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Sample records for backbone conformational dynamics

  1. Molecular dynamics simulations of ligand-induced backbone conformational changes in the binding site of the periplasmic lysine-, arginine-, ornithine-binding protein

    Science.gov (United States)

    Yang, Ami Y.-C.; Mancera, Ricardo L.

    2008-11-01

    The periplasmic lysine-, arginine-, ornithine-binding protein (LAOBP) traps its ligands by a large hinge bending movement between two globular domains. The overall geometry of the binding site remains largely unchanged between the open (unliganded) and closed (liganded) forms, with only a small number of residues exhibiting limited movement of their side chains. However, in the case of the ornithine-bound structure, the backbone peptide bond between Asp11 and Thr12 undergoes a large rotation. Molecular dynamics simulations have been used to investigate the origin and mechanism of this backbone movement. Simulations allowing flexibility of a limited region and of the whole binding site, with and without bound ligands, suggest that this conformational change is induced by the binding of ornithine, leading to the stabilisation of an energetically favourable alternative conformation.

  2. A sampling approach for protein backbone fragment conformations.

    Science.gov (United States)

    Yu, J Y; Zhang, W

    2013-01-01

    In protein structure prediction, backbone fragment bias information can narrow down the conformational space of the whole polypeptide chain significantly. Unlike existing methods that use fragments as building blocks, the paper presents a probabilistic sampling approach for protein backbone torsion angles by modelling angular correlation of (phi, psi) with a directional statistics distribution. Given a protein sequence and secondary structure information, this method samples backbone fragments conformations by using a backtrack sampling algorithm for the hidden Markov model with multiple inputs and a single output. The proposed approach is applied to a fragment library, and some well-known structural motifs are sampled very well on the optimal path. Computational results show that the method can help to obtain native-like backbone fragments conformations.

  3. AbDesign: An algorithm for combinatorial backbone design guided by natural conformations and sequences.

    Science.gov (United States)

    Lapidoth, Gideon D; Baran, Dror; Pszolla, Gabriele M; Norn, Christoffer; Alon, Assaf; Tyka, Michael D; Fleishman, Sarel J

    2015-08-01

    Computational design of protein function has made substantial progress, generating new enzymes, binders, inhibitors, and nanomaterials not previously seen in nature. However, the ability to design new protein backbones for function--essential to exert control over all polypeptide degrees of freedom--remains a critical challenge. Most previous attempts to design new backbones computed the mainchain from scratch. Here, instead, we describe a combinatorial backbone and sequence optimization algorithm called AbDesign, which leverages the large number of sequences and experimentally determined molecular structures of antibodies to construct new antibody models, dock them against target surfaces and optimize their sequence and backbone conformation for high stability and binding affinity. We used the algorithm to produce antibody designs that target the same molecular surfaces as nine natural, high-affinity antibodies; in five cases interface sequence identity is above 30%, and in four of those the backbone conformation at the core of the antibody binding surface is within 1 Å root-mean square deviation from the natural antibodies. Designs recapitulate polar interaction networks observed in natural complexes, and amino acid sidechain rigidity at the designed binding surface, which is likely important for affinity and specificity, is high compared to previous design studies. In designed anti-lysozyme antibodies, complementarity-determining regions (CDRs) at the periphery of the interface, such as L1 and H2, show greater backbone conformation diversity than the CDRs at the core of the interface, and increase the binding surface area compared to the natural antibody, potentially enhancing affinity and specificity. © 2015 Wiley Periodicals, Inc.

  4. Slow dynamics of a protein backbone in molecular dynamics simulation revealed by time-structure based independent component analysis

    Energy Technology Data Exchange (ETDEWEB)

    Naritomi, Yusuke [Department of Supramolecular Biology, Graduate School of Nanobioscience, Yokohama City University, 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045 (Japan); Fuchigami, Sotaro, E-mail: sotaro@tsurumi.yokohama-cu.ac.jp [Department of Medical Life Science, Graduate School of Medical Life Science, Yokohama City University, 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045 (Japan)

    2013-12-07

    We recently proposed the method of time-structure based independent component analysis (tICA) to examine the slow dynamics involved in conformational fluctuations of a protein as estimated by molecular dynamics (MD) simulation [Y. Naritomi and S. Fuchigami, J. Chem. Phys. 134, 065101 (2011)]. Our previous study focused on domain motions of the protein and examined its dynamics by using rigid-body domain analysis and tICA. However, the protein changes its conformation not only through domain motions but also by various types of motions involving its backbone and side chains. Some of these motions might occur on a slow time scale: we hypothesize that if so, we could effectively detect and characterize them using tICA. In the present study, we investigated slow dynamics of the protein backbone using MD simulation and tICA. The selected target protein was lysine-, arginine-, ornithine-binding protein (LAO), which comprises two domains and undergoes large domain motions. MD simulation of LAO in explicit water was performed for 1 μs, and the obtained trajectory of C{sub α} atoms in the backbone was analyzed by tICA. This analysis successfully provided us with slow modes for LAO that represented either domain motions or local movements of the backbone. Further analysis elucidated the atomic details of the suggested local motions and confirmed that these motions truly occurred on the expected slow time scale.

  5. Effect of backbone chemistry on hybridization thermodynamics of oligonucleic acids: a coarse-grained molecular dynamics simulation study.

    Science.gov (United States)

    Ghobadi, Ahmadreza F; Jayaraman, Arthi

    2016-02-28

    In this paper we study how varying oligonucleic acid backbone chemistry affects the hybridization/melting thermodynamics of oligonucleic acids. We first describe the coarse-grained (CG) model with tunable parameters that we developed to enable the study of both naturally occurring oligonucleic acids, such as DNA, and their chemically-modified analogues, such as peptide nucleic acids (PNAs) and locked nucleic acids (LNAs). The DNA melting curves obtained using such a CG model and molecular dynamics simulations in an implicit solvent and with explicit ions match with the melting curves obtained using the empirical nearest-neighbor models. We use these CG simulations to then elucidate the effect of backbone flexibility, charge, and nucleobase spacing along the backbone on the melting curves, potential energy and conformational entropy change upon hybridization and base-pair hydrogen bond residence time. We find that increasing backbone flexibility decreases duplex thermal stability and melting temperature mainly due to increased conformational entropy loss upon hybridization. Removing charges from the backbone enhances duplex thermal stability due to the elimination of electrostatic repulsion and as a result a larger energetic gain upon hybridization. Lastly, increasing nucleobase spacing decreases duplex thermal stability due to decreasing stacking interactions that are important for duplex stability.

  6. Backbone Dynamics of the Monomeric λ Repressor Denatured State Ensemble under Nondenaturing Conditions†

    Science.gov (United States)

    Chugha, Preeti; Oas, Terrence G.

    2014-01-01

    Oxidizing two native methionine residues predominantly populates the denatured state of monomeric λ repressor (MetO-λLS) under nondenaturing conditions. NMR was used to characterize the secondary structure and dynamics of MetO-λLS in standard phosphate buffer. 13Cα and 1Hα chemical shift indices reveal a region of significant helicity between residues 9 and 29. This helical content is further supported by the observation of medium-range amide NOEs. The remaining residues do not exhibit significant helicity as determined by NMR. We determined 15N relaxation parameters for 64 of 85 residues at 600 and 800 MHz. There are two distinct regions of reduced flexibility, residues 8–32 in the N-terminal third and residues 50–83 in the C-terminal third. The middle third, residues 33–50, has greater flexibility. We have analyzed the amplitude of the backbone motions in terms of the physical properties of the amino acids and conclude that conformational restriction of the backbone MetO-λLS is due to nascent helix formation in the region corresponding to native helix 1. The bulkiness of amino acid residues in the C-terminal third leads to the potential for hydrophobic interactions, which is suggested by chemical exchange detected by the difference in spectral density J(0) at the two static magnetic fields. The more flexible middle region is the result of a predominance of small side chains in this region. PMID:17260944

  7. Noncanonical alpha/gamma Backbone Conformations in RNA and the Accuracy of Their Description by the AMBER Force Field

    Czech Academy of Sciences Publication Activity Database

    Zgarbová, M.; Jurečka, P.; Banáš, P.; Havrila, Marek; Šponer, Jiří; Otyepka, M.

    2017-01-01

    Roč. 121, č. 11 (2017), s. 2420-2433 ISSN 1520-6106 Institutional support: RVO:68081707 Keywords : molecular- dynamics simulations * sugar-phosphate backbone * free-energy landscape * ribosomal-rna Subject RIV: BO - Biophysics OBOR OECD: Physical chemistry Impact factor: 3.177, year: 2016

  8. An Unusual Conformational Isomer of Verrucosidin Backbone from a Hydrothermal Vent Fungus, Penicillium sp. Y-50-10

    Directory of Open Access Journals (Sweden)

    Chengqian Pan

    2016-08-01

    Full Text Available A new verrucosidin derivative, methyl isoverrucosidinol (1, was isolated from the marine fungus Penicillium sp. Y-50-10, dwelling in sulfur rich sediment in the Kueishantao hydrothermal vents off Taiwan. The structure was established by spectroscopic means including HRMS and 2D-NMR spectroscopic analysis. The absolute configuration was defined mainly by comparison of quantum chemical TDDFT calculated and experimental ECD spectra. Among hitherto known compounds with a verrucosidine backbone isolated from natural resource, compound 1 represents the first example of a new conformational isomer of its skeleton, exhibiting antibiotic activity against Bacillus subtilis with MIC value 32 μg/mL.

  9. Pendant Dynamics of Ethylene-Oxide Containing Polymers with Diverse Backbones

    Science.gov (United States)

    Bartels, Joshua; Wang, Jing-Han Helen; Chen, Quan; Runt, James; Colby, Ralph

    In the last twenty years, a wide variety of ion conducting polymers have used ether oxygens to facilitate ion conduction, and it is therefore important to understand the dynamics of ether oxygens (EOs) when attached to different polymer backbones. Four different EO-containing polymer architectures are studied by dielectric spectroscopy to understand the backbone effect on the EO dipoles. Polysiloxanes, polyphosphazenes, polymethylmethacrylates, and a polyester ether are compared, with different EO pendant lengths for the siloxane and methylmethacrylate backbones. The flexible polysiloxanes and polyphosphazene backbones impart superior segmental mobility with a glass transition temperature 15 K lower than that of the organic backbone polymers. Short EO pendants are found to impart a lower static dielectric constant at comparable EO content as compared to longer EO pendants of either inorganic or organic backbones. The long-pendant polymethylmethacrylate polymers show two relaxations corresponding to fast EOs near the pendant tail end and slow EOs close to the slower backbone, whereas the long-pendant polysiloxane shows a single relaxation due to the siloxane backbone relaxing faster than the EO pendant. Supported by the NSF Division of Materials Research Polymers Program through Grants DMR-1404586 (RHC) and DMR-1505953 (JR).

  10. Redox-controlled backbone dynamics of human cytochrome c revealed by 15N NMR relaxation measurements

    International Nuclear Information System (INIS)

    Sakamoto, Koichi; Kamiya, Masakatsu; Uchida, Takeshi; Kawano, Keiichi; Ishimori, Koichiro

    2010-01-01

    Research highlights: → The dynamic parameters for the backbone dynamics in Cyt c were determined. → The backbone mobility of Cyt c is highly restricted due to the covalently bound heme. → The backbone mobility of Cyt c is more restricted upon the oxidation of the heme. → The redox-dependent dynamics are shown in the backbone of Cyt c. → The backbone dynamics of Cyt c would regulate the electron transfer from Cyt c. -- Abstract: Redox-controlled backbone dynamics in cytochrome c (Cyt c) were revealed by 2D 15 N NMR relaxation experiments. 15 N T 1 and T 2 values and 1 H- 15 N NOEs of uniformly 15 N-labeled reduced and oxidized Cyt c were measured, and the generalized order parameters (S 2 ), the effective correlation time for internal motion (τ e ), the 15 N exchange broadening contributions (R ex ) for each residue, and the overall correlation time (τ m ) were estimated by model-free dynamics formalism. These dynamic parameters clearly showed that the backbone dynamics of Cyt c are highly restricted due to the covalently bound heme that functions as the stable hydrophobic core. Upon oxidation of the heme iron in Cyt c, the average S 2 value was increased from 0.88 ± 0.01 to 0.92 ± 0.01, demonstrating that the mobility of the backbone is further restricted in the oxidized form. Such increases in the S 2 values were more prominent in the loop regions, including amino acid residues near the thioether bonds to the heme moiety and positively charged region around Lys87. Both of the regions are supposed to form the interaction site for cytochrome c oxidase (CcO) and the electron pathway from Cyt c to CcO. The redox-dependent mobility of the backbone in the interaction site for the electron transfer to CcO suggests an electron transfer mechanism regulated by the backbone dynamics in the Cyt c-CcO system.

