanism underlying receptor activation is not fully elucidated. Here we study the physicochemical nature of membrane receptor behavior by investigating the characteristic molecular vibrations of receptor ligands using computational chemistry and informatics methods. By using information gain, t-tests, and support vector machines, we have identified highly informative features of adenosine receptor (AdoR) ligand and corresponding functional amino acid residues such as Asn (6.55) of AdoR that has informative significance and is indispensable for ligand recognition of AdoRs. These findings may provide new perspectives and insights into the fundamental mechanism of class A G protein-coupled receptor activation. Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  12. Ruthenium water oxidation catalysts containing the non-planar tetradentate ligand, biisoquinoline dicarboxylic acid (biqaH2).

    Science.gov (United States)

    Scherrer, Dominik; Schilling, Mauro; Luber, Sandra; Fox, Thomas; Spingler, Bernhard; Alberto, Roger; Richmond, Craig J

    2016-12-06

    Two ruthenium complexes containing the tetradentate ligand [1,1'-biisoquinoline]-3,3'-dicarboxylic acid, and 4-picoline or 6-bromoisoquinoline as axial ligands have been prepared. The complexes have been fully characterised and initial studies on their potential to function as molecular water oxidation catalysts have been performed. Both complexes catalyse the oxidation of water in acidic media with Ce IV as a stoichiometric chemical oxidant, although turnover numbers and turnover frequencies are modest when compared with the closely related Ru-bda and Ru-pda analogues. Barriers for the water nucleophilic attack and intermolecular coupling pathways were obtained from density functional theory calculations and the crucial influence of the ligand framework in determining the most favourable reaction pathway was elucidated from a combined analysis of the theoretical and experimental results.

  13. Gene Duplication of the zebrafish kit ligand and partitioning of melanocyte development functions to kit ligand a.

    Directory of Open Access Journals (Sweden)

    Keith A Hultman

    2007-01-01

    Full Text Available The retention of particular genes after the whole genome duplication in zebrafish has given insights into how genes may evolve through partitioning of ancestral functions. We examine the partitioning of expression patterns and functions of two zebrafish kit ligands, kit ligand a (kitla and kit ligand b (kitlb, and discuss their possible coevolution with the duplicated zebrafish kit receptors (kita and kitb. In situ hybridizations show that kitla mRNA is expressed in the trunk adjacent to the notochord in the middle of each somite during stages of melanocyte migration and later expressed in the skin, when the receptor is required for melanocyte survival. kitla is also expressed in other regions complementary to kita receptor expression, including the pineal gland, tail bud, and ear. In contrast, kitlb mRNA is expressed in brain ventricles, ear, and cardinal vein plexus, in regions generally not complementary to either zebrafish kit receptor ortholog. However, like kitla, kitlb is expressed in the skin during stages consistent with melanocyte survival. Thus, it appears that kita and kitla have maintained congruent expression patterns, while kitb and kitlb have evolved divergent expression patterns. We demonstrate the interaction of kita and kitla by morpholino knockdown analysis. kitla morphants, but not kitlb morphants, phenocopy the null allele of kita, with defects for both melanocyte migration and survival. Furthermore, kitla morpholino, but not kitlb morpholino, interacts genetically with a sensitized allele of kita, confirming that kitla is the functional ligand to kita. Last, we examine kitla overexpression in embryos, which results in hyperpigmentation caused by an increase in the number and size of melanocytes. This hyperpigmentation is dependent on kita function. We conclude that following genome duplication, kita and kitla have maintained their receptor-ligand relationship, coevolved complementary expression patterns, and that

  14. Ligand-selective activation of heterologously-expressed mammalian olfactory receptor.

    Science.gov (United States)

    Ukhanov, K; Bobkov, Y; Corey, E A; Ache, B W

    2014-10-01

    Mammalian olfactory receptors (ORs) appear to have the capacity to couple to multiple G protein-coupled signaling pathways in a ligand-dependent selective manner. To better understand the mechanisms and molecular range of such ligand selectivity, we expressed the mouse eugenol OR (mOR-EG) in HEK293T cells together with Gα15 to monitor activation of the phospholipase-C (PLC) signaling pathway and/or Gαolf to monitor activation of the adenylate cyclase (AC) signaling pathway, resulting in intracellular Ca(2+) release and/or Ca(2+) influx through a cyclic nucleotide-gated channel, respectively. PLC-dependent responses differed dynamically from AC-dependent responses, allowing them to be distinguished when Gα15 and Gαolf were co-expressed. The dynamic difference in readout was independent of the receptor, the heterologous expression system, and the ligand concentration. Of 17 reported mOR-EG ligands tested, including eugenol, its analogs, and structurally dissimilar compounds (mousse cristal, nootkatone, orivone), some equally activated both signaling pathways, some differentially activated both signaling pathways, and some had no noticeable effect even at 1-5mM. Our findings argue that mOR-EG, when heterologously expressed, can couple to two different signaling pathways in a ligand selective manner. The challenge now is to determine the potential of mOR-EG, and perhaps other ORs, to activate multiple signaling pathways in a ligand selective manner in native ORNs. Copyright © 2014 Elsevier Ltd. All rights reserved.

  15. Nonlinear absorbing cationic iridium(III) complexes bearing benzothiazolylfluorene motif on the bipyridine (N∧N) ligand: synthesis, photophysics and reverse saturable absorption.

    Science.gov (United States)

    Li, Yuhao; Dandu, Naveen; Liu, Rui; Hu, Lei; Kilina, Svetlana; Sun, Wenfang

    2013-07-24

    Four new heteroleptic cationic Ir(III) complexes bearing benzothiazolylfluorene motif on the bipyridine (N∧N) (1 and 2) and phenylpyridine (C∧N) (3 and 4) ligands are synthesized and characterized. The influence of the position of the substituent and the extent of π-conjugation on the photophysics of these complexes is systematically investigated by spectroscopic methods and simulated by time-dependent density functional theory (TDDFT). The complexes exhibit ligand-centered (1)π,π* transitions with admixtures of (1)ILCT (π(benzothiazolylfluorene) → π*(bpy)) and (1)MLCT (metal-to-ligand charge transfer) characters below 475 nm, and very weak (1,3)MLCT and (1,3)LLCT (ligand-to-ligand charge transfer) transitions above 475 nm. The emission of these complexes at room temperature in CH2Cl2 solutions is ascribed to be predominantly from the (3)MLCT/(3)LLCT states for 1 and from the (3)π,π* state for 2, while the emitting state of 3 and 4 are assigned to be an admixture of (3)MLCT, (3)LLCT, and (3)π,π* characters. The variations of the photophysical properties of 1-4 are attributed to different degrees of π-conjugation in the bipyridine and phenylpyridine ligands induced by different positions of the benzothiazolylfluorenyl substituents on the bipyridine ligand and different extents of π-conjugation in the phenylpyridine ligands, which alters the energy and lifetime of the lowest singlet and triplet excited states. 1-4 all possess broadband transient absorption (TA) upon nanosecond laser excitation, which extends from the visible to the NIR region. Therefore, 1-4 all exhibit strong reverse saturable absorption (RSA) at 532 nm for ns laser pulses. However, the TA of complexes 1, 2, and 3 are much stronger than that of 4. This feature, combined with the difference in ground-state absorption and triplet excited-state quantum yield, result in the difference in RSA strength, which follows this trend: 1 ≈ 2 ≈ 3 > 4. Therefore, complexes 1-3 are strong

  16. Stability constants of mixed ligand complexes of lanthanide(III) and yttrium(III) with complexone and substituted salicylic acids

    International Nuclear Information System (INIS)

    Kolhe, Vishnu; Dwivedi, K.

    1996-01-01

    Salicylic acid and substituted salicylic acids are potential antimicrobial agents. Binary complexes of salicylic acid and its substituted derivatives with lanthanide(III) and yttrium(III) metal ions have been reported. There are reports on the ternary metal complexing equilibria with some lanthanide(III) and yttrium(III) metal ions involving aminopolycarboxylic acid as one ligand and salicylic acid (SA) and other related compounds as the second ligands. Ethylene glycol bis(2-aminoethylether)- N, N, N', N'-tetraacetic acid (EGTA) is an important member of aminopolycarboxylic acid and finds many applications in medicine and biology. Recently, few ternary complexes have been reported using EGTA as ligand. In view of biological importance of simple and mixed ligand complexes EGTA, SA and DNSA (3,5-dinitrosalicylic acid), a systematic study has been undertaken for the determination of stability constant and the results are reported. (author). 6 refs., 1 fig., 2 tabs

  17. Phenanthroline-2,9-bistriazoles as selective G-quadruplex ligands

    DEFF Research Database (Denmark)

    Nielsen, Mads Corvinius; Larsen, Anders Foller; Abdikadir, Faisal Hussein

    2014-01-01

    G-quadruplex (G4) ligands are currently receiving considerable attention as potential anticancer therapeutics. A series of phenanthroline-2,9-bistriazoles carrying tethered positive end groups has been synthesized and evaluated as G4 stabilizers. The compounds were efficiently assembled by copper......(I)-catalyzed azide-alkyne cycloaddition (CuAAC) in CH2Cl2 and water in the presence of a complexing agent. Characterization of the target compounds on telomeric and c-KIT G4 sequences led to the identification of guanidinium-substituted compounds as potent G4 DNA ligands with high selectivity over duplex DNA....... The diisopropylguanidium ligands exhibited high selectivity for the proto-oncogenic sequence c-KIT over the human telomeric sequence in the surface plasmon resonance (SPR) assay, whereas the compounds appeared potent on both G4 structures in the FRET melting temperature assay. The phenanthroline-2,9-bistriazole ligands...

  18. Thermodynamics of the complex formation between thorium(IV) and some polydentate ligands in aqueous solution

    International Nuclear Information System (INIS)

    Di Bernado, P.; Cassol, A.; Tomat, G.; Bismondo, A.; Magon, L.

    1983-01-01

    The changes in free energy, enthalpy, and entropy for the formation of thorium(IV)-oxydiacetate, -iminodiacetate, -thiodiacetate, and -succinate complexes have been determined by potentiometric and calorimetric titrations at 25 deg C in aqueous 1 mol dm - 3 sodium perchlorate. All the ligands form 1:1 chelate complexes with the thorium(IV) ion the stability of which is dependent on both the chelate ring dimensions and the nature of the donor group in the chain. The order of the relative stabilities (iminodiacetate > oxydiacetate > thiodiacetate > succinate) is mainly dependent on the reaction enthalpies, since the δS values are close to each other. In the thorium(IV)-oxydiacetate system the maximum number of three ligands for every metal ion was reached. Because of precipitation of solid compounds in the other systems, it was only possible to define complexes with a lower number of co-ordinated ligands: two for succinate and thiodiacetate, and one for iminodiacetate. Owing to the lower stability of the chelate ring of thiodiacetate and succinate complexes and the high basicity of the amino-group of iminodiacetate, these ligands form also unchelated protonated complexes. (author)

  19. Cloud computing approaches for prediction of ligand binding poses and pathways.

    Science.gov (United States)

    Lawrenz, Morgan; Shukla, Diwakar; Pande, Vijay S

    2015-01-22

    We describe an innovative protocol for ab initio prediction of ligand crystallographic binding poses and highly effective analysis of large datasets generated for protein-ligand dynamics. We include a procedure for setup and performance of distributed molecular dynamics simulations on cloud computing architectures, a model for efficient analysis of simulation data, and a metric for evaluation of model convergence. We give accurate binding pose predictions for five ligands ranging in affinity from 7 nM to > 200 μM for the immunophilin protein FKBP12, for expedited results in cases where experimental structures are difficult to produce. Our approach goes beyond single, low energy ligand poses to give quantitative kinetic information that can inform protein engineering and ligand design.