  11. Dynamic power control for wireless backbone mesh networks: a survey

    CSIR Research Space (South Africa)

    Olwal, TO

    2010-01-01

    Full Text Available that there is a limited battery power available at each node but each user demands unlimited utility satisfaction, effective and efficient power control strategies ought to be in place [55]. These strategies may be designed to achieve user oriented quality... (i.e., throughput and delay) [69]. Methods from control theory have been used to analyse the dynamical effects and to design appropriate control strategies (e.g., [8]). The basic block Network Protocols and Algorithms ISSN 1943-3581 2010, Vol. 2...

  12. Pseudoelastic behaviour of a natural material is achieved via reversible changes in protein backbone conformation.

    Science.gov (United States)

    Harrington, Matthew J; Wasko, S Scott; Masic, Admir; Fischer, F Dieter; Gupta, Himadri S; Fratzl, Peter

    2012-11-07

    The egg capsules of marine prosobranch gastropods, commonly know as whelks, function as a protective encapsulant for whelk embryos in wave-swept marine environments. The proteinaceous sheets comprising the wall of whelk egg capsules (WEC) exhibit long-range reversible extensibility with a hysteresis of up to 50 per cent, previously suggested to result from reversible changes in the structure of the constituent protein building blocks. Here, we further investigate the structural changes of the WEC biopolymer at various hierarchical levels using several different time-resolved in situ approaches. We find strong evidence in these biological polymers for a strain-induced reversible transition from an ordered conformational phase to a largely disordered one that leads to the characteristic reversible hysteretic behaviour, which is reminiscent of the pseudoelastic behaviour in some metallic alloys. On the basis of these results, we generate a simple numerical model incorporating a worm-like chain equation to explain the phase transition behaviour of the WEC at the molecular level.

  13. Assessing protein conformational sampling methods based on bivariate lag-distributions of backbone angles

    KAUST Repository

    Maadooliat, Mehdi

    2012-08-27

    Despite considerable progress in the past decades, protein structure prediction remains one of the major unsolved problems in computational biology. Angular-sampling-based methods have been extensively studied recently due to their ability to capture the continuous conformational space of protein structures. The literature has focused on using a variety of parametric models of the sequential dependencies between angle pairs along the protein chains. In this article, we present a thorough review of angular-sampling-based methods by assessing three main questions: What is the best distribution type to model the protein angles? What is a reasonable number of components in a mixture model that should be considered to accurately parameterize the joint distribution of the angles? and What is the order of the local sequence-structure dependency that should be considered by a prediction method? We assess the model fits for different methods using bivariate lag-distributions of the dihedral/planar angles. Moreover, the main information across the lags can be extracted using a technique called Lag singular value decomposition (LagSVD), which considers the joint distribution of the dihedral/planar angles over different lags using a nonparametric approach and monitors the behavior of the lag-distribution of the angles using singular value decomposition. As a result, we developed graphical tools and numerical measurements to compare and evaluate the performance of different model fits. Furthermore, we developed a web-tool (http://www.stat.tamu. edu/~madoliat/LagSVD) that can be used to produce informative animations. © The Author 2012. Published by Oxford University Press.

  14. Research on backbone node deployment for Wireless Mesh Networks in dynamic environments

    Science.gov (United States)

    Li, Meiyi; Cao, Shengling

    2017-08-01

    Wireless Mesh Network is a type of wireless networks in which demands of bandwidth for users has mobility. The backbone node placement of wireless mesh networks in a dynamic scenario is investigated, and the TSDPSO algorithm is used to adapt the dynamic environment, which updates node deployment location to adapt to changes in demand if it detects environmental changes at the beginning of the cycle time. In order to meet the demands of bandwidth for users and network connectivity, particle swarm optimization algorithm is employed to select the gateway location, then nodes to the backbone network is added constantly until all requirement is covered. The experimental results show that algorithm could get effective solution in dynamic environment.

  15. On the role of thermal backbone fluctuations in myoglobin ligand gate dynamics

    Science.gov (United States)

    Krokhotin, Andrey; Niemi, Antti J.; Peng, Xubiao

    2013-05-01

    We construct an energy function that describes the crystallographic structure of sperm whale myoglobin backbone. As a model in our construction, we use the Protein Data Bank entry 1ABS that has been measured at liquid helium temperature. Consequently, the thermal B-factor fluctuations are very small, which is an advantage in our construction. The energy function that we utilize resembles that of the discrete nonlinear Schrödinger equation. Likewise, ours supports topological solitons as local minimum energy configurations. We describe the 1ABS backbone in terms of topological solitons with a precision that deviates from 1ABS by an average root-mean-square distance, which is less than the experimentally observed Debye-Waller B-factor fluctuation distance. We then subject the topological multi-soliton solution to extensive numerical heating and cooling experiments, over a very wide range of temperatures. We concentrate in particular to temperatures above 300 K and below the Θ-point unfolding temperature, which is around 348 K. We confirm that the behavior of the topological multi-soliton is fully consistent with Anfinsen's thermodynamic principle, up to very high temperatures. We observe that the structure responds to an increase of temperature consistently in a very similar manner. This enables us to characterize the onset of thermally induced conformational changes in terms of three distinct backbone ligand gates. One of the gates is made of the helix F and the helix E. The two other gates are chosen similarly, when open they provide a direct access route for a ligand to reach the heme. We find that out of the three gates we investigate, the one which is formed by helices B and G is the most sensitive to thermally induced conformational changes. Our approach provides a novel perspective to the important problem of ligand entry and exit.

  16. A Hamiltonian Replica Exchange Approach and Its Application to the Study of Side-Chain Type and Neighbor Effects on Peptide Backbone Conformations.

    Science.gov (United States)

    Xu, Chao; Wang, Jun; Liu, Haiyan

    2008-08-01

    We presented a Hamiltonian replica exchange approach and applied it to investigate the effects of various factors on the conformational equilibrium of peptide backbone. In different replicas, biasing potentials of varying strengths are applied to all backbone (φ,ψ) torsional angle pairs to overcome sampling barriers. A general form of constructing biasing potentials based on a reference free energy surface is employed to minimize sampling in physically irrelevant parts of the conformational space. An extension of the weighted histogram analysis formulation allows for conformational free energy surfaces to be computed using all replicas, including those with biased Hamiltonians. This approach can significantly reduce the statistical uncertainties in computed free energies. For the peptide systems considered, it allows for effects of the order of 0.5-1 kJ/mol to be quantified using explicit solvent simulations. We applied this approach to capped peptides of 2-5 peptide units containing Ala, Phe, or Val in explicit water solvent and focused on how the conformational equilibrium of a single pair of backbone angles are influenced by changing the residue types of the same and neighboring residues as well as conformations of neighboring residues. For the effects of changing side-chain types of the same residue, our results consistently showed increased preference of β for Phe and Val relative to Ala. As for neighbor effects, our results not only indicated that they can be as large as the effects of changing the side-chain type of the same residue but also led to several new insights. We found that for the N-terminal neighbors, their conformations seem to have large effects. Relative to the β conformer of an N-terminal neighbor, its α conformer stabilizes the β conformer of its next Ala disregarding the residue type of the neighbor. For C-terminal neighbors, their chemical identities seem to play more important roles. Val as the C-terminal neighbor significantly

  17. Dynamical interpretation of nonrelativistic conformal groups

    International Nuclear Information System (INIS)

    Andrzejewski, K.; Gonera, J.

    2013-01-01

    It is shown that N-Galilean conformal algebra with N odd and nontrivial central charge is the maximal symmetry algebra for higher derivative free theory both on classical and quantum levels. By maximal symmetry algebra the Lie algebra of the maximal group of space–time symmetry transformations is understood which preserves higher order free dynamics

  18. Dynamic simulations of the molecular conformations of wild type and mutant xanthan polymers suggest that conformational differences may contribute to observed differences in viscosity.

    Science.gov (United States)

    Levy, S; Schuyler, S C; Maglothin, R K; Staehelin, L A

    1996-02-01

    Xanthan gum is an exopolysaccharide secreted by the bacterium Xanthamonas campestris whose ability to make solutions viscous at low concentrations and over a pH and temperature range have generated much interest in both academic and industrial environments. Mutant Xanthamonas strains have been derived that produce xanthan gums with an altered or variant subunit chemical structure and different measured viscosities when compared with the wild type (wt) form of the polymer. Two variant gums were targeted as potentially interesting in this study, these being the nonacetylated tetramer (natet) and the acetylated tetramer (atet), which both lack a side-chain terminal mannose residue and in one case (natet) lacks an acetate group on an internal mannose residue. Solutions of these tetrameric gums possess viscosities higher (natet) and lower (atet) than the wt gum, and therefore we have attempted to determine whether these molecules possess unique conformational preferences when compared with the wt and with each other. In this manner we can initiate an understanding of how a polysaccharide's conformation contributes to its solution properties. The GEGOP software permits a sampling of the static and dynamic equilibrium states of carbohydrate molecules, and this software was employed to calculate equilibrium states of representative oligosaccharides with chemical structures representative of xanthan-like molecules. Energy minimization techniques revealed similar local minima for all three molecules. Some of these minima are comprised of elongate backbone conformations (A type) in which side chains fold onto backbone surfaces. Other minima with A backbones possessed side chains in less intimate backbone contact especially when calculations were performed with a low dielectric constant. This phenomenon was particularly pronounced in the wt molecule where an increased number of negatively charged side-chain residues experience charge repulsion resulting in reduced side-chain-backbone

  19. Hierarchical Conformational Analysis of Native Lysozyme Based on Sub-Millisecond Molecular Dynamics Simulations.

    Directory of Open Access Journals (Sweden)

    Kai Wang

    Full Text Available Hierarchical organization of free energy landscape (FEL for native globular proteins has been widely accepted by the biophysics community. However, FEL of native proteins is usually projected onto one or a few dimensions. Here we generated collectively 0.2 milli-second molecular dynamics simulation trajectories in explicit solvent for hen egg white lysozyme (HEWL, and carried out detailed conformational analysis based on backbone torsional degrees of freedom (DOF. Our results demonstrated that at micro-second and coarser temporal resolutions, FEL of HEWL exhibits hub-like topology with crystal structures occupying the dominant structural ensemble that serves as the hub of conformational transitions. However, at 100 ns and finer temporal resolutions, conformational substates of HEWL exhibit network-like topology, crystal structures are associated with kinetic traps that are important but not dominant ensembles. Backbone torsional state transitions on time scales ranging from nanoseconds to beyond microseconds were found to be associated with various types of molecular interactions. Even at nanoseconds temporal resolution, the number of conformational substates that are of statistical significance is quite limited. These observations suggest that detailed analysis of conformational substates at multiple temporal resolutions is both important and feasible. Transition state ensembles among various conformational substates at microsecond temporal resolution were observed to be considerably disordered. Life times of these transition state ensembles are found to be nearly independent of the time scales of the participating torsional DOFs.

  20. A Dynamic Epistemic Framework for Conformant Planning

    Directory of Open Access Journals (Sweden)

    Quan Yu

    2016-06-01

    Full Text Available In this paper, we introduce a lightweight dynamic epistemic logical framework for automated planning under initial uncertainty. We reduce plan verification and conformant planning to model checking problems of our logic. We show that the model checking problem of the iteration-free fragment is PSPACE-complete. By using two non-standard (but equivalent semantics, we give novel model checking algorithms to the full language and the iteration-free language.

  1. Conformational dynamics data bank: a database for conformational dynamics of proteins and supramolecular protein assemblies.

    Science.gov (United States)

    Kim, Do-Nyun; Altschuler, Josiah; Strong, Campbell; McGill, Gaël; Bathe, Mark

    2011-01-01

    The conformational dynamics data bank (CDDB, http://www.cdyn.org) is a database that aims to provide comprehensive results on the conformational dynamics of high molecular weight proteins and protein assemblies. Analysis is performed using a recently introduced coarse-grained computational approach that is applied to the majority of structures present in the electron microscopy data bank (EMDB). Results include equilibrium thermal fluctuations and elastic strain energy distributions that identify rigid versus flexible protein domains generally, as well as those associated with specific functional transitions, and correlations in molecular motions that identify molecular regions that are highly coupled dynamically, with implications for allosteric mechanisms. A practical web-based search interface enables users to easily collect conformational dynamics data in various formats. The data bank is maintained and updated automatically to include conformational dynamics results for new structural entries as they become available in the EMDB. The CDDB complements static structural information to facilitate the investigation and interpretation of the biological function of proteins and protein assemblies essential to cell function.