  20. Predicting Nanocrystal Shape through Consideration of Surface-Ligand Interactions

    KAUST Repository

    Bealing, Clive R.; Baumgardner, William J.; Choi, Joshua J.; Hanrath, Tobias; Hennig, Richard G.

    2012-01-01

    Density functional calculations for the binding energy of oleic acid-based ligands on Pb-rich {100} and {111} facets of PbSe nanocrystals determine the surface energies as a function of ligand coverage. Oleic acid is expected to bind

  1. Differential TAM receptor-ligand-phospholipid interactions delimit differential TAM bioactivities.

    Science.gov (United States)

    Lew, Erin D; Oh, Jennifer; Burrola, Patrick G; Lax, Irit; Zagórska, Anna; Través, Paqui G; Schlessinger, Joseph; Lemke, Greg

    2014-09-29

    The TAM receptor tyrosine kinases Tyro3, Axl, and Mer regulate key features of cellular physiology, yet the differential activities of the TAM ligands Gas6 and Protein S are poorly understood. We have used biochemical and genetic analyses to delineate the rules for TAM receptor-ligand engagement and find that the TAMs segregate into two groups based on ligand specificity, regulation by phosphatidylserine, and function. Tyro3 and Mer are activated by both ligands but only Gas6 activates Axl. Optimal TAM signaling requires coincident TAM ligand engagement of both its receptor and the phospholipid phosphatidylserine (PtdSer): Gas6 lacking its PtdSer-binding 'Gla domain' is significantly weakened as a Tyro3/Mer agonist and is inert as an Axl agonist, even though it binds to Axl with wild-type affinity. In two settings of TAM-dependent homeostatic phagocytosis, Mer plays a predominant role while Axl is dispensable, and activation of Mer by Protein S is sufficient to drive phagocytosis.

  2. Tetrathiafulvalene-based azine ligands for anion and metal cation coordination

    Directory of Open Access Journals (Sweden)

    Awatef Ayadi

    2015-08-01

    Full Text Available The synthesis and full characterization of two tetrathiafulvalene-appended azine ligands, namely 2-([2,2’-bi(1,3-dithiolylidene]-4-yl-6-((2,4-dinitrophenylhydrazonomethylpyridine (L1 and 5-([2,2’-bi(1,3-dithiolylidene]-4-yl-2-((2,4-dinitrophenylhydrazonomethylpyridine (L2 are described. The crystal structure of ligand L1 indicates that the ligand is completely planar with the presence of a strong intramolecular N3–H3···O1 hydrogen bonding. Titration experiments with inorganic anions showed that both ligands are suitable candidates for the sensing of fluoride anions. Ligand L2 was reacted with a Re(I cation to yield the corresponding rhenium tricarbonyl complex 3. In the crystal structure of the newly prepared electroactive rhenium complex the TTF is neutral and the rhenium cation is hexacoordinated. The electrochemical behavior of the three compounds indicates that they are promising for the construction of crystalline radical cation salts.

  3. Ligand Electron Density Shape Recognition Using 3D Zernike Descriptors

    Science.gov (United States)

    Gunasekaran, Prasad; Grandison, Scott; Cowtan, Kevin; Mak, Lora; Lawson, David M.; Morris, Richard J.

    We present a novel approach to crystallographic ligand density interpretation based on Zernike shape descriptors. Electron density for a bound ligand is expanded in an orthogonal polynomial series (3D Zernike polynomials) and the coefficients from this expansion are employed to construct rotation-invariant descriptors. These descriptors can be compared highly efficiently against large databases of descriptors computed from other molecules. In this manuscript we describe this process and show initial results from an electron density interpretation study on a dataset containing over a hundred OMIT maps. We could identify the correct ligand as the first hit in about 30 % of the cases, within the top five in a further 30 % of the cases, and giving rise to an 80 % probability of getting the correct ligand within the top ten matches. In all but a few examples, the top hit was highly similar to the correct ligand in both shape and chemistry. Further extensions and intrinsic limitations of the method are discussed.

  4. The affinity of the uranyl ion for nitrogen donor ligands

    Energy Technology Data Exchange (ETDEWEB)

    Jarvis, N.V. (Atomic Energy Corp. of South Africa Ltd., Pretoria (South Africa). Dept. of Process Technology); De Sousa, A.S.; Hancock, R.D. (Univ. of the Witwatersrand, Johannesburg (South Africa). Centre for Molecular Design)

    1992-01-01

    Established ligand design principles are used to predict the solution chemistry of UO[sub 2][sup 2+] with nitrogen donor ligands which do not contain carboxylate donors. pK[sub a]'s of the nitrogen donors are lowered by addition of hydroxylalkyl groups causing UO[sub 2][sup 2+] to have a greater affinity for these ligands than for hydroxide. Potentiometric studies using the ligands N,N,N',N',N''-pentakis(2-hydroxypropyl)-1,4,7-triazaheptane; N,N,N',N',N''-pentakis(2-hydroxyethyl)-1,4,7-triazaheptane; N,N,N',N'-tetrakis(2-hydroxypropyl)1,2-diaminoethane, N,N,N',N'-tetrakis(2-hydroxyethyl)-trans-1,2-diaminocyclohexane; 1,4,8,11-tetrakis(2-hydroxyethyl)-1,4,8,11-tetraazacyclotetradecane and N,N-bis(2-hydroxyethyl)glycine with UO[sub 2][sup 2+] showed that UO[sub 2][sup 2+] has a considerable aqueous solution chemistry with these ligands. (orig.).

  5. Selective high-affinity polydentate ligands and methods of making such

    Energy Technology Data Exchange (ETDEWEB)

    Denardo, Sally J.; Denardo, Gerald L.; Balhorn, Rodney L.

    2018-02-06

    This invention provides novel polydentate selective high affinity ligands (SHALs) that can be used in a variety of applications in a manner analogous to the use of antibodies. SHALs typically comprise a multiplicity of ligands that each bind different region son the target molecule. The ligands are joined directly or through a linker thereby forming a polydentate moiety that typically binds the target molecule with high selectivity and avidity.

  6. Meso-Helical Ag(I) Coordination Polymer Based on a Pyridylimidazole Ligand

    International Nuclear Information System (INIS)

    Kang, Youngjin; Kim, Jinho; Lee, Eunji; Park, Ki-Min; Moon, Suk-Hee

    2016-01-01

    In the fields of material science and metallosupramolecular chemistry, coordination polymers with various helical types have been extensively explored because of their charming structures, and their potential applications in material chemistry. Among them, meso-helical coordination polymers consisting of achiral 1D strands, which are generally constructed by a crystallographic inversion symmetry, are relatively rare. The coordination polymer 1 exhibits a rare one-dimensional meso-helical chain topology constructed by its internal inversion symmetry. The skeleton of this meso-helical chain is preserved up to 300°C. The complexation of silver(I) ion to the free pyim ligand give rise to the enhanced photoluminescence intensity and slightly blue-shifted emission maximum, originated from intraligand (IL) π[BOND]π* transition and rigidochromic effect. Further exploration of complexation of this ligand with other transition metal ions is currently in progress

  7. Characterization of ligand binding to melanocortin 4 receptors using fluorescent peptides with improved kinetic properties.

    Science.gov (United States)

    Link, Reet; Veiksina, Santa; Rinken, Ago; Kopanchuk, Sergei

    2017-03-15

    Melanocortin 4 (MC 4 ) receptors are important drug targets as they regulate energy homeostasis, eating behaviour and sexual functions. The ligand binding process to these G protein-coupled receptors is subject to considerable complexity. Different steps in the complex dynamic regulation can be characterized by ligand binding kinetics. Optimization of these kinetic parameters in terms of on-rate and residence time can increase the rapid onset of drug action and reduce off-target effects. Fluorescence anisotropy (FA) is one of the homogeneous fluorescence-based assays that enable continuous online monitoring of ligand binding kinetics. FA has been implemented for the kinetic study of melanocortin MC 4 receptors expressed on budded baculoviruses. However, the slow dissociation of the fluorescently labelled peptide NDP-α-MSH does not enable reaching equilibrium nor enable more in-depth study of the binding mechanisms. To overcome this problem, two novel red-shifted fluorescent ligands were designed. These cyclized heptapeptide derivatives (UTBC101 and UTBC102) exhibited nanomolar affinity toward melanocortin MC 4 receptors but had relatively different kinetic properties. The dissociation half-lives of UTBC101 (τ 1/2 =160min) and UTBC102 (τ 1/2 =7min) were shorter compared to that what was previously reported for Cy3B-NDP-α-MSH (τ 1/2 =224min). The significantly shorter dissociation half-life of UTBC102 enables equilibrium in screening assays, whereas the higher affinity of UTBC101 helps to resolve a wider range of competitor potencies. These two ligands are suitable for further kinetic screening of novel melanocortin MC 4 receptor specific ligands and could complement each other in these studies. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. PPARγ and Its Ligands: Potential Antitumor Agents in the Digestive System.

    Science.gov (United States)

    Shu, Linjing; Huang, Renhuan; Wu, Songtao; Chen, Zhaozhao; Sun, Ke; Jiang, Yan; Cai, Xiaoxiao

    2016-01-01

    Peroxisome proliferator-activated receptor γ (PPARγ) is a versatile member of the ligand-activated nuclear hormone receptor superfamily of transcription factors, with expression in several different cell lines, especially in the digestive system. After being activated by its ligand, PPARγ can suppress the growth of oral, esophageal, gastric, colorectal, liver, biliary, and pancreatic tumor cells, suggesting that PPARγ ligand is a potential anticancer agent in PPARγ-expressing tumors. This review highlights key advances in understanding the effects of PPARγ ligands in the treatment of tumors in the digestive system.

  9. Bystander protein protects potential vaccine-targeting ligands against intestinal proteolysis.

    Science.gov (United States)

    Reuter, Fabian; Bade, Steffen; Hirst, Timothy R; Frey, Andreas

    2009-07-20

    Endowing mucosal vaccines with ligands that target antigen to mucosal lymphoid tissues may improve immunization efficacy provided that the ligands withstand the proteolytic environment of the gastro-intestinal tract until they reach their destination. Our aim was to investigate whether and how three renowned ligands - Ulex europaeus agglutinin I and the B subunits of cholera toxin and E. coli heat-labile enterotoxin - master this challenge. We assessed the digestive power of natural murine intestinal fluid (natIF) using assays for trypsin, chymotrypsin and pancreatic elastase along with a test for nonspecific proteolysis. The natIF was compared with simulated murine intestinal fluid (simIF) that resembled the trypsin, chymotrypsin and elastase activities of its natural counterpart but lacked or contained albumins as additional protease substrates. The ligands were exposed to the digestive fluids and degradation was determined. The studies revealed that (i) the three pancreatic endoproteases constitute only one third of the total protease activity of natIF and (ii) the ligands resist proteolysis in natIF and protein-enriched simIF over 3 h but (iii) are partially destroyed in simIF that lacks additional protease substrate. We assume that the proteins of natIF are preferred substrates for the intestinal proteases and thus can protect vaccine-targeting ligands from destruction.