  2. Backbone dynamics of the EIAV-Tat protein from 15N relaxation studies

    International Nuclear Information System (INIS)

    Ejchart, A.; Herrmann, F.; Roesch, P.; Sticht, H.; Willbold, D.

    1994-01-01

    The work investigates the mobility of EIAV-Tat protein backbone by measuring the relaxation parameters of the 15 N nitrogens. High degree of the flexibility, non-typical of rigid, well structured proteins was shown

  3. Backbone dynamics of reduced plastocyanin from the cyanobacterium Anabaena variabilis: Regions involved in electron transfer have enhanced mobility

    DEFF Research Database (Denmark)

    Ma, L.X.; Hass, M.A.S.; Vierick, N.

    2003-01-01

    The dynamics of the backbone of the electron-transfer protein plastocyanin from the cyanobacterium Anabaena variabilis were determined from the N-15 and C-13(alpha) R-1 and R-2) relaxation rates and steady-state [H-1]-N-15 and [H-1]-C-13 nuclear Overhauser effects (NOEs) using the model-free appr......The dynamics of the backbone of the electron-transfer protein plastocyanin from the cyanobacterium Anabaena variabilis were determined from the N-15 and C-13(alpha) R-1 and R-2) relaxation rates and steady-state [H-1]-N-15 and [H-1]-C-13 nuclear Overhauser effects (NOEs) using the model...... are the "northern" hydrophobic site close to the metal site, the metal site itself, and the "eastern" face of the molecule. In particular, the mobility of the latter region is interesting in light of recent findings indicating that residues also on the eastern face of plastocyanins from prokaryotes are important...

  4. Solution structure and backbone dynamics of recombinant Cucurbita maxima trypsin inhibitor-V determined by NMR spectroscopy.

    Science.gov (United States)

    Liu, J; Prakash, O; Cai, M; Gong, Y; Huang, Y; Wen, L; Wen, J J; Huang, J K; Krishnamoorthi, R

    1996-02-06

    The solution structure of recombinant Cucurbita maxima trypsin inhibitor-V (rCMTI-V), whose N-terminal is unacetylated and carries an extra glycine residue, was determined by means of two-dimensional (2D) homo and 3D hetero NMR experiments in combination with a distance geometry and simulated annealing algorithm. A total of 927 interproton distances and 123 torsion angle constraints were utilized to generate 18 structures. The root mean squared deviation (RMSD) of the mean structure is 0.53 A for main-chain atoms and 0.95 A for all the non-hydrogen atoms of residues 3-40 and 49-67. The average structure of rCMTI-V is found to be almost the same as that of the native protein [Cai, M., Gong, Y., Kao, J.-L., & Krishnamoorthi, R. (1995) Biochemistry 34, 5201-5211]. The backbone dynamics of uniformly 15N-labeled rCMTI-V were characterized by 2D 1H-15N NMR methods. 15N spin-lattice and spin-spin relaxation rate constants (R1 and R2, respectively) and [1H]-15N steady-state heteronuclear Overhauser effect enhancements were measured for the peptide NH units and, using the model-free formalism [Lipari, G., & Szabo, A. (1982) J. Am. Chem. Soc. 104, 4546-4559, 4559-4570], the following parameters were determined: overall tumbling correlation time for the protein molecule (tau m), generalized order parameters for the individual N-H vectors (S2), effective correlation times for their internal motions (tau e), and terms to account for motions on a slower time scale (second) due to chemical exchange and/or conformational averaging (R(ex)). Most of the backbone NH groups of rCMTI-V are found to be highly constrained ((S2) = 0.83) with the exception of those in the binding loop (residues 41-48, (S2) = 0.71) and the N-terminal region ((S2) = 0.73). Main-chain atoms in these regions show large RMSD values in the average NMR structure. Residues involved in turns also appear to have more mobility ((S2) = 0.80). Dynamical properties of rCMTI-V were compared with those of two other

  5. Conformation analysis of trehalose. Molecular dynamics simulation and molecular mechanics

    International Nuclear Information System (INIS)

    Donnamaira, M.C.; Howard, E.I.; Grigera, J.R.

    1992-09-01

    Conformational analysis of the disaccharide trehalose is done by molecular dynamics and molecular mechanics. In spite of the different force fields used in each case, comparison between the molecular dynamics trajectories of the torsional angles of glycosidic linkage and energy conformational map shows a good agreement between both methods. By molecular dynamics it is observed a moderate mobility of the glycosidic linkage. The demands of computer time is comparable in both cases. (author). 6 refs, 4 figs

  6. Backbone dynamics of the EIAV-Tat protein from {sup 15}N relaxation studies

    Energy Technology Data Exchange (ETDEWEB)

    Ejchart, A.; Herrmann, F.; Roesch, P.; Sticht, H.; Willbold, D. [Bayreuth Univ., Bayreuth (Germany)

    1994-12-31

    The work investigates the mobility of EIAV-Tat protein backbone by measuring the relaxation parameters of the {sup 15}N nitrogens. High degree of the flexibility, non-typical of rigid, well structured proteins was shown. 3 refs, 2 figs.

  7. Backbone dynamics of reduced plastocyanin from the cyanobacterium Anabaena variabilis: Regions involved in electron transfer have enhanced mobility

    DEFF Research Database (Denmark)

    Ma, L.X.; Hass, M.A.S.; Vierick, N.

    2003-01-01

    The dynamics of the backbone of the electron-transfer protein plastocyanin from the cyanobacterium Anabaena variabilis were determined from the N-15 and C-13(alpha) R-1 and R-2) relaxation rates and steady-state [H-1]-N-15 and [H-1]-C-13 nuclear Overhauser effects (NOEs) using the model......-free approach. The C-13 relaxation studies were performed using C-13 in natural abundance. Overall, it is found that the protein backbone is rigid. However, the regions that are important for the function of the protein show moderate mobility primarily on the microsecond to millisecond time scale. These regions...... are the "northern" hydrophobic site close to the metal site, the metal site itself, and the "eastern" face of the molecule. In particular, the mobility of the latter region is interesting in light of recent findings indicating that residues also on the eastern face of plastocyanins from prokaryotes are important...

  8. Dynamical realizations of l-conformal Newton–Hooke group

    International Nuclear Information System (INIS)

    Galajinsky, Anton; Masterov, Ivan

    2013-01-01

    The method of nonlinear realizations and the technique previously developed in [A. Galajinsky, I. Masterov, Nucl. Phys. B 866 (2013) 212, (arXiv:1208.1403)] are used to construct a dynamical system without higher derivative terms, which holds invariant under the l-conformal Newton–Hooke group. A configuration space of the model involves coordinates, which parametrize a particle moving in d spatial dimensions and a conformal mode, which gives rise to an effective external field. The dynamical system describes a generalized multi-dimensional oscillator, which undergoes accelerated/decelerated motion in an ellipse in accord with evolution of the conformal mode. Higher derivative formulations are discussed as well. It is demonstrated that the multi-dimensional Pais–Uhlenbeck oscillator enjoys the l=3/2 -conformal Newton–Hooke symmetry for a particular choice of its frequencies

  9. Ras conformational switching: simulating nucleotide-dependent conformational transitions with accelerated molecular dynamics.

    Directory of Open Access Journals (Sweden)

    Barry J Grant

    2009-03-01

    Full Text Available Ras mediates signaling pathways controlling cell proliferation and development by cycling between GTP- and GDP-bound active and inactive conformational states. Understanding the complete reaction path of this conformational change and its intermediary structures is critical to understanding Ras signaling. We characterize nucleotide-dependent conformational transition using multiple-barrier-crossing accelerated molecular dynamics (aMD simulations. These transitions, achieved for the first time for wild-type Ras, are impossible to observe with classical molecular dynamics (cMD simulations due to the large energetic barrier between end states. Mapping the reaction path onto a conformer plot describing the distribution of the crystallographic structures enabled identification of highly populated intermediate structures. These structures have unique switch orientations (residues 25-40 and 57-75 intermediate between GTP and GDP states, or distinct loop3 (46-49, loop7 (105-110, and alpha5 C-terminus (159-166 conformations distal from the nucleotide-binding site. In addition, these barrier-crossing trajectories predict novel nucleotide-dependent correlated motions, including correlations of alpha2 (residues 66-74 with alpha3-loop7 (93-110, loop2 (26-37 with loop10 (145-151, and loop3 (46-49 with alpha5 (152-167. The interconversion between newly identified Ras conformations revealed by this study advances our mechanistic understanding of Ras function. In addition, the pattern of correlated motions provides new evidence for a dynamic linkage between the nucleotide-binding site and the membrane interacting C-terminus critical for the signaling function of Ras. Furthermore, normal mode analysis indicates that the dominant collective motion that occurs during nucleotide-dependent conformational exchange, and captured in aMD (but absent in cMD simulations, is a low-frequency motion intrinsic to the structure.

  10. Is DNA a nonlinear dynamical system where solitary conformational ...

    Indian Academy of Sciences (India)

    Unknown

    DNA is considered as a nonlinear dynamical system in which solitary conformational waves can be excited. The history of the approach, the main results, and arguments in favour and against are presented. Perspectives are discussed pertaining to studies of DNA's nonlinear properties. 1. Introduction. In recent years, many ...

  11. Is DNA a nonlinear dynamical system where solitary conformational ...

    Indian Academy of Sciences (India)

    Unknown

    DNA is considered as a nonlinear dynamical system in which solitary conformational waves can be excited. The history of the approach, the ..... nucleotides; K is the coupling constant along each strand;. R0 is the radius of DNA; a is .... Let us note that the system of equations (12)–(17) can be divided into two independent ...

  12. Dynamics of particles around time conformal Schwarzschild black hole

    Science.gov (United States)

    Jawad, Abdul; Ali, Farhad; Shahzad, M. Umair; Abbas, G.

    2016-11-01

    In this work, we present the new technique for discussing the dynamical motion of neutral as well as charged particles in the absence/presence of a magnetic field around the time conformal Schwarzschild black hole. Initially, we find the numerical solutions of geodesics of the Schwarzschild black hole and the time conformal Schwarzschild black hole. We observe that the Schwarzschild spacetime admits the time conformal factor e^{ɛ f(t)}, where f( t) is an arbitrary function and ɛ is very small, which causes a perturbation in the spacetimes. This technique also re-scales the energy content of spacetime. We also investigate the thermal stability, horizons and energy conditions corresponding to time conformal Schwarzschild spacetime. Also, we examine the dynamics of a neutral and charged particle around a time conformal Schwarzschild black hole. We investigate the circumstances under which the particle can escape from the vicinity of a black hole after collision with another particle. We analyze the effective potential and effective force of a particle in the presence of a magnetic field with angular momentum graphically.

  13. Solid State Nuclear Magnetic Resonance Investigation of Polymer Backbone Dynamics in Poly(Ethylene Oxide) Based Lithium and Sodium Polyether-ester-sulfonate Ionomers

    Energy Technology Data Exchange (ETDEWEB)

    Roach, David J.; Dou, Shichen; Colby, Ralph H.; Mueller, Karl T.

    2013-01-01

    Polymer backbone dynamics of single ion conducting poly(ethylene oxide) (PEO)-based ionomer samples with low glass transition temperatures (Tg) have been investigated using solid-state nuclear magnetic resonance (NMR). Experiments detecting 13C with 1H decoupling under magic angle spinning (MAS) conditions identified the different components of the polymer backbone (PEO spacer and isophthalate groups) and their relative mobilities for a suite of lithium- and sodium-containing ionomer samples with varying cation contents. Variable temperature (203-373 K) 1H-13C cross-polarization MAS (CP-MAS) experiments also provided qualitative assessment of the differences in the motions of the polymer backbone components as a function of cation content and identity. Each of the main backbone components exhibit distinct motions, following the trends expected for motional characteristics based on earlier Quasi Elastic Neutron Scattering and 1H spin-lattice relaxation rate measurements. Previous 1H and 7Li spin-lattice relaxation measurements focused on both the polymer backbone and cation motion on the nanosecond timescale. The studies presented here assess the slower timescale motion of the polymer backbone allowing for a more comprehensive understanding of the polymer dynamics. The temperature dependences of 13C linewidths were used to both qualitatively and quantitatively examine the effects of cation content and identity on PEO spacer mobility. Variable contact time 1H-13C CP-MAS experiments were used to further assess the motions of the polymer backbone on the microsecond timescale. The motion of the PEO spacer, reported via the rate of magnetization transfer from 1H to 13C nuclei, becomes similar for T ≳ 1.1 Tg in all ionic samples, indicating that at similar elevated reduced temperatures the motions of the polymer backbones on the microsecond timescale become insensitive to ion interactions. These results present an improved picture, beyond those of previous findings, for

  14. Dynamics of DNA conformations and DNA-protein interaction

    DEFF Research Database (Denmark)

    Metzler, R.; Ambjörnsson, T.; Lomholt, Michael Andersen

    2005-01-01

    Optical tweezers, atomic force microscopes, patch clamping, or fluorescence techniques make it possible to study both the equilibrium conformations and dynamics of single DNA molecules as well as their interaction with binding proteins. In this paper we address the dynamics of local DNA...... denaturation (bubble breathing), deriving its dynamic response to external physical parameters and the DNA sequence in terms of the bubble relaxation time spectrum and the autocorrelation function of bubble breathing. The interaction with binding proteins that selectively bind to the DNA single strand exposed...

  15. Dynamic conformational changes in munc18 prevent syntaxin binding.

    Directory of Open Access Journals (Sweden)

    Dana Bar-On

    2011-03-01

    Full Text Available The Sec1/munc18 protein family is essential for vesicle fusion in eukaryotic cells via binding to SNARE proteins. Protein kinase C modulates these interactions by phosphorylating munc18a thereby reducing its affinity to one of the central SNARE members, syntaxin-1a. The established hypothesis is that the reduced affinity of the phosphorylated munc18a to syntaxin-1a is a result of local electrostatic repulsion between the two proteins, which interferes with their compatibility. The current study challenges this paradigm and offers a novel mechanistic explanation by revealing a syntaxin-non-binding conformation of munc18a that is induced by the phosphomimetic mutations. In the present study, using molecular dynamics simulations, we explored the dynamics of the wild-type munc18a versus phosphomimetic mutant munc18a. We focused on the structural changes that occur in the cavity between domains 3a and 1, which serves as the main syntaxin-binding site. The results of the simulations suggest that the free wild-type munc18a exhibits a dynamic equilibrium between several conformations differing in the size of its cavity (the main syntaxin-binding site. The flexibility of the cavity's size might facilitate the binding or unbinding of syntaxin. In silico insertion of phosphomimetic mutations into the munc18a structure induces the formation of a conformation where the syntaxin-binding area is rigid and blocked as a result of interactions between residues located on both sides of the cavity. Therefore, we suggest that the reduced affinity of the phosphomimetic mutant/phosphorylated munc18a is a result of the closed-cavity conformation, which makes syntaxin binding energetically and sterically unfavorable. The current study demonstrates the potential of phosphorylation, an essential biological process, to serve as a driving force for dramatic conformational changes of proteins modulating their affinity to target proteins.

  16. Backbone dynamics of a biologically active human FGF-1 monomer, complexed to a hexasaccharide heparin-analogue, by {sup 15}N NMR relaxation methods

    Energy Technology Data Exchange (ETDEWEB)

    Canales-Mayordomo, Angeles; Fayos, Rosa [Centro de Investigaciones Biologicas, CSIC, Departamento de Estructura y Funcion de Proteinas (Spain); Angulo, Jesus; Ojeda, Rafael [Instituto de Investigaciones Quimicas, CSIC, Grupo de Carbohidratos (Spain); Martin-Pastor, Manuel [Unidad de RM y Unidad de RMN de Biomoleculas Asociada al CSIC, Laboratorio de Estructura e Estructura de Biomoleculas Jose Carracido (Spain); Nieto, Pedro M.; Martin-Lomas, Manuel [Instituto de Investigaciones Quimicas, CSIC, Grupo de Carbohidratos (Spain); Lozano, Rosa; Gimenez-Gallego, Guillermo; Jimenez-Barbero, Jesus [Centro de Investigaciones Biologicas, CSIC, Departamento de Estructura y Funcion de Proteinas (Spain)], E-mail: jjbarbero@cib.csic.es

    2006-08-15

    The binding site and backbone dynamics of a bioactive complex formed by the acidic fibroblast growth factor (FGF-1) and a specifically designed heparin hexasaccharide has been investigated by HSQC and relaxation NMR methods. The comparison of the relaxation data for the free and bound states has allowed showing that the complex is monomeric, and still induces mutagenesis, and that the protein backbone presents reduced motion in different timescale in its bound state, except in certain points that are involved in the interaction with the fibroblast growth factor receptor (FGFR)

  17. Backbone dynamics of a biologically active human FGF-1 monomer, complexed to a hexasaccharide heparin-analogue, by 15N NMR relaxation methods

    International Nuclear Information System (INIS)

    Canales-Mayordomo, Angeles; Fayos, Rosa; Angulo, Jesus; Ojeda, Rafael; Martin-Pastor, Manuel; Nieto, Pedro M.; Martin-Lomas, Manuel; Lozano, Rosa; Gimenez-Gallego, Guillermo; Jimenez-Barbero, Jesus

    2006-01-01

    The binding site and backbone dynamics of a bioactive complex formed by the acidic fibroblast growth factor (FGF-1) and a specifically designed heparin hexasaccharide has been investigated by HSQC and relaxation NMR methods. The comparison of the relaxation data for the free and bound states has allowed showing that the complex is monomeric, and still induces mutagenesis, and that the protein backbone presents reduced motion in different timescale in its bound state, except in certain points that are involved in the interaction with the fibroblast growth factor receptor (FGFR)

  18. Dynamic neutron scattering from conformational dynamics. II. Application using molecular dynamics simulation and Markov modeling.

    Science.gov (United States)

    Yi, Zheng; Lindner, Benjamin; Prinz, Jan-Hendrik; Noé, Frank; Smith, Jeremy C

    2013-11-07

    Neutron scattering experiments directly probe the dynamics of complex molecules on the sub pico- to microsecond time scales. However, the assignment of the relaxations seen experimentally to specific structural rearrangements is difficult, since many of the underlying dynamical processes may exist on similar timescales. In an accompanying article, we present a theoretical approach to the analysis of molecular dynamics simulations with a Markov State Model (MSM) that permits the direct identification of structural transitions leading to each contributing relaxation process. Here, we demonstrate the use of the method by applying it to the configurational dynamics of the well-characterized alanine dipeptide. A practical procedure for deriving the MSM from an MD is introduced. The result is a 9-state MSM in the space of the backbone dihedral angles and the side-chain methyl group. The agreement between the quasielastic spectrum calculated directly from the atomic trajectories and that derived from the Markov state model is excellent. The dependence on the wavevector of the individual Markov processes is described. The procedure means that it is now practicable to interpret quasielastic scattering spectra in terms of well-defined intramolecular transitions with minimal a priori assumptions as to the nature of the dynamics taking place.

  19. Jet-medium interaction and conformal relativistic fluid dynamics

    Science.gov (United States)

    Yan, Li; Jeon, Sangyong; Gale, Charles

    2018-03-01

    A formalism to study the mode-by-mode response to the energy deposition of external hard partons propagating in a relativistic fluid is developed, based on a semianalytical solution of conformal fluid dynamics. The soft-particle production resulting from the jet-medium interaction is calculated, and the recoil of the viscous medium is studied for different orientations of the relativistic jets and for different values of the specific shear viscosity η /s .

  20. Temperature-dependent spectral density analysis applied to monitoring backbone dynamics of major urinary protein-I complexed with the pheromone 2-sec-butyl-4,5-dihydrothiazole

    International Nuclear Information System (INIS)

    Backbone dynamics of mouse major urinary protein I (MUP-I) was studied by 15 N NMR relaxation. Data were collected at multiple temperatures for a complex of MUP-I with its natural pheromonal ligand, 2-sec-4,5-dihydrothiazole, and for the free protein. The measured relaxation rates were analyzed using the reduced spectral density mapping. Graphical analysis of the spectral density values provided an unbiased qualitative picture of the internal motions. Varying temperature greatly increased the range of analyzed spectral density values and therefore improved reliability of the analysis. Quantitative parameters describing the dynamics on picosecond to nanosecond time scale were obtained using a novel method of simultaneous data fitting at multiple temperatures. Both methods showed that the backbone flexibility on the fast time scale is slightly increased upon pheromone binding, in accordance with the previously reported results. Zero-frequency spectral density values revealed conformational changes on the microsecond to millisecond time scale. Measurements at different temperatures allowed to monitor temperature depencence of the motional parameters

  1. Energies and 2 '-Hydroxyl Group Orientations of RNA Backbone Conformations. Benchmark CCSD(T)/CBS Database, Electronic Analysis, and Assessment of DFT Methods and MD Simulations

    Czech Academy of Sciences Publication Activity Database

    Mládek, Arnošt; Banáš, P.; Jurečka, P.; Otyepka, M.; Zgarbová, M.; Šponer, Jiří

    2014-01-01

    Roč. 10, č. 1 (2014), s. 463-480 ISSN 1549-9618 R&D Projects: GA ČR(CZ) GAP208/12/1878; GA MŠk(CZ) ED1.1.00/02.0068 Institutional support: RVO:68081707 Keywords : DENSITY-FUNCTIONAL THEORY * SUGAR-PHOSPHATE BACKBONE * QUANTUM-CHEMICAL CALCULATIONS Subject RIV: BO - Biophysics Impact factor: 5.498, year: 2014

  2. Conformal Dynamics for TeV Physics and Cosmology

    DEFF Research Database (Denmark)

    Sannino, Francesco

    2009-01-01

    We introduce the topic of dynamical breaking of the electroweak symmetry and its link to unparticle physics and cosmology. The knowledge of the phase diagram of strongly coupled theories plays a fundamental role when trying to construct viable extensions of the standard model (SM). Therefore we...... of these complex models appears here for the first time. We will introduce recent extensions of the SM featuring minimal conformal gauge theories known as minimal walking models. Finally we will discuss the electroweak phase transition at nonzero temperature for models of dynamical electroweak symmetry breaking....

  3. Exploration of the Conformational Dynamics of Major Histocompatibility Complex Molecules.

    Science.gov (United States)

    Yanaka, Saeko; Sugase, Kenji

    2017-01-01

    Major histocompatibility complex (MHC) molecules are loaded with a wide variety of self- and non-self-peptides in their binding grooves and present these to T cell receptors (TCRs) in order to activate the adaptive immune system. A large number of crystal structures of different MHC alleles with different bound peptides have been determined, and they have been found to be quite similar to one another regardless of the bound peptide sequence. The structures do not change markedly even when forming complexes with TCRs. Nonetheless, the degree of TCR activation does differ markedly depending on the peptide presented by the MHC. Recent structural studies in solution rather than as crystals have suggested that the conformational dynamics of MHC molecules may be responsible for the MHC stability differences. Furthermore, it was shown that the conformational dynamics of MHC molecules is important for peptide loading and presentation to TCR. Here, we describe the static and dynamic structures of MHC molecules and appropriate methods to analyze them. We focus particularly on nuclear magnetic resonance (NMR), one of the most powerful tools to study dynamic properties of proteins. The number of such studies in the literature is limited, but in this review, we show that NMR is valuable for elucidating the structural dynamics of MHC molecules.

  4. The conformational dynamics of the mitochondrial Hsp70 chaperone.

    Science.gov (United States)

    Mapa, Koyeli; Sikor, Martin; Kudryavtsev, Volodymyr; Waegemann, Karin; Kalinin, Stanislav; Seidel, Claus A M; Neupert, Walter; Lamb, Don C; Mokranjac, Dejana

    2010-04-09

    Heat shock proteins 70 (Hsp70) represent a ubiquitous and conserved family of molecular chaperones involved in a plethora of cellular processes. The dynamics of their ATP hydrolysis-driven and cochaperone-regulated conformational cycle are poorly understood. We used fluorescence spectroscopy to analyze, in real time and at single-molecule resolution, the effects of nucleotides and cochaperones on the conformation of Ssc1, a mitochondrial member of the family. We report that the conformation of its ADP state is unexpectedly heterogeneous, in contrast to a uniform ATP state. Substrates are actively involved in determining the conformation of Ssc1. The J protein Mdj1 does not interact transiently with the chaperone, as generally believed, but rather is released slowly upon ATP hydrolysis. Analysis of the major bacterial Hsp70 revealed important differences between highly homologous members of the family, possibly explaining tuning of Hsp70 chaperones to meet specific functions in different organisms and cellular compartments. 2010 Elsevier Inc. All rights reserved.

  5. Conformity of LINAC-Based Stereotactic Radiosurgery Using Dynamic Conformal Arcs and Micro-Multileaf Collimator

    International Nuclear Information System (INIS)

    Hazard, Lisa J.; Wang, Brian; Skidmore, Thomas B.; Chern, Shyh-Shi; Salter, Bill J.; Jensen, Randy L.; Shrieve, Dennis C.