  10. Spectroscopic studies of an europium(III) tris-β-diketonate complex bearing a pyrazolylpyridine ligand

    International Nuclear Information System (INIS)

    Moreira dos Santos, Antonio; Coelho, Ana C.; Almeida Paz, Filipe A.; Rocha, Joao; Goncalves, Isabel S.; Carlos, Luis D.

    2008-01-01

    A new europium(III) complex, Eu(BTA) 3 (ethyl[3-(2-pyridyl)-1-pyrazolyl]acetate) (where BTA: 1-benzoyl-3,3,3-trifluoroacetonate), was synthesised by simple ligand exchange with the solvent adduct Eu(BTA) 3 (H 2 O) 2 . The compound was characterised by elemental analysis, thermogravimetry, FTIR, FT Raman and photoluminescence spectroscopies. A significant increase of the 5 D 0 lifetime of the complex, relative to the value found for the water-coordinated adduct (from 0.657 ± 0.001 to 0.835 ± 0.002 ms), and a larger contribution of the ligand levels to the excitation spectrum indicate a better photoluminescence performance for the former complex

  11. Redox noninnocence of carbene ligands: carbene radicals in (catalytic) C-C bond formation

    NARCIS (Netherlands)

    Dzik, W.I.; Zhang, X.P.; de Bruin, B.

    2011-01-01

    In this Forum contribution, we highlight the radical-type reactivities of one-electron-reduced Fischer-type carbenes. Carbene complexes of group 6 transition metals (Cr, Mo, and W) can be relatively easily reduced by an external reducing agent, leading to one-electron reduction of the carbene ligand

  12. Surfactant Ligand Removal and Rational Fabrication of Inorganically Connected Quantum Dots

    KAUST Repository

    Zhang, Haitao

    2011-12-14

    A novel method is reported to create inorganically connected nanocrystal (NC) assemblies for both II-VI and IV-VI semiconductors by removing surfactant ligands using (NH 4) 2S. This surface modification process differs from ligand exchange methods in that no new surfactant ligands are introduced and the post-treated NC surfaces are nearly bare. The detailed mechanism study shows that the high reactivity between (NH 4) 2S and metal-surfactant ligand complexes enables the complete removal of surfactant ligands in seconds and converts the NC metal-rich shells into metal sulfides. The post-treated NCs are connected through metal-sulfide bonding and form a larger NCs film assembly, while still maintaining quantum confinement. Such "connected but confined" NC assemblies are promising new materials for electronic and optoelectronic devices. © 2011 American Chemical Society.

  13. Synthesis and electrochemical study of iron, chromium and tungsten aminocarbenes: Role of ligand structure and central metal nature

    Energy Technology Data Exchange (ETDEWEB)

    Hoskovcova, Irena [Department of Inorganic Chemistry, Institute of Chemical Technology, Technicka 5, 166 28 Prague 6 (Czech Republic); Rohacova, Jana; Dvorak, Dalimil; Tobrman, Tomas [Department of Organic Chemistry, Institute of Chemical Technology, Technicka 5, 166 28 Prague 6 (Czech Republic); Zalis, Stanislav [J. Heyrovsky Institute of Physical Chemistry, Academy of Science of the Czech Republic, Dolejskova 3, 182 23 Prague 8 (Czech Republic); Zverinova, Radka [Department of Inorganic Chemistry, Institute of Chemical Technology, Technicka 5, 166 28 Prague 6 (Czech Republic); J. Heyrovsky Institute of Physical Chemistry, Academy of Science of the Czech Republic, Dolejskova 3, 182 23 Prague 8 (Czech Republic); Ludvik, Jiri, E-mail: jiri.ludvik@jh-inst.cas.c [J. Heyrovsky Institute of Physical Chemistry, Academy of Science of the Czech Republic, Dolejskova 3, 182 23 Prague 8 (Czech Republic)

    2010-11-30

    Several series of Fischer-type aminocarbene complexes with central Fe, Cr or W atoms and with various carbene substitution were synthesized and electrochemically investigated by dc-polarography and cyclic voltammetry. The shifts and changes of reduction and oxidation potentials were evaluated using the linear free energy relationship (LFER) approach with respect to (a) the type of coordination, (b) the substitution on the carbene ligand and (c) the nature of the central metal atom. The analysis of measured data confirms that the reduction center is localized on the carbene moiety and is strongly influenced by both electronic and sterical properties of its substituents. The oxidation proceeds on the metal and depends mainly on its nature and on the {pi}-acidity of the ligands. Electrochemistry thus represents an important experimental approach to the description and understanding of the molecular electronic structure and redox properties. Experimental results are supported by DFT calculation of HOMO and LUMO orbitals shape and composition.

  14. Adsorption of hairy particles with mobile ligands: Molecular dynamics and density functional study

    Science.gov (United States)

    Borówko, M.; Sokołowski, S.; Staszewski, T.; Pizio, O.

    2018-01-01

    We study models of hairy nanoparticles in contact with a hard wall. Each particle is built of a spherical core with a number of ligands attached to it and each ligand is composed of several spherical, tangentially jointed segments. The number of segments is the same for all ligands. Particular models differ by the numbers of ligands and of segments per ligand, but the total number of segments is constant. Moreover, our model assumes that the ligands are tethered to the core in such a manner that they can "slide" over the core surface. Using molecular dynamics simulations we investigate the differences in the structure of a system close to the wall. In order to characterize the distribution of the ligands around the core, we have calculated the end-to-end distances of the ligands and the lengths and orientation of the mass dipoles. Additionally, we also employed a density functional approach to obtain the density profiles. We have found that if the number of ligands is not too high, the proposed version of the theory is capable to predict the structure of the system with a reasonable accuracy.

  15. What Is the True Color of Fresh Meat? A Biophysical Undergraduate Laboratory Experiment Investigating the Effects of Ligand Binding on Myoglobin Using Optical, EPR, and NMR Spectroscopy

    Science.gov (United States)

    Linenberger, Kimberly; Bretz, Stacey Lowery; Crowder, Michael W.; McCarrick, Robert; Lorigan, Gary A.; Tierney, David L.

    2011-01-01

    With an increased focus on integrated upper-level laboratories, we present an experiment integrating concepts from inorganic, biological, and physical chemistry content areas. Students investigate the effects of ligand strength on the spectroscopic properties of the heme center in myoglobin using UV-vis, [superscript 1]H NMR, and EPR…

  16. Luteolin, a flavonoid, inhibits CD40 ligand expression by activated human basophils.

    Science.gov (United States)

    Hirano, Toru; Arimitsu, Junsuke; Higa, Shinji; Naka, Tetsuji; Ogata, Atsushi; Shima, Yoshihito; Fujimoto, Minoru; Yamadori, Tomoki; Ohkawara, Tomoharu; Kuwabara, Yusuke; Kawai, Mari; Kawase, Ichiro; Tanaka, Toshio

    2006-01-01

    We have previously shown that flavonoids such as luteolin, apigenin and fisetin inhibit interleukin 4 and interleukin 13 production. In this study, we investigated whether luteolin can suppress CD40 ligand expression by basophils. A human basophilic cell line, KU812, was stimulated with A23187 and phorbol myristate acetate (PMA) with or without various concentrations of luteolin or other flavonoids for 12 h, and CD40 ligand expression was analyzed by FACS. The effect of luteolin on CD40 ligand mRNA expression was studied by semiquantitative reverse transcription PCR analysis. In addition, CD40 ligand expression was also measured in purified basophils that had been stimulated for 12 h with A23187 plus PMA with or without various concentrations of luteolin. CD40 ligand expression by KU812 cells was enhanced noticeably in response to A23187 and even more strikingly augmented by A23187 plus PMA. The expression was significantly suppressed by 10 or 30 microM of luteolin, whereas myricetin failed to inhibit. Reverse transcription PCR analyses demonstrated that luteolin inhibited CD40 ligand mRNA expression by stimulated KU812 cells. Of the six flavonoids examined, luteolin, apigenin, fisetin and quercetin at 30 microM showed a significant inhibitory effect on CD40 ligand expression. The incubation of purified basophils with A23187 plus PMA significantly enhanced CD40 ligand expression, and the presence of luteolin again had an inhibitory effect. Luteolin inhibits CD40 ligand expression by activated basophils.

  17. Force spectroscopy studies on protein-ligand interactions: a single protein mechanics perspective.

    Science.gov (United States)

    Hu, Xiaotang; Li, Hongbin

    2014-10-01

    Protein-ligand interactions are ubiquitous and play important roles in almost every biological process. The direct elucidation of the thermodynamic, structural and functional consequences of protein-ligand interactions is thus of critical importance to decipher the mechanism underlying these biological processes. A toolbox containing a variety of powerful techniques has been developed to quantitatively study protein-ligand interactions in vitro as well as in living systems. The development of atomic force microscopy-based single molecule force spectroscopy techniques has expanded this toolbox and made it possible to directly probe the mechanical consequence of ligand binding on proteins. Many recent experiments have revealed how ligand binding affects the mechanical stability and mechanical unfolding dynamics of proteins, and provided mechanistic understanding on these effects. The enhancement effect of mechanical stability by ligand binding has been used to help tune the mechanical stability of proteins in a rational manner and develop novel functional binding assays for protein-ligand interactions. Single molecule force spectroscopy studies have started to shed new lights on the structural and functional consequence of ligand binding on proteins that bear force under their biological settings. Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  18. Convergent [18]F-labeling and evaluation of N-benzyl-phenethylamines as 5-HT2A receptor PET ligands

    DEFF Research Database (Denmark)

    Petersen, Ida Nymann; Villadsen, Jonas; Hansen, Hanne Demant

    2016-01-01

    Positron emission tomography (PET) investigations of the 5-HT2A receptor (5-HT2AR) system can be used as a research tool in diseases such as depression, Alzheimer's disease and schizophrenia. We have previously developed a (11)C-labeled agonist PET ligand ([(11)C]Cimbi-36), and the aim of this st......Positron emission tomography (PET) investigations of the 5-HT2A receptor (5-HT2AR) system can be used as a research tool in diseases such as depression, Alzheimer's disease and schizophrenia. We have previously developed a (11)C-labeled agonist PET ligand ([(11)C]Cimbi-36), and the aim...... of this study was to identify a (18)F-labeled analogue of this PET-ligand. Thus, we developed a convergent radiochemical approach giving easy access to 5 different (18)F-labeled ligands structurally related to Cimbi-36 from a common (18)F-labeled intermediate. After intravenous injection, all ligands entered...... the pig brain. However, since within-scan intervention with ketanserin, a known orthosteric 5-HT2A receptor antagonist, did not result in significant blocking, the radioligands seem unsuitable for neuroimaging of the 5-HT2AR in vivo....