    2009-01-01

    Purpose: To assess the conformity of dynamic conformal arc linear accelerator-based stereotactic radiosurgery and to describe a standardized method of isodose surface (IDS) selection. Methods and Materials: In 174 targets, the conformity index (CI) at the prescription IDS used for treatment was calculated as CI = (PIV/PVTV)/(PVTV/TV), where TV is the target volume, PIV (prescription isodose volume) is the total volume encompassed by the prescription IDS, and PVTV is the TV encompassed by the IDS. In addition, a 'standardized' prescription IDS (sIDS) was chosen according to the following criteria: 95% of the TV was encompassed by the PIV and 99% of TV was covered by 95% of the prescription dose. The CIs at the sIDS were also calculated. Results: The median CI at the prescription IDS and sIDS was 1.63 and 1.47, respectively (p < 0.001). In 132 of 174 cases, the volume of normal tissue in the PIV was reduced by the prescription to the sIDS compared with the prescription IDS, in 20 cases it remained unchanged, and in 22 cases it was increased. Conclusion: The CIs obtained with linear accelerator-based stereotactic radiosurgery are comparable to those previously reported for gamma knife stereotactic radiosurgery. Using a uniform method to select the sIDS, adequate target coverage was usually achievable with prescription to an IDS greater than that chosen by the treating physician (prescription IDS), providing sparing of normal tissue. Thus, the sIDS might aid physicians in identifying a prescription IDS that balances coverage and conformity

  6. MERA: a webserver for evaluating backbone torsion angle distributions in dynamic and disordered proteins from NMR data

    Energy Technology Data Exchange (ETDEWEB)

    Mantsyzov, Alexey B. [M.V. Lomonosov Moscow State University, Faculty of Fundamental Medicine (Russian Federation); Shen, Yang; Lee, Jung Ho [National Institutes of Health, Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases (United States); Hummer, Gerhard [Max Planck Institute of Biophysics (Germany); Bax, Ad, E-mail: bax@nih.gov [National Institutes of Health, Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases (United States)

    2015-09-15

    MERA (Maximum Entropy Ramachandran map Analysis from NMR data) is a new webserver that generates residue-by-residue Ramachandran map distributions for disordered proteins or disordered regions in proteins on the basis of experimental NMR parameters. As input data, the program currently utilizes up to 12 different parameters. These include three different types of short-range NOEs, three types of backbone chemical shifts ({sup 15}N, {sup 13}C{sup α}, and {sup 13}C′), six types of J couplings ({sup 3}J{sub HNHα}, {sup 3}J{sub C′C′}, {sup 3}J{sub C′Hα}, {sup 1}J{sub HαCα}, {sup 2}J{sub CαN} and {sup 1}J{sub CαN}), as well as the {sup 15}N-relaxation derived J(0) spectral density. The Ramachandran map distributions are reported in terms of populations of their 15° × 15° voxels, and an adjustable maximum entropy weight factor is available to ensure that the obtained distributions will not deviate more from a newly derived coil library distribution than required to account for the experimental data. MERA output includes the agreement between each input parameter and its distribution-derived value. As an application, we demonstrate performance of the program for several residues in the intrinsically disordered protein α-synuclein, as well as for several static and dynamic residues in the folded protein GB3.

  7. Solution NMR Structures of Oxidized and Reduced Ehrlichia chaffeensis thioredoxin: NMR-Invisible Structure Owing to Backbone Dynamics

    Energy Technology Data Exchange (ETDEWEB)

    Buchko, Garry W.; Hewitt, Stephen N.; Van Voorhis, Wesley C.; Myler, Peter J.

    2018-01-02

    Thioredoxins (Trxs) are small ubiquitous proteins that participate in a diverse variety of redox reactions via the reversible oxidation of two cysteine thiol groups in a structurally conserved active site, CGPC. Here, we describe the NMR solution structures of a Trx from Ehrlichia chaffeensis (Ec-Trx, ECH_0218), the etiological agent responsible for human monocytic ehrlichiosis, in both the oxidized and reduced states. The overall topology of the calculated structures is similar in both redox states and similar to other Trx structures, a five-strand, mixed -sheet (1:3:2:4:5) surrounded by four -helices. Unlike other Trxs studied by NMR in both redox states, the 1H-15N HSQC spectra of reduced Ec-Trx was missing eight amide cross peaks relative to the spectra of oxidized Ec-Trx. These missing amides correspond to residues C32-E39 in the active site containing helix (2) and S72-I75 in a loop near the active site and suggest a substantial change in the backbone dynamics associated with the formation of an intramolecular C32-C35 disulfide bond.

  8. Extracting Markov Models of Peptide Conformational Dynamics from Simulation Data.

    Science.gov (United States)

    Schultheis, Verena; Hirschberger, Thomas; Carstens, Heiko; Tavan, Paul

    2005-07-01

    A high-dimensional time series obtained by simulating a complex and stochastic dynamical system (like a peptide in solution) may code an underlying multiple-state Markov process. We present a computational approach to most plausibly identify and reconstruct this process from the simulated trajectory. Using a mixture of normal distributions we first construct a maximum likelihood estimate of the point density associated with this time series and thus obtain a density-oriented partition of the data space. This discretization allows us to estimate the transfer operator as a matrix of moderate dimension at sufficient statistics. A nonlinear dynamics involving that matrix and, alternatively, a deterministic coarse-graining procedure are employed to construct respective hierarchies of Markov models, from which the model most plausibly mapping the generating stochastic process is selected by consideration of certain observables. Within both procedures the data are classified in terms of prototypical points, the conformations, marking the various Markov states. As a typical example, the approach is applied to analyze the conformational dynamics of a tripeptide in solution. The corresponding high-dimensional time series has been obtained from an extended molecular dynamics simulation.

  9. Structure and conformational dynamics of scaffolded DNA origami nanoparticles.

    Science.gov (United States)

    Pan, Keyao; Bricker, William P; Ratanalert, Sakul; Bathe, Mark

    2017-06-20

    Synthetic DNA is a highly programmable nanoscale material that can be designed to self-assemble into 3D structures that are fully determined by underlying Watson-Crick base pairing. The double crossover (DX) design motif has demonstrated versatility in synthesizing arbitrary DNA nanoparticles on the 5-100 nm scale for diverse applications in biotechnology. Prior computational investigations of these assemblies include all-atom and coarse-grained modeling, but modeling their conformational dynamics remains challenging due to their long relaxation times and associated computational cost. We apply all-atom molecular dynamics and coarse-grained finite element modeling to DX-based nanoparticles to elucidate their fine-scale and global conformational structure and dynamics. We use our coarse-grained model with a set of secondary structural motifs to predict the equilibrium solution structures of 45 DX-based DNA origami nanoparticles including a tetrahedron, octahedron, icosahedron, cuboctahedron and reinforced cube. Coarse-grained models are compared with 3D cryo-electron microscopy density maps for these five DNA nanoparticles and with all-atom molecular dynamics simulations for the tetrahedron and octahedron. Our results elucidate non-intuitive atomic-level structural details of DX-based DNA nanoparticles, and offer a general framework for efficient computational prediction of global and local structural and mechanical properties of DX-based assemblies that are inaccessible to all-atom based models alone. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

  10. Conformational dynamics of amyloid proteins at the aqueous interface

    Science.gov (United States)

    Armbruster, Matthew; Horst, Nathan; Aoki, Brendy; Malik, Saad; Soto, Patricia

    2013-03-01

    Amyloid proteins is a class of proteins that exhibit distinct monomeric and oligomeric conformational states hallmark of deleterious neurological diseases for which there are not yet cures. Our goal is to examine the extent of which the aqueous/membrane interface modulates the folding energy landscape of amyloid proteins. To this end, we probe the dynamic conformational ensemble of amyloids (monomer prion protein and Alzheimer's Ab protofilaments) interacting with model bilayers. We will present the results of our coarse grain molecular modeling study in terms of the existence of preferential binding spots of the amyloid to the bilayer and the response of the bilayer to the interaction with the amyloid. NSF Nebraska EPSCoR First Award

  11. 1H, 13C, 15N backbone NMR assignments of the Staphylococcus aureus small multidrug-resistance pump (Smr) in a functionally active conformation.

    Science.gov (United States)

    Poget, Sébastien F; Harris, Richard; Cahill, Sean M; Girvin, Mark E

    2010-10-01

    The plasmid-encoded small multidrug resistance pump from S. aureus transports a variety of quaternary ammonium and other hydrophobic compounds, enhancing the bacterial host's resistance to common hospital disinfectants. The protein folds as a homo-dimer of four transmembrane helices each, and appears to be fully functional only in lipid bilayers. Here we report the backbone resonance assignments and implied secondary structure for (2)H(13)C(15)N Smr reconstituted into lipid bicelles. Significant changes were observed between the chemical shifts of the protein in lipid bicelles compared to those in detergent micelles.

  12. Dynamics of DNA conformations and DNA-protein interaction

    DEFF Research Database (Denmark)

    Metzler, R.; Ambjörnsson, T.; Lomholt, Michael Andersen

    2005-01-01

    denaturation (bubble breathing), deriving its dynamic response to external physical parameters and the DNA sequence in terms of the bubble relaxation time spectrum and the autocorrelation function of bubble breathing. The interaction with binding proteins that selectively bind to the DNA single strand exposed......Optical tweezers, atomic force microscopes, patch clamping, or fluorescence techniques make it possible to study both the equilibrium conformations and dynamics of single DNA molecules as well as their interaction with binding proteins. In this paper we address the dynamics of local DNA...... in a denaturation bubble are shown to involve an interesting competition of time scales, varying between kinetic blocking of protein binding up to full binding protein-induced denaturation of the DNA. We will also address the potential to use DNA physics for the design of nanosensors. Finally, we report recent...

  13. Microsecond molecular dynamics simulation shows effect of slow loop dynamics on backbone amide order parameters of proteins

    DEFF Research Database (Denmark)

    Maragakis, Paul; Lindorff-Larsen, Kresten; Eastwood, Michael P

    2008-01-01

    . Molecular dynamics (MD) simulation provides a complementary approach to the study of protein dynamics on similar time scales. Comparisons between NMR spectroscopy and MD simulations can be used to interpret experimental results and to improve the quality of simulation-related force fields and integration...

  14. Structuring and sampling complex conformation space: Weighted ensemble dynamics simulations.

    Science.gov (United States)

    Gong, Linchen; Zhou, Xin

    2009-08-01

    Based on multiple simulation trajectories, which started from dispersively selected initial conformations, the weighted ensemble dynamics method is designed to robustly and systematically explore the hierarchical structure of complex conformational space through the spectral analysis of the variance-covariance matrix of trajectory-mapped vectors. The nondegenerate ground state of the matrix directly predicts the ergodicity of simulation data. The ground state could be adopted as statistical weights of trajectories to correctly reconstruct the equilibrium properties, even though each trajectory only explores part of the conformational space. Otherwise, the degree of degeneracy simply gives the number of metastable states of the system under the time scale of individual trajectory. Manipulation on the eigenvectors leads to the classification of trajectories into nontransition ones within the states and transition ones between them. The transition states may also be predicted without a priori knowledge of the system. We demonstrate the application of the general method both to the system with a one-dimensional glassy potential and with the one of alanine dipeptide in explicit solvent.

  15. Impact of arsenic/phosphorus substitution on the intrinsic conformational properties of the phosphodiester backbone of DNA investigated using ab initio quantum mechanical calculations.

    Science.gov (United States)

    Denning, Elizabeth J; Mackerell, Alexander D

    2011-04-20

    Deoxyribonucleic acid (DNA) is composed of five major elements carbon, hydrogen, nitrogen, oxygen, and phosphorus. The substitution of any of these elements in DNA would be anticipated to have major biological implications. However, recent studies have suggested that the substitution of arsenic into DNA (As-DNA) in bacteria may be possible. To help evaluate this possibility, ab initio quantum mechanical calculations are used to show that arsenodiester and phosphodiester linkages have similar geometric and conformational properties. Based on these results, it is suggested that the As-DNA will have similar conformational properties to phosphorus-based DNA, including the maintenance of base stacking.