  19. Synthesis, crystal structures, and thermal and spectroscopic properties of two Cd(II) metal-organic frameworks with a versatile ligand

    Energy Technology Data Exchange (ETDEWEB)

    Li, Jia-Ming; He, Kun-Huan; Shi, Zhong-Feng [Qinzhou Univ. (China). Guangxi Colleges and Univs. Key Lab. of Beibu Gulf Oil and Natural Gas Resource Effective Utilization; Gao, Hui-Yuan; Jiang, Yi-Min [Guangxi Normal Univ., Guilin (China). Key Lab. for the Chemistry and Molecular Engineering of Medicinal Resources

    2016-11-01

    Two new metal-organic frameworks, namely, [Cd(L)(H{sub 2}O)]{sub n} (1) and {[Cd_0_._5(L)(4,4"'-bipy)_0_._5][Cd_0_._5(H_2O)(4,4"'-bipy)_0_._5].H_2O}{sub n} (2), where H{sub 2}L = N-pyrazinesulfonyl-glycine and 4,4{sup '}-bipy = 4,4{sup '}-bipyridine, have been synthesized and characterized by single-crystal X-ray diffraction, IR spectroscopy, elemental, thermogravimetric, and photoluminescent analysis. X-ray diffraction crystallographic analyses indicate that 1 displays a distorted octahedral metal coordination in a 3-connected (4, 8{sup 2}) topology, while the molecular structure of 2 has a 4-connected (4, 4) topology with two perfectly octahedrally coordinated Cd centers. The L{sup 2-} ligand serves as a N,N,O-tridentate, μ{sub 2}-pyrazine-bridging, and μ{sub 2}-carboxylate-bridging ligand in 1, and as a N,O-bidentate and μ{sub 2}-carboxylate-bridging ligand in 2. In the crystal, a 3D supramolecular architecture is formed by O-H..O hydrogen bond interactions in 1, but through O-H..O as well as π..π stacking in 2. The two compounds show intense fluorescence in the solid state at room temperature.

  20. The Evaluation of Novel Camphor-derived Pyridyl Ligands as ...

    African Journals Online (AJOL)

    The structures of the copper (II) complexes of the ligands were calculated using ONIOM density functional theory and the results suggest that chiral induction to the alkene functional group is indeed lacking. This explains the moderate experimental selectivities obtained. Keywords: Camphor ligands, asymmetric catalysis, ...

  1. Mixed-Ligand Complexes Of Nickel (II) With 2-Acetylpyridine ...

    African Journals Online (AJOL)

    The preparation and spectral properties of five nickel (II) mixed-ligands complexes (Ni [2-Actsc.Y]CI2), derived from 2-acetylpyridinethiosermicarbazones and some nitrogen/sulphur monodentate ligands such as thiophene, ammonia, picoline, pyridine and aniline are described. The complexes have been characterized on ...

  2. Some new IIB group complexes of an imidazolidine ligand ...

    Indian Academy of Sciences (India)

    The spectral data indicate that the ligand is coordinated to zinc(II) as a bidentate ligand in imidazolidine form but it binds to ..... confirmed by determination of the minimum inhibitory ...... Yue F, Gang L, Xiu-Mei T, Ji-De W and Wei W 2008. Chin.

  3. Electrolytic formation of technetium complexes with π-acceptor ligands

    International Nuclear Information System (INIS)

    Cerda, F.; Kremer, C.; Gambino, D.; Kremer, E.

    1994-01-01

    Electrolytic reduction of pertechnetate was performed in aqueous solution containing π-acceptor ligands. Cyanide and 1,10-phenanthroline were the selected ligands. In both cases, electrolyses produced a cathodic TcO 2 deposit and soluble Tc complexes. When cyanide was the ligand, the complexes formed were [Tc(CN) 6 ] 5- and [TcO 2 (CN) 4 ] 3- . When working with the amine, [Tc(phen) 3 ] 2+ and another positively charged species were found after reaction. Results are compared with previous studies with amines, and the usefulness of the electrolytic route to obtain Tc complexes is evaluated. (author) 11 refs.; 2 figs.; 1 tab

  4. Attenuated apoptosis response to Fas-ligand in active ulcerative colitis

    DEFF Research Database (Denmark)

    Seidelin, Jakob B; Nielsen, Ole H

    2008-01-01

    BACKGROUND: From mainly carcinoma cell line studies, apoptosis has been thought to play a major role in the pathogenesis of ulcerative colitis (UC). Apoptosis has been suggested to be due to a Fas ligand / Fas receptor interaction, but has never been studied in cells from patients with active UC...... was subsequently reached were included. Cultures of isolated colonic crypts were obtained from biopsies and cultured for 4 to 16 hours with Fas ligand or Fas ligand and costimulation with interferon-gamma (IFN-gamma). Control experiments were performed on HT29 cells. Apoptosis was assessed by independent methods....... RESULTS: Isolated colonocytes from healthy subjects or patients with remission in UC had a dose-dependent response to Fas ligand. This response was abolished in patients with active UC (P

  5. Pesticide-related poison center exposures in children and adolescents aged ≤19 years in Texas, 2000-2013.

    Science.gov (United States)

    Trueblood, Amber B; Forrester, Mathias B; Han, Daikwon; Shipp, Eva M; Cizmas, Leslie H

    2016-11-01

    Although national poison center data show that pesticides were the 8th most commonly reported substance category (3.27%) for children aged ≤5 years in 2014, there is limited information on childhood and adolescent pesticide exposures. This study assessed pesticide-related poison center exposures in children and adolescents aged ≤19 years from 2000-2013 in Texas to characterize the potential burden of pesticides. Pesticide-related poison center exposures among children and adolescents aged ≤19 years reported to Texas poison centers were identified. The distribution of exposures was estimated by gender, age category, medical outcome, management site, exposure route, and pesticide category. From 2000 to 2013, there were 61,147 pesticide-related poison center exposures in children and adolescents aged ≤19 years. The prevalence was highest among males at 864.24 per 100,000 population. The prevalence of unintentional exposures was highest among children aged ≤5 years at 2310.69 per 100,000 population, whereas the prevalence of intentional exposures was highest among adolescents aged 13-19 years at 13.82 per 100,000 population. A majority of medical outcomes reported were classified as having no effect (30.24%) and not followed, but minimal clinical effects possible (42.74%). Of all the exposures, 81.24% were managed on site. However, 57% of intentional exposures were referred to or treated at a health-care facility. The most common routes of exposure were ingestion (80.83%) and dermal (17.21%). The most common pesticide categories included rodenticides (30.02%), pyrethrins/pyrethroids (20.69%), and other and unspecified insecticides (18.14%). The study found differences in the frequency of exposures by intent for sex and age categories, and identified the most common medical outcomes, management site, exposure route, and pesticide category. Through characterizing pesticide-related poison center exposures, future interventions can be designed to address groups

  6. Roles of Bridging Ligand Topology and Conformation in Controlling Exchange Interactions between Paramagnetic Molybdenum Fragments in Dinuclear and Trinuclear Complexes.

    Science.gov (United States)

    Ung VÂ, V&acaron;n Ân; Cargill Thompson, Alexander M. W.; Bardwell, David A.; Gatteschi, Dante; Jeffery, John C.; McCleverty, Jon A.; Totti, Federico; Ward, Michael D.

    1997-07-30

    The magnetic properties of two series of dinuclear complexes, and one trinuclear complex, have been examined as a function of the bridging pathway between the metal centers. The first series of dinuclear complexes is [{Mo(V)(O)(Tp)Cl}(2)(&mgr;-OO)], where "OO" is [1,4-O(C(6)H(4))(n)O](2)(-) (n = 1, 1; n = 2, 3), [4,4'-O(C(6)H(3)-2-Me)(2)O](2)(-) (4), or [1,3-OC(6)H(4)O](2)(-) (2) [Tp = tris(3,5-dimethylpyrazolyl)hydroborate]. The second series of dinuclear complexes is [{Mo(I)(NO)(Tp)Cl}(2)(&mgr;-NN)], where "NN" is 4,4'-bipyridyl (5), 3,3'-dimethyl-4,4'-bipyridine (6), 3,8-phenanthroline (7), or 2,7-diazapyrene (8). The trinuclear complex is [{Mo(V)(O)(Tp)Cl}(3)(1,3,5-C(6)H(3)O(3))] (9), whose crystal structure was determined [9.5CH(2)Cl(2): C(56)H(81)B(3)Cl(13)Mo(3)N(18)O(6); monoclinic, P2(1)/n; a = 13.443, b = 41.46(2), c = 14.314(6) Å; beta = 93.21(3) degrees; V = 7995(5) Å(3); Z = 4; R(1) = 0.106]. In these complexes, the sign and magnitude of the exchange coupling constant J is clearly related to both the topology and the conformation of the bridging ligand [where J is derived from H = -JS(1)().S(2)() for 1-8 and H = -J(S(1)().S(2)() + S(2)().S(3)() + S(1)().S(3)()) for 9]. The values are as follows: 1, -80 cm(-)(1); 2, +9.8 cm(-)(1); 3, -13.2 cm(-)(1); 4, -2.8 cm(-)(1); 5, -33 cm(-)(1); 6, -3.5 cm(-)(1); 7, -35.6 cm(-)(1); 8, -35.0 cm(-)(1); 9, +14.4 cm(-)(1). In particular the following holds: (1) J is negative (antiferromagnetic exchange) across the para-substituted bridges ligands of 1 and 3-8 but positive (ferromagnetic exchange) across the meta-substituted bridging ligands of 2 and 9. (2) J decreases in magnitude dramatically as the bridging ligand conformation changes from planar to twisted (compare 3 and 4, or 6 and 8). These observations are consistent with a spin-polarization mechanism for the exchange interaction, propagated across the pi-system of the bridging ligand by via overlap of bridging ligand p(pi) orbitals with the d(pi) magnetic

  7. Synergistic extraction of manganese(II) with thenoyltrifluoroacetone and neutral unidentate and bidentate ligands

    International Nuclear Information System (INIS)

    Nakamura, S.; Imura, H.; Suzuki, N.

    1984-01-01

    Synergistic effect of neutral bidentate ligands, L, such as 1,10-phenanthroline(phen), 2,9-dimethyl-1,10-phenanthroline(dmp) and 2,2'-bipyridine(bpy) and of neutral unidentate ligands TBP and TOPO have been studied in the extraction of Mn(II) labelled with 54 Mn using 2-thenoyl-trifluoroacetone(HTTA) in various organic solvents. The following factors play important role in the synergistic extraction involving bidentate ligands: a two-phase partition of bidentate ligands, and their protonation and complex formation with Mn(II) in the aqueous phase. The mixed ligand complex, Mn(TTA) 2 L is formed in all bidentate ligand systems. The adduct formation constant (βsub(s,1)) decreases in the following order: phen (lg βsub(s,1)=12.64)>dmp(11.32)>.bpy(8.54) in the cyclohexane system. This order is ascribed to the bacisity and the steric effect of the bidentate ligands. Organic solvents influence both the adduct formation and the partition of the ligands, and βsub(s,1) decreases in the order cyclohexane > carbon tetrachloride > cholrobenzene approx.= benzene > chloroform. (author)

  8. The Evaluation of Novel Camphor-derived Pyridyl Ligands as ...

    African Journals Online (AJOL)

    NJD

    2009-03-03

    Mar 3, 2009 ... The structures of the copper (II) complexes of the ligands were calculated using ONIOM density functional theory and the results suggest that chiral induction to the alkene functional group is indeed lacking. This explains the moderate experimental selectivities obtained. KEYWORDS. Camphor ligands ...

  9. Mixed ligand chelate therapy for plutonium and cadmium poisoning

    Energy Technology Data Exchange (ETDEWEB)

    Schubert, J; Derr, S K [Hope Coll., Holland, MI (USA)

    1978-09-28

    Some experiments with mice are described in which complete removal of tissue deposits of /sup 239/Pu and prevention of mortality in animals given lethal doses of Cd were achieved using a mixed ligand chelate treatment (MLC). The mixed ligand consisted of diethylenetriaminepentaacetic acid and salicylic acid.