  16. Social influences in opinion dynamics: The role of conformity

    Science.gov (United States)

    Javarone, Marco Alberto

    2014-11-01

    We study the effects of social influences in opinion dynamics. In particular, we define a simple model, based on the majority rule voting, in order to consider the role of conformity. Conformity is a central issue in social psychology as it represents one of people’s behaviors that emerges as a result of their interactions. The proposed model represents agents, arranged in a network and provided with an individual behavior, that change opinion in function of those of their neighbors. In particular, agents can behave as conformists or as nonconformists. In the former case, agents change opinion in accordance with the majority of their social circle (i.e., their neighbors); in the latter case, they do the opposite, i.e., they take the minority opinion. Moreover, we investigate the nonconformity both on a global and on a local perspective, i.e., in relation to the whole population and to the social circle of each nonconformist agent, respectively. We perform a computational study of the proposed model, with the aim to observe if and how the conformity affects the related outcomes. Moreover, we want to investigate whether it is possible to achieve some kind of equilibrium, or of order, during the evolution of the system. Results highlight that the amount of nonconformist agents in the population plays a central role in these dynamics. In particular, conformist agents play the role of stabilizers in fully-connected networks, whereas the opposite happens in complex networks. Furthermore, by analyzing complex topologies of the agent network, we found that in the presence of radical nonconformist agents the topology of the system has a prominent role; otherwise it does not matter since we observed that a conformist behavior is almost always more convenient. Finally, we analyze the results of the model by considering that agents can change also their behavior over time, i.e., conformists can become nonconformists and vice versa.

  17. Temperature dependent conformation studies of Calmodulin Protein using Molecular Dynamics

    Science.gov (United States)

    Aneja, Sahil; Bhartiya, Vivek Kumar; Negi, Sunita

    2016-10-01

    Calmodulin (CaM) protein plays a very crucial role in the calcium signaling inside the eukaryotic cell structure [1, 2]. It can also bind to other proteins/targets and facilitate various activities inside the cell [3, 4]. Temperature dependent conformation changes in the CaM protein are studied with extensive molecular dynamics simulations. The quantitative comparison of simulation data with various forms of experimental results probing different aspects of the folding process can facilitate robust assessment of the accuracy of the calculations. It can also provide a detailed structural interpretation for the experimental observations as well as physical interpretation for theory behind different aspects of the experiment. Earlier these kinds of studies have been performed experimentally using fluorescence measurements as in [5]. The calcium bound form of CaM is observed to undergo a reversible conformation change in the range 295-301 K at calcium ion concentration 150 mM. The transition temperature was observed to depend on the calcium ion concentration of the protein. Leap-dynamics approach was used earlier to study the temperature dependent conformation change of CaM [6]. At 290 K, both the N- and C-lobes were stable, at 325 K, the C-lobe unfolds whereas at 360 both the lobes unfold [6]. In this work, we perform molecular dynamics simulations of 100 ns each for the temperatures 325 K and 375 K on the apo form of CaM, 3CLN and 1CFD. A remarkable dependence of the temperature is observed on the overall dynamics of both the forms of the protein as reported in our earlier study [7, 8]. 1CFD shows a much flexible linker as compared to 3CLN whereas the overall dynamics of the lobes mainly N-lobe is observed to be more in later case. Salt bridge formation between the residues 2 (ASP) and 148 (LYS) leads to a more compact form of 1CFD at 325 K. The unfolding of the protein is observed to increase with the increase in the temperature similar to the earlier reported

  18. a Combined Molecular Dynamics and NMR Spectroscopic Protocol for the Conformational Analysis of Oligosaccharides.

    Science.gov (United States)

    Varma, Vikram

    A combined experimental and theoretical protocol for the conformational analysis of oligosaccharides is presented. Three disaccharides, methyl alpha - scD-mannopyranosyl-(1 to 3)-alpha- scD-mannopyranoside, methyl beta- scD-galactopyranosyl-(1 to 4)-beta- scD-glucopyranoside, and propyl beta- scD-2-acetamido -2-deoxy glucopyranosyl-(1 to 3)- alpha- scL-rhamnopyranoside, are used to evaluate a protocol for conformational analysis that makes use of molecular dynamics calculations with the CHARMM force field. Dynamics trajectories computed in vacuo and in water are used to calculate time-averaged NMR parameters such as spin-lattice relaxation times (T_1 ), Nuclear Overhauser Enhancements (NOE), and heteronuclear spin-spin coupling constants (^3J _{rm CH}). The calculated NMR parameters are then compared to experimental values and used to evaluate the computational procedure. The energetically accessible conformations are effectively sampled by the simulations. The method has been extended to the conformational analysis of higher-order oligosaccharides corresponding to the cell-wall polysaccharide of the Streptococcus Group A, and the Shigella flexneri Y O-antigen. The Streptococcus Group A cell-wall polysaccharide is comprised of a backbone of rhamnopyranosyl units connected by alternating alpha- scL-(1 to 3) and alpha- scL -(1 to 2) linkages, to which are attached N-acetyl-beta- scD-glucosamine ( beta- scD-GlcpNAc) residues at the 3 positions of the rhamnose backbone.rm A&rm B^'qquad A^'& rm Bqquad Acr[{-alpha}{-}L{-}Rha {it p}{-}(1to2){-alpha }{-}L{-}Rha{it p} {-}(1to3){-alpha}{ -}L{-}Rha{it p}-(1to2) -alpha-L-Rha{it p}{-}(1 to3){-alpha}{-}L{- }Rha{it p}{-}cr&uparrow(1 to3)&uparrow(1to3)crbeta {-}D{-}&rm Glc{it p }NAcqquadbeta{-}D{-}& rm Glc{it p}NAccr&rm C ^'&rm C] A branched trisaccharide (A^' -(C)B), a tetrasaccharide (A^' -(C)B-A), a pentasaccharide (C^' -B^'-A ^'-(C)B), and two hexasaccharides (C^'-B^ '-A^' -(C)B-A) and (A-(C^')B ^'-A^' -(C)B), have been chosen

  19. Global brain dynamics during social exclusion predict subsequent behavioral conformity

    Science.gov (United States)

    Wasylyshyn, Nick; Hemenway Falk, Brett; Garcia, Javier O; Cascio, Christopher N; O’Donnell, Matthew Brook; Bingham, C Raymond; Simons-Morton, Bruce; Vettel, Jean M; Falk, Emily B

    2018-01-01

    Abstract Individuals react differently to social experiences; for example, people who are more sensitive to negative social experiences, such as being excluded, may be more likely to adapt their behavior to fit in with others. We examined whether functional brain connectivity during social exclusion in the fMRI scanner can be used to predict subsequent conformity to peer norms. Adolescent males (n = 57) completed a two-part study on teen driving risk: a social exclusion task (Cyberball) during an fMRI session and a subsequent driving simulator session in which they drove alone and in the presence of a peer who expressed risk-averse or risk-accepting driving norms. We computed the difference in functional connectivity between social exclusion and social inclusion from each node in the brain to nodes in two brain networks, one previously associated with mentalizing (medial prefrontal cortex, temporoparietal junction, precuneus, temporal poles) and another with social pain (dorsal anterior cingulate cortex, anterior insula). Using predictive modeling, this measure of global connectivity during exclusion predicted the extent of conformity to peer pressure during driving in the subsequent experimental session. These findings extend our understanding of how global neural dynamics guide social behavior, revealing functional network activity that captures individual differences. PMID:29529310

  20. Global brain dynamics during social exclusion predict subsequent behavioral conformity.

    Science.gov (United States)

    Wasylyshyn, Nick; Hemenway Falk, Brett; Garcia, Javier O; Cascio, Christopher N; O'Donnell, Matthew Brook; Bingham, C Raymond; Simons-Morton, Bruce; Vettel, Jean M; Falk, Emily B

    2018-02-01

    Individuals react differently to social experiences; for example, people who are more sensitive to negative social experiences, such as being excluded, may be more likely to adapt their behavior to fit in with others. We examined whether functional brain connectivity during social exclusion in the fMRI scanner can be used to predict subsequent conformity to peer norms. Adolescent males (n = 57) completed a two-part study on teen driving risk: a social exclusion task (Cyberball) during an fMRI session and a subsequent driving simulator session in which they drove alone and in the presence of a peer who expressed risk-averse or risk-accepting driving norms. We computed the difference in functional connectivity between social exclusion and social inclusion from each node in the brain to nodes in two brain networks, one previously associated with mentalizing (medial prefrontal cortex, temporoparietal junction, precuneus, temporal poles) and another with social pain (dorsal anterior cingulate cortex, anterior insula). Using predictive modeling, this measure of global connectivity during exclusion predicted the extent of conformity to peer pressure during driving in the subsequent experimental session. These findings extend our understanding of how global neural dynamics guide social behavior, revealing functional network activity that captures individual differences.

  1. Effect of hydrophobic groups on the adsorption conformation of modified polycarboxylate superplasticizer investigated by molecular dynamics simulation

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Hongxia [State Key Laboratory of High Performance Civil Engineering Materials, Nanjing 210008, Jiangsu (China); Jiangsu Sobute New Materials Co. Ltd., Nanjing 211103, Jiangsu (China); Wang, Yanwei, E-mail: wangyanwei@cnjsjk.cn [State Key Laboratory of High Performance Civil Engineering Materials, Nanjing 210008, Jiangsu (China); Jiangsu Sobute New Materials Co. Ltd., Nanjing 211103, Jiangsu (China); Yang, Yong; Shu, Xin; Yan, Han [State Key Laboratory of High Performance Civil Engineering Materials, Nanjing 210008, Jiangsu (China); Jiangsu Sobute New Materials Co. Ltd., Nanjing 211103, Jiangsu (China); Ran, Qianping, E-mail: qpran@cnjsjk.cn [State Key Laboratory of High Performance Civil Engineering Materials, Nanjing 210008, Jiangsu (China); Jiangsu Sobute New Materials Co. Ltd., Nanjing 211103, Jiangsu (China)

    2017-06-15

    Highlights: • Adsorption conformation of comb-like PCE was studied by all-atom MD simulations. • A comparison is made between vacuum-based and solution-based simulations. • Effects of hydrophobic modifications on adsorption properties are elucidated. - Abstract: All-atom molecular dynamics (MD) simulations were used to study the adsorption conformations of hydrophobically-modified comb-shaped polycarboxylate ether-based (PCE) superplasticizer molecules on a model surface of dicalcium silicate (C{sub 2}S) in vacuum and in an explicit solution, respectively. Three different hydrophobic modifying groups, namely, the ethyl group, the n-butyl group and the phenyl group, decorated to the backbone, were examined. Comparing the hydrophobically-modified PCEs to the unmodified one, differences were found in the binding energy, the adsorption conformation and the water density at the interface. The interaction between PCE molecules and C{sub 2}S was weakened in a solution with explicit solvents than that obtained from vacuum-based simulations. The presence of hydrophobic groups lowered the polymer-surface binding energy, decreased the radius of gyration (Rg) of the adsorbed polymer, increased the peak position in the heavy-atom density profiles in the direction perpendicular to the surface, and also caused the adsorbed conformations to be more globular in shape. The parallel and perpendicular components (relative to the surface plane) of the geometric sizes of the adsorbed polymers were calculated, and the results showed that the presence of hydrophobically modifying groups decreased the in-plane radius while increased the adsorption layer thickness compared to the unmodified control. The presence of PCEs perturbed the dense water layer above the C{sub 2}S surface and lowered the water density. Perturbations to the interfacial water density were found to correlate nicely with the adsorbed conformations of PCEs.

  2. Human EGF-derived direct and reverse short linear motifs: conformational dynamics insight into the receptor-binding residues.

    Science.gov (United States)

    Moldogazieva, Nurbubu T; Shaitan, Konstantin V; Antonov, Mikhail Yu; Mokhosoev, Innokenty M; Levtsova, Olga V; Terentiev, Alexander A

    2018-04-01

    Short linear motifs (SLiMs) have been recognized to perform diverse functions in a variety of regulatory proteins through the involvement in protein-protein interactions, signal transduction, cell cycle regulation, protein secretion, etc. However, detailed molecular mechanisms underlying their functions including roles of definite amino acid residues remain obscure. In our previous studies, we demonstrated that conformational dynamics of amino acid residues in oligopeptides derived from regulatory proteins such as alpha-fetoprotein (AFP), carcino-embryonic antigen (CEA), and pregnancy specific β1-glycoproteins (PSGs) contributes greatly to their biological activities. In the present work, we revealed the 22-member linear modules composed of direct and reverse AFP 14-20 -like heptapeptide motifs linked by CxxGY/FxGx consensus motif within epidermal growth factor (EGF), growth factors of EGF family and numerous regulatory proteins containing EGF-like modules. We showed, first, the existence of similarity in amino acid signatures of both direct and reverse motifs in terms of their physicochemical properties. Second, molecular dynamics (MD) simulation study demonstrated that key receptor-binding residues in human EGF in the aligned positions of the direct and reverse motifs may have similar distribution of conformational probability densities and dynamic behavior despite their distinct physicochemical properties. Third, we found that the length of a polypeptide chain (from 7 to 53 residues) has no effect, while disulfide bridging and backbone direction significantly influence the conformational distribution and dynamics of the residues. Our data may contribute to the atomic level structure-function analysis and protein structure decoding; additionally, they may provide a basis for novel protein/peptide engineering and peptide-mimetic drug design.