  10. Phosphorus ligand imaging with two-photon fluorescence spectroscopy: towards rational catalyst immobilization

    NARCIS (Netherlands)

    Marras, F.; Kluwer, A.M.; Siekierzycka, J.R.; Vozza, A.; Brouwer, A.M.; Reek, J.N.H.

    2010-01-01

    Spotless catalysts: Ligand immobilization was studied by two-photon fluorescence microscopy with a fluorescent nixantphos ligand as probe (see picture). In the immobilization process ligand aggregates form in solution and are deposited on the support, where they appear as bright spots in

  11. Ligand sphere conversions in terminal carbide complexes

    DEFF Research Database (Denmark)

    Morsing, Thorbjørn Juul; Reinholdt, Anders; Sauer, Stephan P. A.

    2016-01-01

    Metathesis is introduced as a preparative route to terminal carbide complexes. The chloride ligands of the terminal carbide complex [RuC(Cl)2(PCy3)2] (RuC) can be exchanged, paving the way for a systematic variation of the ligand sphere. A series of substituted complexes, including the first...... example of a cationic terminal carbide complex, [RuC(Cl)(CH3CN)(PCy3)2]+, is described and characterized by NMR, MS, X-ray crystallography, and computational studies. The experimentally observed irregular variation of the carbide 13C chemical shift is shown to be accurately reproduced by DFT, which also...... demonstrates that details of the coordination geometry affect the carbide chemical shift equally as much as variations in the nature of the auxiliary ligands. Furthermore, the kinetics of formation of the sqaure pyramidal dicyano complex, trans-[RuC(CN)2(PCy3)2], from RuC has been examined and the reaction...

  12. Urate is a ligand for the transcriptional regulator PecS.

    Science.gov (United States)

    Perera, Inoka C; Grove, Anne

    2010-09-24

    PecS is a member of the MarR (multiple antibiotic resistance regulator) family, which has been shown in Erwinia to regulate the expression of virulence genes. MarR homologs typically bind a small molecule ligand, resulting in attenuated DNA binding. For PecS, the natural ligand has not been identified. We have previously shown that urate is a ligand for the Deinococcus radiodurans-encoded MarR homolog HucR (hypothetical uricase regulator) and identified residues responsible for ligand binding. We show here that all four residues involved in urate binding and propagation of conformational changes to DNA recognition helices are conserved in PecS homologs, suggesting that urate is the ligand for PecS. Consistent with this prediction, Agrobacterium tumefaciens PecS specifically binds urate, and urate attenuates DNA binding in vitro. PecS binds two operator sites in the intergenic region between the divergent pecS gene and pecM genes, one of which features two partially overlapping repeats to which PecS binds as a dimer on opposite faces of the duplex. Notably, urate dissociates PecS from cognate DNA, allowing transcription of both genes in vivo. Taken together, our data show that urate is a ligand for PecS and suggest that urate serves a novel function in signaling the colonization of a host plant. Copyright © 2010 Elsevier Ltd. All rights reserved.

  13. Activation of the Hg-C Bond of Methylmercury by [S2]-Donor Ligands.

    Science.gov (United States)

    Karri, Ramesh; Banerjee, Mainak; Chalana, Ashish; Jha, Kunal Kumar; Roy, Gouriprasanna

    2017-10-16

    Here we report that [S 2 ]-donor ligands Bmm OH , Bmm Me , and Bme Me bind rapidly and reversibly to the mercury centers of organomercurials, RHgX, and facilitate the cleavage of Hg-C bonds of RHgX to produce stable tetracoordinated Hg(II) complexes and R 2 Hg. Significantly, the rate of cleavage of Hg-C bonds depends critically on the X group of RHgX (X = BF 4 - , Cl - , I - ) and the [S 2 ]-donor ligands used to induce the Hg-C bonds. For instance, the initial rate of cleavage of the Hg-C bond of MeHgI induced by Bme Me is almost 2-fold higher than the initial rate obtained by Bmm OH or Bmm Me , indicating that the spacer between the two imidazole rings of [S 2 ]-donor ligands plays a significant role here in the cleavage of Hg-C bonds. Surprisingly, we noticed that the initial rate of cleavage of the Hg-C bond of MeHgI induced by Bme Me (or Bmm Me ) is almost 10-fold and 100-fold faster than the cleavage of Hg-C bonds of MeHgCl and [MeHg]BF 4 respectively, under identical reaction conditions, suggesting that the Hg-C bond of [MeHg]BF 4 is highly inert at room temperature (21 °C). We also show here that the nature of the final stable cleaved products, i.e. Hg(II) complexes, depends on the X group of RHgX and the [S 2 ]-donor ligands. For instance, the reaction of Bmm Me with MeHgCl (1:1 molar ratio) afforded the formation of the 16-membered metallacyclic dinuclear mercury compound (Bmm Me ) 2 Hg 2 Cl 4 , in which the two Cl atoms are located inside the ring, whereas due to the large size of the I atom, a similar reaction with MeHgI yielded polymeric [(Bmm Me ) 2 HgI 2 ] m ·(MeHgI) n . However, the treatment of Bmm Me with ionic [RHg]BF 4 led to the formation of the tetrathione-coordinated mononuclear mercury compound [(Bmm Me ) 2 Hg](BF 4 ) 2 , where BF 4 - serves as a counteranion.

  14. Converging ligand-binding free energies obtained with free-energy perturbations at the quantum mechanical level.

    Science.gov (United States)

    Olsson, Martin A; Söderhjelm, Pär; Ryde, Ulf

    2016-06-30

    In this article, the convergence of quantum mechanical (QM) free-energy simulations based on molecular dynamics simulations at the molecular mechanics (MM) level has been investigated. We have estimated relative free energies for the binding of nine cyclic carboxylate ligands to the octa-acid deep-cavity host, including the host, the ligand, and all water molecules within 4.5 Å of the ligand in the QM calculations (158-224 atoms). We use single-step exponential averaging (ssEA) and the non-Boltzmann Bennett acceptance ratio (NBB) methods to estimate QM/MM free energy with the semi-empirical PM6-DH2X method, both based on interaction energies. We show that ssEA with cumulant expansion gives a better convergence and uses half as many QM calculations as NBB, although the two methods give consistent results. With 720,000 QM calculations per transformation, QM/MM free-energy estimates with a precision of 1 kJ/mol can be obtained for all eight relative energies with ssEA, showing that this approach can be used to calculate converged QM/MM binding free energies for realistic systems and large QM partitions. © 2016 The Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc. © 2016 The Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc.

  15. Novel Somatostatin Receptor Ligands Therapies for Acromegaly

    Directory of Open Access Journals (Sweden)

    Rosa Maria Paragliola

    2018-03-01

    Full Text Available Surgery is considered the treatment of choice in acromegaly, but patients with persistent disease after surgery or in whom surgery cannot be considered require medical therapy. Somatostatin receptor ligands (SRLs octreotide (OCT, lanreotide, and the more recently approved pasireotide, characterized by a broader receptor ligand binding profile, are considered the mainstay in the medical management of acromegaly. However, in the attempt to offer a more efficacious and better tolerated medical approach, recent research has been aimed to override some limitations related to the use of currently approved drugs and novel SRLs therapies, with potential attractive features, have been proposed. These include both new formulation of older molecules and new molecules. Novel OCT formulations are aimed in particular to improve patients’ compliance and to reduce injection discomfort. They include an investigational ready-to-use subcutaneous depot OCT formulation (CAM2029, delivered via prefilled syringes and oral OCT that uses a “transient permeability enhancer” technology, which allows for OCT oral absorption. Another new delivery system is a long-lasting OCT implant (VP-003, which provide stable doses of OCT throughout a period of several months. Finally, a new SRL DG3173 (somatoprim seems to be more selective for GH secretion, suggesting possible advantages in the presence of hyperglycemia or diabetes. How much these innovations will actually be beneficial to acromegaly patients in real clinical practice remains to be seen.

  16. Non-conventional Frizzled ligands and Wnt receptors.

    Science.gov (United States)

    Hendrickx, Marijke; Leyns, Luc

    2008-05-01

    The Wnt family of secreted signaling factors plays numerous roles in embryonic development and in stem cell biology. In the adult, Wnt signaling is involved in tissue homeostasis and mutations that lead to the overexpression of Wnt can be linked to cancer. Wnt signaling is transduced intracellularly by the Frizzled (Fzd) family of receptors. In the canonical pathway, accumulation of beta-catenin and the subsequent formation of a complex with T cell factors (TCF) or lymphoid enhancing factors (Lef) lead to target gene activation. The identification of Ryk as an alternative Wnt receptor and the discovery of the novel Fzd ligands Norrie disease protein (NDP) and R-Spondin, changed the traditional view of Wnts binding to Fzd receptors. Mouse R-Spondin cooperates with Wnt signaling and Low density lipoprotein (LDL) receptor related protein (LRP) to activate beta-catenin dependent gene expression and is involved in processes such as limb and placental development in the mouse. NDP is the product of the Norrie disease gene and controls vascular development in the retina, inner ear and in the female reproductive system during pregnancy. In this review a functional overview of the interactions of the different Wnt and non-Wnt ligands with the Fzd receptors is given as well as a survey of Wnts binding to Ryk and we discuss the biological significance of these interactions.

  17. istar: a web platform for large-scale protein-ligand docking.

    Directory of Open Access Journals (Sweden)

    Hongjian Li

    Full Text Available Protein-ligand docking is a key computational method in the design of starting points for the drug discovery process. We are motivated by the desire to automate large-scale docking using our popular docking engine idock and thus have developed a publicly-accessible web platform called istar. Without tedious software installation, users can submit jobs using our website. Our istar website supports 1 filtering ligands by desired molecular properties and previewing the number of ligands to dock, 2 monitoring job progress in real time, and 3 visualizing ligand conformations and outputting free energy and ligand efficiency predicted by idock, binding affinity predicted by RF-Score, putative hydrogen bonds, and supplier information for easy purchase, three useful features commonly lacked on other online docking platforms like DOCK Blaster or iScreen. We have collected 17,224,424 ligands from the All Clean subset of the ZINC database, and revamped our docking engine idock to version 2.0, further improving docking speed and accuracy, and integrating RF-Score as an alternative rescoring function. To compare idock 2.0 with the state-of-the-art AutoDock Vina 1.1.2, we have carried out a rescoring benchmark and a redocking benchmark on the 2,897 and 343 protein-ligand complexes of PDBbind v2012 refined set and CSAR NRC HiQ Set 24Sept2010 respectively, and an execution time benchmark on 12 diverse proteins and 3,000 ligands of different molecular weight. Results show that, under various scenarios, idock achieves comparable success rates while outperforming AutoDock Vina in terms of docking speed by at least 8.69 times and at most 37.51 times. When evaluated on the PDBbind v2012 core set, our istar platform combining with RF-Score manages to reproduce Pearson's correlation coefficient and Spearman's correlation coefficient of as high as 0.855 and 0.859 respectively between the experimental binding affinity and the predicted binding affinity of the docked

  18. istar: a web platform for large-scale protein-ligand docking.