  3. Binary cluster collision dynamics and minimum energy conformations

    Energy Technology Data Exchange (ETDEWEB)

    Muñoz, Francisco [Max Planck Institute of Microstructure Physics, Weinberg 2, 06120 Halle (Germany); Departamento de Física, Facultad de Ciencias, Universidad de Chile, Santiago (Chile); Centro para el Desarrollo de la Nanociencia y Nanotecnología, CEDENNA, Avenida Ecuador 3493, Santiago (Chile); Rogan, José; Valdivia, J.A. [Departamento de Física, Facultad de Ciencias, Universidad de Chile, Santiago (Chile); Centro para el Desarrollo de la Nanociencia y Nanotecnología, CEDENNA, Avenida Ecuador 3493, Santiago (Chile); Varas, A. [Departamento de Física, Facultad de Ciencias, Universidad de Chile, Santiago (Chile); Nano-Bio Spectroscopy Group, ETSF Scientific Development Centre, Departamento de Física de Materiales, Universidad del País Vasco UPV/EHU, Av. Tolosa 72, E-20018 San Sebastián (Spain); Kiwi, Miguel, E-mail: m.kiwi.t@gmail.com [Departamento de Física, Facultad de Ciencias, Universidad de Chile, Santiago (Chile); Centro para el Desarrollo de la Nanociencia y Nanotecnología, CEDENNA, Avenida Ecuador 3493, Santiago (Chile)

    2013-10-15

    The collision dynamics of one Ag or Cu atom impinging on a Au{sub 12} cluster is investigated by means of DFT molecular dynamics. Our results show that the experimentally confirmed 2D to 3D transition of Au{sub 12}→Au{sub 13} is mostly preserved by the resulting planar Au{sub 12}Ag and Au{sub 12}Cu minimum energy clusters, which is quite remarkable in view of the excess energy, well larger than the 2D–3D potential barrier height. The process is accompanied by a large s−d hybridization and charge transfer from Au to Ag or Cu. The dynamics of the collision process mainly yields fusion of projectile and target, however scattering and cluster fragmentation also occur for large energies and large impact parameters. While Ag projectiles favor fragmentation, Cu favors scattering due to its smaller mass. The projectile size does not play a major role in favoring the fragmentation or scattering channels. By comparing our collision results with those obtained by an unbiased minimum energy search of 4483 Au{sub 12}Ag and 4483 Au{sub 12}Cu configurations obtained phenomenologically, we find that there is an extra bonus: without increase of computer time collisions yield the planar lower energy structures that are not feasible to obtain using semi-classical potentials. In fact, we conclude that phenomenological potentials do not even provide adequate seeds for the search of global energy minima for planar structures. Since the fabrication of nanoclusters is mainly achieved by synthesis or laser ablation, the set of local minima configurations we provide here, and their distribution as a function of energy, are more relevant than the global minimum to analyze experimental results obtained at finite temperatures, and is consistent with the dynamical coexistence of 2D and 3D liquid Au clusters conformations obtained previously.

  4. Conformational dynamics of free and catalytically active thermolysin are indistinguishable by hydrogen/deuterium exchange mass spectrometry.

    Science.gov (United States)

    Liu, Yu-Hong; Konermann, Lars

    2008-06-17

    Conformational dynamics are thought to be a prerequisite for the catalytic activity of enzymes. However, the exact relationship between structural fluctuations and function is not well understood. In this work hydrogen/deuterium exchange (HDX) and electrospray ionization mass spectrometry (ESI-MS) are used for exploring the conformational dynamics of thermolysin. Amide HDX reflects the internal mobility of proteins; regions that undergo frequent unfolding-refolding show faster exchange than segments that are highly stable. Thermolysin is a zinc protease with an active site that is located between two lobes. Substrate turnover is associated with hinge bending that leads to a closed conformation. Product release regenerates the open form, such that steady-state catalysis involves a continuous closing/opening cycle. HDX/ESI-MS with proteolytic peptide mapping in the absence of substrate shows that elements in the periphery of the two lobes are most mobile. A comparison with previous X-ray data suggests that these peripheral regions undergo quite pronounced structural changes during the catalytic cycle. In contrast, active site residues exhibit only a moderate degree of backbone flexibility, and the central zinc appears to be in a fairly rigid environment. The presence of both rigid and moderately flexible elements in the active site may reflect a carefully tuned balance that is required for function. Interestingly, the HDX behavior of catalytically active thermolysin is indistinguishable from that of the free enzyme. This result is consistent with the view that catalytically relevant motions preexist in the resting state and that enzyme function can only be performed within the limitations given by the intrinsic dynamics of the protein. The data presented in this work indicate the prevalence of stochastic elements in the function of thermolysin, rather than supporting a deterministic mechanism.

  5. A stochastic model of protein conformational dynamics and electronic-conformational coupling in biological energy transduction

    Science.gov (United States)

    Cartling, Bo

    1985-11-01

    The principles of biological energy transduction are discussed by means of a mathematical model of a donor-acceptor system of electron transfer enzymes in which electronic and conformational states are coupled. The internal nuclear motion of the enzymes is considered to be composed of transitions between local potential energy wells, which define conformational states, and vibrations within these. The conformational transitions are treated as a stochastic process of the diffusion type on a conformational potential energy surface. Dissipative processes are avoided by restricting electron transfer with respect to conformational states and molecular mechanisms of such electron gating are discussed. Different types of transient kinetics, determined by the relative rates of electronic and conformational transitions, are demonstrated in terms of probability density functions, which describe the probability for the system to be in different electronic and conformational states as a function of time. The experimental basis for the concepts and mechanisms introduced is discussed and further experiments are proposed. The applicability of the mathematical model to other systems is indicated.

  6. Effect of hydrophobic groups on the adsorption conformation of modified polycarboxylate superplasticizer investigated by molecular dynamics simulation

    Science.gov (United States)

    Zhao, Hongxia; Wang, Yanwei; Yang, Yong; Shu, Xin; Yan, Han; Ran, Qianping

    2017-06-01

    All-atom molecular dynamics (MD) simulations were used to study the adsorption conformations of hydrophobically-modified comb-shaped polycarboxylate ether-based (PCE) superplasticizer molecules on a model surface of dicalcium silicate (C2S) in vacuum and in an explicit solution, respectively. Three different hydrophobic modifying groups, namely, the ethyl group, the n-butyl group and the phenyl group, decorated to the backbone, were examined. Comparing the hydrophobically-modified PCEs to the unmodified one, differences were found in the binding energy, the adsorption conformation and the water density at the interface. The interaction between PCE molecules and C2S was weakened in a solution with explicit solvents than that obtained from vacuum-based simulations. The presence of hydrophobic groups lowered the polymer-surface binding energy, decreased the radius of gyration (Rg) of the adsorbed polymer, increased the peak position in the heavy-atom density profiles in the direction perpendicular to the surface, and also caused the adsorbed conformations to be more globular in shape. The parallel and perpendicular components (relative to the surface plane) of the geometric sizes of the adsorbed polymers were calculated, and the results showed that the presence of hydrophobically modifying groups decreased the in-plane radius while increased the adsorption layer thickness compared to the unmodified control. The presence of PCEs perturbed the dense water layer above the C2S surface and lowered the water density. Perturbations to the interfacial water density were found to correlate nicely with the adsorbed conformations of PCEs.

  7. Dynamic neutron scattering from conformational dynamics. I. Theory and Markov models.

    Science.gov (United States)

    Lindner, Benjamin; Yi, Zheng; Prinz, Jan-Hendrik; Smith, Jeremy C; Noé, Frank

    2013-11-07

    The dynamics of complex molecules can be directly probed by inelastic neutron scattering experiments. However, many of the underlying dynamical processes may exist on similar timescales, which makes it difficult to assign processes seen experimentally to specific structural rearrangements. Here, we show how Markov models can be used to connect structural changes observed in molecular dynamics simulation directly to the relaxation processes probed by scattering experiments. For this, a conformational dynamics theory of dynamical neutron and X-ray scattering is developed, following our previous approach for computing dynamical fingerprints of time-correlation functions [F. Noé, S. Doose, I. Daidone, M. Löllmann, J. Chodera, M. Sauer, and J. Smith, Proc. Natl. Acad. Sci. U.S.A. 108, 4822 (2011)]. Markov modeling is used to approximate the relaxation processes and timescales of the molecule via the eigenvectors and eigenvalues of a transition matrix between conformational substates. This procedure allows the establishment of a complete set of exponential decay functions and a full decomposition into the individual contributions, i.e., the contribution of every atom and dynamical process to each experimental relaxation process.

  8. Characterization of conformational dynamics of bistable RNA by equilibrium and non-equilibrium NMR.

    Science.gov (United States)

    Fürtig, Boris; Reining, Anke; Sochor, Florian; Oberhauser, Eva Marie; Heckel, Alexander; Schwalbe, Harald

    2014-12-19

    Unlike proteins, a given RNA sequence can adopt more than a single conformation. The two (or more) conformations are long-lived and have similar stabilities, but interconvert only slowly. Such bi- or multistability is often linked to the biological functions of the RNA. This unit describes how nuclear magnetic resonance (NMR) spectroscopy can be used to characterize the conformational dynamics of bistable RNAs. Copyright © 2014 John Wiley & Sons, Inc.

  9. Testing Backbone.js

    CERN Document Server

    Roemer, Ryan

    2013-01-01

    This book is packed with the step by step tutorial and instructions in recipe format helping you setup test infrastructure and gradually advance your skills to plan, develop, and test your backbone applications.If you are a JavaScript developer looking for recipes to create and implement test support for your backbone application, then this book is ideal for you.

  10. Mapping the conformational landscape of a dynamic enzyme by multitemperature and XFEL crystallography

    Energy Technology Data Exchange (ETDEWEB)

    Keedy, Daniel A.; Kenner, Lillian R.; Warkentin, Matthew; Woldeyes, Rahel A.; Hopkins, Jesse B.; Thompson, Michael C.; Brewster, Aaron S.; Van Benschoten, Andrew H.; Baxter, Elizabeth L.; Uervirojnangkoorn, Monarin; McPhillips, Scott E.; Song, Jinhu; Alonso-Mori, Roberto; Holton, James M.; Weis, William I.; Brunger, Axel T.; Soltis, S. Michael; Lemke, Henrik; Gonzalez, Ana; Sauter, Nicholas K.; Cohen, Aina E.; van den Bedem, Henry; Thorne, Robert E.; Fraser, James S.

    2015-09-30

    Determining the interconverting conformations of dynamic proteins in atomic detail is a major challenge for structural biology. Conformational heterogeneity in the active site of the dynamic enzyme cyclophilin A (CypA) has been previously linked to its catalytic function, but the extent to which the different conformations of these residues are correlated is unclear. Here we compare the conformational ensembles of CypA by multitemperature synchrotron crystallography and fixed-target X-ray free-electron laser (XFEL) crystallography. The diffraction-before-destruction nature of XFEL experiments provides a radiation-damage-free view of the functionally important alternative conformations of CypA, confirming earlier synchrotron-based results. We monitored the temperature dependences of these alternative conformations with eight synchrotron datasets spanning 100-310 K. Multiconformer models show that many alternative conformations in CypA are populated only at 240 K and above, yet others remain populated or become populated at 180 K and below. These results point to a complex evolution of conformational heterogeneity between 180-–240 K that involves both thermal deactivation and solvent-driven arrest of protein motions in the crystal. The lack of a single shared conformational response to temperature within the dynamic active-site network provides evidence for a conformation shuffling model, in which exchange between rotamer states of a large aromatic ring in the middle of the network shifts the conformational ensemble for the other residues in the network. Together, our multitemperature analyses and XFEL data motivate a new generation of temperature- and time-resolved experiments to structurally characterize the dynamic underpinnings of protein function.

  11. From Raw Data to Protein Backbone Chemical Shifts Using NMRFx Processing and NMRViewJ Analysis.

    Science.gov (United States)

    Johnson, Bruce A

    2018-01-01

    Assignment of the chemical shifts of the backbone atoms (HN, N, CA, CB, and C) of proteins is often a prerequisite to using NMR information in the study of proteins. These chemical shifts and their perturbations are the basis for the analysis of protein dynamics, ligand binding, and backbone conformation. They are generally assigned prior to full side-chain assignments and the determination of the complete three-dimensional molecular structure. This chapter describes the use of two software packages, NMRFx Processor and NMRViewJ, in going from raw NMR data to backbone assignments. The step-by-step procedure describes processing of the data and the use of manual and automated features of the RunAbout tool in NMRViewJ to perform the assignments.