    Science.gov (United States)

    Li, Hongjian; Leung, Kwong-Sak; Ballester, Pedro J; Wong, Man-Hon

    2014-01-01

    Protein-ligand docking is a key computational method in the design of starting points for the drug discovery process. We are motivated by the desire to automate large-scale docking using our popular docking engine idock and thus have developed a publicly-accessible web platform called istar. Without tedious software installation, users can submit jobs using our website. Our istar website supports 1) filtering ligands by desired molecular properties and previewing the number of ligands to dock, 2) monitoring job progress in real time, and 3) visualizing ligand conformations and outputting free energy and ligand efficiency predicted by idock, binding affinity predicted by RF-Score, putative hydrogen bonds, and supplier information for easy purchase, three useful features commonly lacked on other online docking platforms like DOCK Blaster or iScreen. We have collected 17,224,424 ligands from the All Clean subset of the ZINC database, and revamped our docking engine idock to version 2.0, further improving docking speed and accuracy, and integrating RF-Score as an alternative rescoring function. To compare idock 2.0 with the state-of-the-art AutoDock Vina 1.1.2, we have carried out a rescoring benchmark and a redocking benchmark on the 2,897 and 343 protein-ligand complexes of PDBbind v2012 refined set and CSAR NRC HiQ Set 24Sept2010 respectively, and an execution time benchmark on 12 diverse proteins and 3,000 ligands of different molecular weight. Results show that, under various scenarios, idock achieves comparable success rates while outperforming AutoDock Vina in terms of docking speed by at least 8.69 times and at most 37.51 times. When evaluated on the PDBbind v2012 core set, our istar platform combining with RF-Score manages to reproduce Pearson's correlation coefficient and Spearman's correlation coefficient of as high as 0.855 and 0.859 respectively between the experimental binding affinity and the predicted binding affinity of the docked conformation. istar

  19. AFAL: a web service for profiling amino acids surrounding ligands in proteins

    Science.gov (United States)

    Arenas-Salinas, Mauricio; Ortega-Salazar, Samuel; Gonzales-Nilo, Fernando; Pohl, Ehmke; Holmes, David S.; Quatrini, Raquel

    2014-11-01

    With advancements in crystallographic technology and the increasing wealth of information populating structural databases, there is an increasing need for prediction tools based on spatial information that will support the characterization of proteins and protein-ligand interactions. Herein, a new web service is presented termed amino acid frequency around ligand (AFAL) for determining amino acids type and frequencies surrounding ligands within proteins deposited in the Protein Data Bank and for assessing the atoms and atom-ligand distances involved in each interaction (availability: http://structuralbio.utalca.cl/AFAL/index.html). AFAL allows the user to define a wide variety of filtering criteria (protein family, source organism, resolution, sequence redundancy and distance) in order to uncover trends and evolutionary differences in amino acid preferences that define interactions with particular ligands. Results obtained from AFAL provide valuable statistical information about amino acids that may be responsible for establishing particular ligand-protein interactions. The analysis will enable investigators to compare ligand-binding sites of different proteins and to uncover general as well as specific interaction patterns from existing data. Such patterns can be used subsequently to predict ligand binding in proteins that currently have no structural information and to refine the interpretation of existing protein models. The application of AFAL is illustrated by the analysis of proteins interacting with adenosine-5'-triphosphate.

  20. Evaluation of several two-step scoring functions based on linear interaction energy, effective ligand size, and empirical pair potentials for prediction of protein-ligand binding geometry and free energy.

    Science.gov (United States)

    Rahaman, Obaidur; Estrada, Trilce P; Doren, Douglas J; Taufer, Michela; Brooks, Charles L; Armen, Roger S

    2011-09-26

    The performances of several two-step scoring approaches for molecular docking were assessed for their ability to predict binding geometries and free energies. Two new scoring functions designed for "step 2 discrimination" were proposed and compared to our CHARMM implementation of the linear interaction energy (LIE) approach using the Generalized-Born with Molecular Volume (GBMV) implicit solvation model. A scoring function S1 was proposed by considering only "interacting" ligand atoms as the "effective size" of the ligand and extended to an empirical regression-based pair potential S2. The S1 and S2 scoring schemes were trained and 5-fold cross-validated on a diverse set of 259 protein-ligand complexes from the Ligand Protein Database (LPDB). The regression-based parameters for S1 and S2 also demonstrated reasonable transferability in the CSARdock 2010 benchmark using a new data set (NRC HiQ) of diverse protein-ligand complexes. The ability of the scoring functions to accurately predict ligand geometry was evaluated by calculating the discriminative power (DP) of the scoring functions to identify native poses. The parameters for the LIE scoring function with the optimal discriminative power (DP) for geometry (step 1 discrimination) were found to be very similar to the best-fit parameters for binding free energy over a large number of protein-ligand complexes (step 2 discrimination). Reasonable performance of the scoring functions in enrichment of active compounds in four different protein target classes established that the parameters for S1 and S2 provided reasonable accuracy and transferability. Additional analysis was performed to definitively separate scoring function performance from molecular weight effects. This analysis included the prediction of ligand binding efficiencies for a subset of the CSARdock NRC HiQ data set where the number of ligand heavy atoms ranged from 17 to 35. This range of ligand heavy atoms is where improved accuracy of predicted ligand

  1. Outcome of the first wwPDB/CCDC/D3R Ligand Validation Workshop

    Science.gov (United States)

    Adams, Paul D.; Aertgeerts, Kathleen; Bauer, Cary; Bell, Jeffrey A.; Berman, Helen M.; Bhat, Talapady N.; Blaney, Jeff; Bolton, Evan; Bricogne, Gerard; Brown, David; Burley, Stephen K.; Case, David A.; Clark, Kirk L.; Darden, Tom; Emsley, Paul; Feher, Victoria A.; Feng, Zukang; Groom, Colin R.; Harris, Seth F.; Hendle, Jorg; Holder, Thomas; Joachimiak, Andrzej; Kleywegt, Gerard J.; Krojer, Tobias; Marcotrigiano, Joseph; Mark, Alan E.; Markley, John L.; Miller, Matthew; Minor, Wladek; Montelione, Gaetano T.; Murshudov, Garib; Nakagawa, Atsushi; Nakamura, Haruki; Nicholls, Anthony; Nicklaus, Marc; Nolte, Robert T.; Padyana, Anil K.; Peishoff, Catherine E.; Pieniazek, Susan; Read, Randy J.; Shao, Chenghua; Sheriff, Steven; Smart, Oliver; Soisson, Stephen; Spurlino, John; Stouch, Terry; Svobodova, Radka; Tempel, Wolfram; Terwilliger, Thomas C.; Tronrud, Dale; Velankar, Sameer; Ward, Suzanna; Warren, Gregory L.; Westbrook, John D.; Williams, Pamela; Yang, Huanwang; Young, Jasmine

    2016-01-01

    Summary Crystallographic studies of ligands bound to biological macromolecules (proteins and nucleic acids) represent an important source of information concerning drug-target interactions, providing atomic level insights into the physical chemistry of complex formation between macromolecules and ligands. Of the more than 115,000 entries extant in the Protein Data Bank archive, ~75% include at least one non-polymeric ligand. Ligand geometrical and stereochemical quality, the suitability of ligand models for in silico drug discovery/design, and the goodness-of-fit of ligand models to electron density maps vary widely across the archive. We describe the proceedings and conclusions from the first Worldwide Protein Data Bank/Cambridge Crystallographic Data Centre/Drug Design Data Resource (wwPDB/CCDC/D3R) Ligand Validation Workshop held at the Research Collaboratory for Structural Bioinformatics at Rutgers University on July 30–31, 2015. Experts in protein crystallography from academe and industry came together with non-profit and for-profit software providers for crystallography and with experts in computational chemistry and data archiving to discuss and make recommendations on best practices, as framed by a series of questions central to structural studies of macromolecule-ligand complexes. What data concerning bound ligands should be archived in the Protein Data Bank? How should the ligands be best represented? How should structural models of macromolecule-ligand complexes be validated? What supplementary information should accompany publications of structural studies of biological macromolecules? Consensus recommendations on best practices developed in response to each of these questions are provided, together with some details regarding implementation. Important issues addressed but not resolved at the workshop are also enumerated. PMID:27050687

  2. Phonon Raman spectra of colloidal CdTe nanocrystals: effect of size, non-stoichiometry and ligand exchange

    Directory of Open Access Journals (Sweden)

    Lokteva Irina

    2011-01-01

    Full Text Available Abstract Resonant Raman study reveals the noticeable effect of the ligand exchange on the nanocrystal (NC surface onto the phonon spectra of colloidal CdTe NC of different size and composition. The oleic acid ligand exchange for pyridine ones was found to change noticeably the position and width of the longitudinal optical (LO phonon mode, as well as its intensity ratio to overtones. The broad shoulder above the LO peak frequency was enhanced and sharpened after pyridine treatment, as well as with decreasing NC size. The low-frequency mode around 100 cm-1 which is commonly related with the disorder-activated acoustical phonons appears in smaller NCs but is not enhanced after pyridine treatment. Surprisingly, the feature at low-frequency shoulder of the LO peak, commonly assigned to the surface optical phonon mode, was not sensitive to ligand exchange and concomitant close packing of the NCs. An increased structural disorder on the NC surface, strain and modified electron-phonon coupling is discussed as the possible reason of the observed changes in the phonon spectrum of ligand-exchanged CdTe NCs. PACS: 63.20.-e, 78.30.-j, 78.67.-n, 78.67.Bf

  3. Expression Profiles of Ligands for Activating Natural Killer Cell Receptors on HIV Infected and Uninfected CD4⁺ T Cells.

    Science.gov (United States)

    Tremblay-McLean, Alexandra; Bruneau, Julie; Lebouché, Bertrand; Lisovsky, Irene; Song, Rujun; Bernard, Nicole F

    2017-10-12

    Natural Killer (NK) cell responses to HIV-infected CD4 T cells (iCD4) depend on the integration of signals received through inhibitory (iNKR) and activating NK receptors (aNKR). iCD4 activate NK cells to inhibit HIV replication. HIV infection-dependent changes in the human leukocyte antigen (HLA) ligands for iNKR on iCD4 are well documented. By contrast, less is known regarding the HIV infection related changes in ligands for aNKR on iCD4. We examined the aNKR ligand profiles HIV p24⁺ HIV iCD4s that maintained cell surface CD4 (iCD4⁺), did not maintain CD4 (iCD4 - ) and uninfected CD4 (unCD4) T cells for expression of unique long (UL)-16 binding proteins-1 (ULBP-1), ULBP-2/5/6, ULBP-3, major histocompatibility complex (MHC) class 1-related (MIC)-A, MIC-B, CD48, CD80, CD86, CD112, CD155, Intercellular adhesion molecule (ICAM)-1, ICAM-2, HLA-E, HLA-F, HLA-A2, HLA-C, and the ligands to NKp30, NKp44, NKp46, and killer immunoglobulin-like receptor 3DS1 (KIR3DS1) by flow cytometry on CD4 T cells from 17 HIV-1 seronegative donors activated and infected with HIV. iCD4⁺ cells had higher expression of aNKR ligands than did unCD4. However, the expression of aNKR ligands on iCD4 where CD4 was downregulated (iCD4 - ) was similar to (ULBP-1, ULBP-2/5/6, ULBP-3, MIC-A, CD48, CD80, CD86 and CD155) or significantly lower than (MIC-B, CD112 and ICAM-2) what was observed on unCD4. Thus, HIV infection can be associated with increased expression of aNKR ligands or either baseline or lower than baseline levels of aNKR ligands, concomitantly with the HIV-mediated downregulation of cell surface CD4 on infected cells.

  4. High-affinity multivalent wheat germ agglutinin ligands by one-pot click reaction

    Directory of Open Access Journals (Sweden)

    Henning S. G. Beckmann

    2012-06-01

    Full Text Available A series of six mono-, di-, and trivalent N,N’-diacetylchitobiose derivatives was conveniently prepared by employing a one-pot procedure for Cu(II-catalyzed diazo transfer and Cu(I-catalyzed azide–alkyne cycloaddition (CuAAC starting from commercially available amines. These glycoclusters were probed for their binding potencies to the plant lectin wheat germ agglutinin (WGA from Triticum vulgaris by an enzyme-linked lectin assay (ELLA employing covalently immobilized N-acetylglucosamine (GlcNAc as a reference ligand. IC50 values were in the low micromolar/high nanomolar range, depending on the linker between the two disaccharides. Binding enhancements β up to 1000 for the divalent ligands and 2800 for a trivalent WGA ligand, compared to N,N’-diacetylchitobiose as the corresponding monovalent ligand, were observed. Molecular modeling studies, in which the chitobiose moieties were fitted into crystallographically determined binding sites of WGA, correlate the binding enhancements of the multivalent ligands with their ability to bind to the protein in a chelating mode. The best WGA ligand is a trivalent cluster with an IC50 value of 220 nM. Calculated per mol of contained chitobiose, this is the best WGA ligand known so far.

  5. The treatment model of the guidance center for gamblers and their relatives in Vienna/Austria.

    Science.gov (United States)

    Horodecki, I

    1992-06-01

    Within 8 years, "Gamblers Anonymous" in Vienna evolved into a guidance center for gamblers and their relatives, with professional aid. It is a non-profit institution and the therapeutic team consists of one psychologist, one social-worker and one psychiatrist. The clients can remain anonymous, but about 90% of them reveal their identity. The treatment model integrating professional therapy and self-help is presented. The reasons we decided to base our work on an "addiction model" of pathological gambling are explained. All the clients consulting our center in 1990 (N=237) are described according to age, sex, types of gambling, duration of problem gambling, family status, profession, income, debts, and income/debt relationship. Finally, the treatment program of our center is presented.

  6. Protein-ligand interfaces are polarized: discovery of a strong trend for intermolecular hydrogen bonds to favor donors on the protein side with implications for predicting and designing ligand complexes.

    Science.gov (United States)

    Raschka, Sebastian; Wolf, Alex J; Bemister-Buffington, Joseph; Kuhn, Leslie A

    2018-04-01

    Understanding how proteins encode ligand specificity is fascinating and similar in importance to deciphering the genetic code. For protein-ligand recognition, the combination of an almost infinite variety of interfacial shapes and patterns of chemical groups makes the problem especially challenging. Here we analyze data across non-homologous proteins in complex with small biological ligands to address observations made in our inhibitor discovery projects: that proteins favor donating H-bonds to ligands and avoid using groups with both H-bond donor and acceptor capacity. The resulting clear and significant chemical group matching preferences elucidate the code for protein-native ligand binding, similar to the dominant patterns found in nucleic acid base-pairing. On average, 90% of the keto and carboxylate oxygens occurring in the biological ligands formed direct H-bonds to the protein. A two-fold preference was found for protein atoms to act as H-bond donors and ligand atoms to act as acceptors, and 76% of all intermolecular H-bonds involved an amine donor. Together, the tight chemical and geometric constraints associated with satisfying donor groups generate a hydrogen-bonding lock that can be matched only by ligands bearing the right acceptor-rich key. Measuring an index of H-bond preference based on the observed chemical trends proved sufficient to predict other protein-ligand complexes and can be used to guide molecular design. The resulting Hbind and Protein Recognition Index software packages are being made available for rigorously defining intermolecular H-bonds and measuring the extent to which H-bonding patterns in a given complex match the preference key.

  7. Protein-ligand interfaces are polarized: discovery of a strong trend for intermolecular hydrogen bonds to favor donors on the protein side with implications for predicting and designing ligand complexes

    Science.gov (United States)

    Raschka, Sebastian; Wolf, Alex J.; Bemister-Buffington, Joseph; Kuhn, Leslie A.

    2018-02-01

    Understanding how proteins encode ligand specificity is fascinating and similar in importance to deciphering the genetic code. For protein-ligand recognition, the combination of an almost infinite variety of interfacial shapes and patterns of chemical groups makes the problem especially challenging. Here we analyze data across non-homologous proteins in complex with small biological ligands to address observations made in our inhibitor discovery projects: that proteins favor donating H-bonds to ligands and avoid using groups with both H-bond donor and acceptor capacity. The resulting clear and significant chemical group matching preferences elucidate the code for protein-native ligand binding, similar to the dominant patterns found in nucleic acid base-pairing. On average, 90% of the keto and carboxylate oxygens occurring in the biological ligands formed direct H-bonds to the protein. A two-fold preference was found for protein atoms to act as H-bond donors and ligand atoms to act as acceptors, and 76% of all intermolecular H-bonds involved an amine donor. Together, the tight chemical and geometric constraints associated with satisfying donor groups generate a hydrogen-bonding lock that can be matched only by ligands bearing the right acceptor-rich key. Measuring an index of H-bond preference based on the observed chemical trends proved sufficient to predict other protein-ligand complexes and can be used to guide molecular design. The resulting Hbind and Protein Recognition Index software packages are being made available for rigorously defining intermolecular H-bonds and measuring the extent to which H-bonding patterns in a given complex match the preference key.

  8. X-ray absorption spectroscopic studies of the dinuclear iron center in methane monooxygenase and the sulfure and chlorine centers in photographic materials

    Energy Technology Data Exchange (ETDEWEB)

    DeWitt, J.G.

    1992-12-01

    The dinuclear iron center of the hydroxylase component of soluble methane monooxygenase (MMO) from Methylococcus capsulatus and Methylosinus trichosporiwn has been studied by X-ray absorption spectroscopy. Analysis of the Fe K-edge EXAFS revealed that the first shell coordination of the Fe(HI)Fe(IH) oxidized state of the hydroxylase from M. capsulatus consists of approximately 6 N and 0 atoms at an average distance of 2.04 [Angstrom]. The Fe-Fe distance was determined to be 3.4 [Angstrom]. No evidence for the presence of a short oxo bridge in the iron center of the oxidized hydroxylase was found, suggesting that the active site of MMO is significantly different from the active sites of the dinuclear iron proteins hemery and ribonucleotide reductase. In addition, the results of the first shell fits suggest that there are more oxygen than nitrogen donor ligands.

  9. X-ray absorption spectroscopic studies of the dinuclear iron center in methane monooxygenase and the sulfure and chlorine centers in photographic materials

    Energy Technology Data Exchange (ETDEWEB)

    DeWitt, Jane G. [Stanford Univ., CA (United States)

    1992-12-01

    The dinuclear iron center of the hydroxylase component of soluble methane monooxygenase (MMO) from Methylococcus capsulatus and Methylosinus trichosporiwn has been studied by X-ray absorption spectroscopy. Analysis of the Fe K-edge EXAFS revealed that the first shell coordination of the Fe(HI)Fe(IH) oxidized state of the hydroxylase from M. capsulatus consists of approximately 6 N and 0 atoms at an average distance of 2.04 Å. The Fe-Fe distance was determined to be 3.4 Å. No evidence for the presence of a short oxo bridge in the iron center of the oxidized hydroxylase was found, suggesting that the active site of MMO is significantly different from the active sites of the dinuclear iron proteins hemery and ribonucleotide reductase. In addition, the results of the first shell fits suggest that there are more oxygen than nitrogen donor ligands.

  10. An Efficient ABC_DE_Based Hybrid Algorithm for Protein–Ligand Docking

    Directory of Open Access Journals (Sweden)

    Boxin Guan

    2018-04-01

    Full Text Available Protein–ligand docking is a process of searching for the optimal binding conformation between the receptor and the ligand. Automated docking plays an important role in drug design, and an efficient search algorithm is needed to tackle the docking problem. To tackle the protein–ligand docking problem more efficiently, An ABC_DE_based hybrid algorithm (ADHDOCK, integrating artificial bee colony (ABC algorithm and differential evolution (DE algorithm, is proposed in the article. ADHDOCK applies an adaptive population partition (APP mechanism to reasonably allocate the computational resources of the population in each iteration process, which helps the novel method make better use of the advantages of ABC and DE. The experiment tested fifty protein–ligand docking problems to compare the performance of ADHDOCK, ABC, DE, Lamarckian genetic algorithm (LGA, running history information guided genetic algorithm (HIGA, and swarm optimization for highly flexible protein–ligand docking (SODOCK. The results clearly exhibit the capability of ADHDOCK toward finding the lowest energy and the smallest root-mean-square deviation (RMSD on most of the protein–ligand docking problems with respect to the other five algorithms.

  11. Analytical developments for screening of lanthanides/ligands interactions

    International Nuclear Information System (INIS)

    Varenne, F.

    2012-01-01

    This work investigates the potential of hyphenated capillary electrophoresis and inductively coupled mass spectrometry to classify different ligands according to their europium binding affinity in a hydro-organic medium. On the one hand, this method enables to evaluate the affinity of phosphorus-containing ligands in less than two hours and using less than 15 ng of ligand. On the other hand, complexation constants could be determined. The results are in excellent agreement with the values obtained by spectrophotometric titrations.Moreover, a library of copolymers for solid/liquid extraction of europium is investigated. The extraction protocol enables to classify copolymers according to their europium affinity in a hydro-organic medium. This screening requires 60 mg of copolymers. For the most promising recognition properties and selectivity La 3+ /Eu 3+ /Lu 3+ are evaluated. (author)

  12. Designer ligands. Part 15. Synthesis and characterisation of novel Mn(lI), Ni(II) and Zn(II) complexes of 1,10-phenanthroline-derived ligands

    CSIR Research Space (South Africa)

    Wellington, Kevin W

    2009-01-01

    Full Text Available Series of manganese(II), nickel(II) and zinc(II) complexes have been prepared using 1,10-phenanthroline-derived ligands, and their coordination geometries have been assigned using infrared data. It is apparent that, depending on the ligand...

  13. The use of random-effects models to identify health care center-related characteristics modifying the effect of antipsychotic drugs

    Directory of Open Access Journals (Sweden)

    Nordon C

    2017-12-01

    Full Text Available Clementine Nordon,1 Constance Battin,1 Helene Verdoux,2 Josef Maria Haro,3 Mark Belger,4 Lucien Abenhaim,1 Tjeerd Pieter van Staa5 On behalf of the IMI GetReal WP2 Group 1Epidemiological Research, Analytica LASER, Paris, 2Population Health Research Center, Team Pharmaco-Epidemiology, UMR 1219, Bordeaux-2 University, INSERM, Bordeaux, France; 3Parc Sanitari Sant Joan de Deu, CIBERSAM, University of Barcelona, Barcelona, Spain; 4Eli Lilly and Company Limited, Erl Wood Manor, Windlesham, 5Farr Institute, University of Manchester, Manchester, UK Purpose: A case study was conducted, exploring methods to identify drugs effects modifiers, at a health care center level.Patients and methods: Data were drawn from the Schizophrenia Outpatient Health Outcome cohort, including hierarchical information on 6641 patients, recruited from 899 health care centers from across ten European countries. Center-level characteristics included the following: psychiatrist’s gender, age, length of practice experience, practice setting and type, countries’ Healthcare System Efficiency score, and psychiatrist density in the country. Mixed multivariable linear regression models were used: 1 to estimate antipsychotic drugs’ effectiveness (defined as the association between patients’ outcome at 3 months – dependent variable, continuous – and antipsychotic drug initiation at baseline – drug A vs other antipsychotic drug; 2 to estimate the similarity between clustered data (using the intra-cluster correlation coefficient; and 3 to explore antipsychotic drug effects modification by center-related characteristics (using the addition of an interaction term.Results: About 23% of the variance found for patients’ outcome was explained by unmeasured confounding at a center level. Psychiatrists’ practice experience was found to be associated with patient outcomes (p=0.04 and modified the relative effect of “drug A” (p<0.001, independent of center- or patient-related

  14. Ligand-Free Nanocrystals of Highly Emissive Cs4PbBr6 Perovskite

    KAUST Repository

    Zhang, Yuhai

    2018-02-23

    Although ligands of long carbon chains are very crucial to form stable colloidal perovskite nanocrystals (NCs), they create a severe barrier for efficient charge injection or extraction in quantum-dot-based optoelectronics, such as light emitting diode or solar cell. Here, we report a new approach to preparing ligand-free perovskite NCs of CsPbBr, which retained high photoluminescence quantum yield (44%). Such an approach involves a polar solvent (acetonitrile) and two small molecules (ammonium acetate and cesium chloride), which replace the organic ligand and still protect the nanocrystals from dissolution. The successful removal of hydrophobic long ligands was evidenced by Fourier transform infrared spectroscopy, ζ potential analysis, and thermogravimetric analysis. Unlike conventional perovskite NCs that are extremely susceptible to polar solvents, the ligand-free CsPbBr NCs show robust resistance to polar solvents. Our ligand-free procedure opens many possibilities not only from a material hybridization perspective but also in optimizing charge injection and extraction in semiconductor quantum-dot-based optoelectronics applications.

  15. Thermodynamics of Ligand Binding to a Heterogeneous RNA Population in the Malachite Green Aptamer

    Science.gov (United States)

    Sokoloski, Joshua E.; Dombrowski, Sarah E.; Bevilacqua, Philip C.

    2011-01-01

    The malachite green aptamer binds two closely related ligands, malachite green (MG) and tetramethylrosamine (TMR), with near equal affinity. The MG ligand consists of three phenyl rings emanating from a central carbon, while TMR has two of the three rings connected by an ether linkage. The binding pockets for MG and TMR in the aptamer, known from high-resolution structure, differ only in the conformation of a few nucleotides. Herein, we applied isothermal titration calorimetry (ITC) to compare the thermodynamics for binding of MG and TMR to the aptamer. Binding heat capacities were obtained from ITC titrations over the temperature range of 15 to 60 °C. Two temperature regimes were found for MG binding: one from 15 to 45 °C where MG bound with a large negative heat capacity and an apparent stoichiometry (n) of ~0.4, and another from 50 to 60 °C where MG bound with positive heat capacity and n~1.1. The binding of TMR, on the other hand, revealed only one temperature regime for binding, with a more modest negative heat capacity and n~1.2. The large difference in heat capacity between the two ligands suggests that significantly more conformational rearrangement occurs upon the binding of MG than TMR, which is consistent with differences in solvent accessible surface area calculated for available ligand-bound structures. Lastly, we note that binding stoichiometry of MG was improved not only by raising the temperature, but also by lowering the concentration of Mg2+ or increasing the time between ITC injections. These studies suggest that binding of a dynamical ligand to a functional RNA requires the RNA itself to have significant dynamics. PMID:22192051

  16. Interactions of ligands with active and inactive conformations of the dopamine D2 receptor.

    Science.gov (United States)

    Malmberg, A; Mohell, N; Backlund Höök, B; Johansson, A M; Hacksell, U; Nordvall, G

    1998-04-10

    The affinities of 19 pharmacologically diverse dopamine D2 receptor ligands were determined for the active and inactive conformations of cloned human dopamine D2 receptors expressed in Ltk cells. The agonist [3H]quinpirole was used to selectively label the guanine nucleotide-binding protein-coupled, active receptor conformation. The antagonist [3H]raclopride, in the presence of the non-hydrolysable GTP-analogue Gpp(NH)p and sodium ions and in the absence of magnesium ions, was used to label the free inactive receptor conformation. The intrinsic activities of the ligands were determined in a forskolin-stimulated cyclic AMP assay using the same cells. An excellent correlation was shown between the affinity ratios (KR/KRG) of the ligands for the two receptor conformations and their intrinsic activity (r=0.96). The ligands included eight structurally related and enantiopure 2-aminotetralin derivatives; the enantiomers of 5-hydroxy-2-(dipropylamino)tetralin, 5-methoxy-2-(dipropylamino)tetralin, 5-fluoro-2-(dipropylamino)tetralin and 2-(dipropylamino)tetralin. The (S)-enantiomers behaved as full agonists in the cyclic AMP assay and displayed a large KR/KRG ratio. The (R)-enantiomers were classified as partial agonists and had lower ratios. The structure-affinity relationships of these compounds at the active and the inactive receptor conformations were analysed separately, and used in conjunction with a homology based receptor model of the dopamine D2 receptor. This led to proposed binding modes for agonists, antagonists and partial agonists in the 2-aminotetralin series. The concepts used in this study should be of value in the design of ligands with predetermined affinity and intrinsic activity.

  17. Epidemiology of livestock-related injuries in a major trauma center in Kashan, Iran

    Directory of Open Access Journals (Sweden)

    Mohammadzadeh Mahdi

    2013-02-01

    Full Text Available 【Abstract】Objective: Livestock-related injuries are one of the important factors causing morbidity and mor-tality in patients admitted to hospital. Treatment of these patients is still a major problem in health care system. The aim of current study was to assess the epidemiology of livestock-related injuries in a major trauma center in Iran from 2006 to 2011. Methods: In a prospective study, patients with live-stock-related injuries who were consecutively admitted to the trauma center in Kashan, Iran between 2006 and 2011 were evaluated. The data collected included patient’s demographics, place and nature of accident, damaged organ, educational level, transport and outcome. Data were ex-pressed as mean±standard deviation. Results: A total of 129 patients were included in this study, accounting for 0.3% of all trauma admission (40 273 cases. The mean age was (55.27±14.45 years. Men were affected four times more than women. Falling down from livestock is the main mechanism of trauma in all groups. Upper and lower extremities were most frequently injured (n=72, followed by the head, neck and spine (n=33 for each. There was one death resulting from livestock-related injury in this study. Conclusion: Despite the low incidence, livestock-re-lated injuries can damage major organs of human body and therefore appropriate training program to increase the safety awareness in home and outdoor is very important. Key words: Epidemiology; Livestock; Iran; Wounds and injuries

  18. Solid state structure of thorium(IV) complexes with common aminopoly-carboxylate ligands

    International Nuclear Information System (INIS)

    Thuery, Pierre

    2011-01-01

    The crystal structures of the complexes formed by reaction of thorium(IV) nitrate with iminodiacetic acid (H 2 IDA), nitrilotriacetic acid (H 3 NTA), and ethylenediaminetetraacetic acid (H 4 EDTA) under hydrothermal conditions are reported. In [Th(HIDA) 2 (C 2 O 4 )].H 2 O (1), the metal atom is chelated by two carboxylate groups from two HIDA - anions and by two oxalate ligands formed in situ; two additional oxygen atoms from two more HIDA - anions complete the ten-coordinate environment of bi-capped square anti-prismatic geometry. The uncoordinated nitrogen atom is protonated and involved in hydrogen bonding. Two different ligands are present in [Th(NTA)(H 2 NTA)(H 2 O)].H 2 O (2), one of them being a O 3 ,N-chelating tri-anion which acts also as a bridge toward two neighboring metal ions, and the other being a bis-monodentate bridging species with an uncoordinated carboxylic arm and a central ammonium group. An aqua ligand completes the nine-coordinated, capped square anti-prismatic metal environment. The EDTA 4- anion in [Th(EDTA)(H 2 O)].2H 2 O (3) is chelating through one oxygen atom from each carboxylate group and the two nitrogen atoms, as in a previously reported molecular complex. Two carboxylate groups are bridging, which, with the addition of an aqua ligand, gives a capped square anti-prismatic coordination polyhedron. Aminopoly-carboxylate ligands have been much investigated in relation with actinide decorporation and nuclear wastes management studies, and the present results add to the structural information available on their complexes with thorium(IV), which has mainly been obtained up to now by extended X-ray absorption fine structure (EXAFS) spectroscopy. In particular, the bridging (non-chelating) coordination mode of H 2 NTA - is a novel feature in this context. All three complexes crystallize as two-dimensional assemblies and are thus novel examples of thorium-organic coordination polymers. (author)

  19. Synthesis of freestanding water-soluble indium oxide nanocrystals capped by alanine nitric acid via ligand exchange for thin film transistors and effects of ligands on the electrical properties

    International Nuclear Information System (INIS)

    Choi, Jin-Kyu; Koh, Ye-Seul; Jeong, Hyun-Dam

    2015-01-01

    We demonstrate synthesis of freestanding water-soluble indium oxide nanocrystals (In 2 O 3 NCs) by ligand exchange to β-alanine nitric acid (Ala·HNO 3 ) and its application for active channel layer in thin film transistors (TFTs), with investigation of the effect of curing temperatures on the TFT properties in terms of thermal behaviour of the ligand molecules at 150, 300, and 350 °C. After ligand exchange from long alkyl ligand (myristic acid, MA) to short Ala·HNO 3 , the mobility of NC TFTs cured at 150 °C increased by over 1 order of magnitude, from 1.3 × 10 −4 cm 2 V -1 s −1 to 4.5 × 10 −3 cm 2 V -1 s −1 , due to enhanced tunnelling rate (Γ) between adjective NCs. Higher curing temperatures such as 300 and 350 °C, inducing thermal decomposition of the organic ligands, led to further enhancement of the mobility, particularly up to 2.2 cm 2 V -1 s −1 for the In 2 O 3 NC-Ala·HNO 3 TFT cured at 350 °C. It is also found that the ligand exchange of In 2 O 3 NC in acidic condition (e.g. HNO 3 ) would be simple and effective to reduce the surface defects by surface etching, which may lead to better device performances. - Graphical abstract: Display Omitted - Highlights: • Freestanding water-soluble In 2 O 3 nanocrystals (NCs) were synthesized by ligand exchange. • Thin film transistors (TFTs) of colloidal NCs were fabricated by spin-coating method. • Water-soluble In 2 O 3 NC TFTs showed higher mobilities due to shorter ligand length. • Surface defects of NCs were notably reduced by surface etching during ligand exchange

  20. Magnetic ligand fishing as a targeting tool for HPLC-HRMS-SPE-NMR: α-glucosidase inhibitory ligands and alkylresorcinol glycosides from Eugenia catharinae

    DEFF Research Database (Denmark)

    Wubshet, Sileshi Gizachew; Brighente, Inês M. C.; Moaddel, Ruin

    2015-01-01

    A bioanalytical platform combining magnetic ligand fishing for α-glucosidase inhibition profiling and HPLC-HRMS-SPE-NMR for structural identification of α-glucosidase inhibitory ligands, both directly from crude plant extracts, is presented. Magnetic beads with N-terminus-coupled α-glucosidase we...