  12. Dynamic collimator trajectory algorithm for multiple metastases dynamic conformal arc treatment planning.

    Science.gov (United States)

    MacDonald, R Lee; Thomas, Christopher G; Syme, Alasdair

    2018-01-01

    To develop an algorithm for dynamic collimator positioning to optimize beam's eye view (BEV) fitting of targets in dynamic conformal arc (DCA)-based radiotherapy procedures, of particular use in multiple metastases stereotactic radiosurgery procedures. A trajectory algorithm was developed to dynamically modify the angle of the collimator as a function of arc-based control point to provide optimized collimation of target volume(s). Central to this algorithm is a concept denoted herein as "whitespace" defined as any nontarget area in the BEV that is not covered by any collimation system and is open to exposure from the radiation beam. Calculating whitespace at all collimator angles and every control point, a two-dimensional topographical map depicting the tightness-of-fit of the MLC was generated. A bidirectional gradient trajectory algorithm identified a number of candidate trajectories of continuous collimator motion. Minimization of integrated whitespace was used to identify an optimal solution for the navigation of the parameter space. Plans with dynamic collimator trajectories were designed for multiple metastases targets and were compared with fixed collimator angle dynamic conformal arc (DCA) plans and standard VMAT plans. Algorithm validation was performed on simple test cases with known solutions. The whitespace metric showed a strong correlation (R 2 = 0.90) with mean dose to proximal normal tissue. Seventeen cases were studied using our algorithm to generate dynamic conformal arc (DCA) plans with optimized collimator trajectories for three and four target SRS patients and comparing them to DCA plans generated with optimized fixed collimator angles per arc and standard VMAT plans generated via template. Optimized collimator trajectories were found to produce a reduction in monitor units of up to 49.7 ± 5.1% when compared to VMAT across 17 patients, and all organ-at-risk and normal brain metrics were found to be superior or comparable. Dynamic collimator

  13. Conformational dynamics of ATP/Mg:ATP in motor proteins via data mining and molecular simulation

    Science.gov (United States)

    Bojovschi, A.; Liu, Ming S.; Sadus, Richard J.

    2012-08-01

    The conformational diversity of ATP/Mg:ATP in motor proteins was investigated using molecular dynamics and data mining. Adenosine triphosphate (ATP) conformations were found to be constrained mostly by inter cavity motifs in the motor proteins. It is demonstrated that ATP favors extended conformations in the tight pockets of motor proteins such as F1-ATPase and actin whereas compact structures are favored in motor proteins such as RNA polymerase and DNA helicase. The incorporation of Mg2+ leads to increased flexibility of ATP molecules. The differences in the conformational dynamics of ATP/Mg:ATP in various motor proteins was quantified by the radius of gyration. The relationship between the simulation results and those obtained by data mining of motor proteins available in the protein data bank is analyzed. The data mining analysis of motor proteins supports the conformational diversity of the phosphate group of ATP obtained computationally.

  14. Conformational Dynamics of apo-GlnBP Revealed by Experimental and Computational Analysis

    KAUST Repository

    Feng, Yitao

    2016-10-13

    The glutamine binding protein (GlnBP) binds l-glutamine and cooperates with its cognate transporters during glutamine uptake. Crystal structure analysis has revealed an open and a closed conformation for apo- and holo-GlnBP, respectively. However, the detailed conformational dynamics have remained unclear. Herein, we combined NMR spectroscopy, MD simulations, and single-molecule FRET techniques to decipher the conformational dynamics of apo-GlnBP. The NMR residual dipolar couplings of apo-GlnBP were in good agreement with a MD-derived structure ensemble consisting of four metastable states. The open and closed conformations are the two major states. This four-state model was further validated by smFRET experiments and suggests the conformational selection mechanism in ligand recognition of GlnBP. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

  15. Application of two-dimensional NMR spectroscopy and molecular dynamics simulations to the conformational analysis of oligosaccharides corresponding to the cell-wall polysaccharide of Streptococcus group A.

    Science.gov (United States)

    Kreis, U C; Varma, V; Pinto, B M

    1995-06-01

    This paper describes the use of a protocol for conformational analysis of oligosaccharide structures related to the cell-wall polysaccharide of Streptococcus group A. The polysaccharide features a branched structure with an L-rhamnopyranose (Rhap) backbone consisting of alternating alpha-(1-->2) and alpha-(1-->3) links and D-N-acetylglucosamine (GlcpNAc) residues beta-(1-->3)-connected to alternating rhamnose rings: [formula: see text] Oligomers consisting of three to six residues have been synthesized and nuclear magnetic resonance (NMR) assignments have been made. The protocol for conformational analysis of the solution structure of these oligosaccharides involves experimental and theoretical methods. Two-dimensional NMR spectroscopy methods (TOCSY, ROESY and NOESY) are utilized to obtain chemical shift data and proton-proton distances. These distances are used as constraints in 100 ps molecular dynamics simulations in water using QUANTA and CHARMm. In addition, the dynamics simulations are performed without constraints. ROE build-up curves are computed from the averaged structures of the molecular dynamics simulations using the CROSREL program and compared with the experimental curves. Thus, a refinement of the initial structure may be obtained. The alpha-(1-->2) and the beta-(1-->3) links are unambiguously defined by the observed ROE cross peaks between the A-B',A'-B and C-B,C'-B' residues, respectively. The branch-point of the trisaccharide CBA' is conformationally well-defined. Assignment of the conformation of the B-A linkage (alpha-(1-->3)) was problematic due to TOCSY relay, but could be solved by NOESY and T-ROESY techniques. A conformational model for the polysaccharide is proposed.

  16. The Conformation and Assignment of the Proton NMR Spectrum in Water of DX600, a Bioactive Peptide with a Random Coil Conformation

    Directory of Open Access Journals (Sweden)

    Wayne E. Steinmetz

    2011-01-01

    Full Text Available DX600, a small peptide with 26 residues, is a potent, highly selective inhibitor of angiotensin converting enzyme 2 (ACE2. A range of NMR methods including TOCSY and ROESY yield an assignment of its proton spectrum in water and constraints on its conformation. Constrained molecular dynamics simulations of solvated DX600 show that the peptide's most abundant conformer adopts a predominantly random coil conformation. Constrained by the disulfide bond, its backbone defines an overhand knot with frayed ends.

  17. Backbone dynamics of a bacterially expressed peptide from the receptor binding domain of Pseudomonas aeruginosa pilin strain PAK from heteronuclear 1H-15N NMR spectroscopy

    Energy Technology Data Exchange (ETDEWEB)

    Campbell, A. Patricia [University of Washington, Department of Medicinal Chemistry, School of Pharmacy (United States); Spyracopoulos, Leo [Department of Biochemistry (Canada); Irvin, Randall T. [University of Alberta, Department of Medical Microbiology and Immunology (Canada); Sykes, Brian D. [Department of Biochemistry (Canada)

    2000-07-15

    The backbone dynamics of a {sup 15}N-labeled recombinant PAK pilin peptide spanning residues 128-144 in the C-terminal receptor binding domain of Pseudomonas aeruginosa pilin protein strain PAK (Lys{sup 128}-Cys-Thr-Ser-Asp-Gln-Asp-Glu-Gln-Phe-Ile-Pro-Lys-Gly-Cys-Ser-Lys{sup 144}) were probed by measurements of {sup 15}N NMR relaxation. This PAK(128-144) sequence is a target for the design of a synthetic peptide vaccine effective against multiple strains of P. aeruginosa infection. The {sup 15}N longitudinal (T{sub 1}) and transverse (T{sub 2}) relaxation rates and the steady-state heteronuclear {l_brace}{sup 1}H{r_brace}-{sup 15}N NOE were measured at three fields (7.04, 11.74 and 14.1 Tesla), five temperatures (5, 10, 15, 20, and 25 deg. C ) and at pH 4.5 and 7.2. Relaxation data was analyzed using both the 'model-free' formalism [Lipari, G. and Szabo, A. (1982) J. Am. Chem. Soc., 104, 4546-4559 and 4559-4570] and the reduced spectral density mapping approach [Farrow, N.A., Szabo, A., Torchia, D.A. and Kay, L.E. (1995) J. Biomol. NMR, 6, 153-162]. The relaxation data, spectral densities and order parameters suggest that the type I and type II {beta}-turns spanning residues Asp{sup 134}-Glu-Gln-Phe{sup 137} and Pro{sup 139}-Lys-Gly-Cys{sup 142}, respectively, are the most ordered and structured regions of the peptide. The biological implications of these results will be discussed in relation to the role that backbone motions play in PAK pilin peptide immunogenicity, and within the framework of developing a pilin peptide vaccine capable of conferring broad immunity across P. aeruginosa strains.

  18. Exact Solutions for Internuclear Vectors and Backbone Dihedral Angles from NH Residual Dipolar Couplings in Two Media, and their Application in a Systematic Search Algorithm for Determining Protein Backbone Structure

    International Nuclear Information System (INIS)

    Wang Lincong; Donald, Bruce Randall

    2004-01-01

    We have derived a quartic equation for computing the direction of an internuclear vector from residual dipolar couplings (RDCs) measured in two aligning media, and two simple trigonometric equations for computing the backbone (φ,ψ) angles from two backbone vectors in consecutive peptide planes. These equations make it possible to compute, exactly and in constant time, the backbone (φ,ψ) angles for a residue from RDCs in two media on any single backbone vector type. Building upon these exact solutions we have designed a novel algorithm for determining a protein backbone substructure consisting of α-helices and β-sheets. Our algorithm employs a systematic search technique to refine the conformation of both α-helices and β-sheets and to determine their orientations using exclusively the angular restraints from RDCs. The algorithm computes the backbone substructure employing very sparse distance restraints between pairs of α-helices and β-sheets refined by the systematic search. The algorithm has been demonstrated on the protein human ubiquitin using only backbone NH RDCs, plus twelve hydrogen bonds and four NOE distance restraints. Further, our results show that both the global orientations and the conformations of α-helices and β-strands can be determined with high accuracy using only two RDCs per residue. The algorithm requires, as its input, backbone resonance assignments, the identification of α-helices and β-sheets as well as sparse NOE distance and hydrogen bond restraints.Abbreviations: NMR - nuclear magnetic resonance; RDC - residual dipolar coupling; NOE - nuclear Overhauser effect; SVD - singular value decomposition; DFS - depth-first search; RMSD - root mean square deviation; POF - principal order frame; PDB - protein data bank; SA - simulated annealing; MD - molecular dynamics

  19. Brownian dynamics simulation of the cross-talking effect among modified histones on conformations of nucleosomes

    Science.gov (United States)

    Duan, Zhao-Wen; Li, Wei; Xie, Ping; Dou, Shuo-Xing; Wang, Peng-Ye

    2010-04-01

    Using Brownian dynamics simulation, we studied the effect of histone modifications on conformations of an array of nucleosomes in a segment of chromatin. The simulation demonstrated that the segment of chromatin shows the dynamic behaviour that its conformation can switch between a state with nearly all of the histones being wrapped by DNA and a state with nearly all of the histones being unwrapped by DNA, thus involving the “cross-talking" interactions among the histones. Each state can stay for a sufficiently long time. These conformational states are essential for gene expression or gene silence. The simulation also shows that these conformational states can be inherited by the daughter DNAs during DNA replication, giving a theoretical explanation of the epigenetic phenomenon.

  20. Brownian dynamics simulation of the cross-talking effect among modified histones on conformations of nucleosomes

    International Nuclear Information System (INIS)

    Zhao-Wen, Duan; Wei, Li; Ping, Xie; Shuo-Xing, Dou; Peng-Ye, Wang

    2010-01-01

    Using Brownian dynamics simulation, we studied the effect of histone modifications on conformations of an array of nucleosomes in a segment of chromatin. The simulation demonstrated that the segment of chromatin shows the dynamic behaviour that its conformation can switch between a state with nearly all of the histones being wrapped by DNA and a state with nearly all of the histones being unwrapped by DNA, thus involving the “cross-talking” interactions among the histones. Each state can stay for a sufficiently long time. These conformational states are essential for gene expression or gene silence. The simulation also shows that these conformational states can be inherited by the daughter DNAs during DNA replication, giving a theoretical explanation of the epigenetic phenomenon. (cross-disciplinary physics and related areas of science and technology)

  1. Extracting Conformational Ensembles of Small Molecules from Molecular Dynamics Simulations: Ampicillin as a Test Case

    Directory of Open Access Journals (Sweden)

    Giuliano Malloci

    2016-01-01

    Full Text Available The accurate and exhaustive description of the conformational ensemble sampled by small molecules in solution, possibly at different physiological conditions, is of primary interest in many fields of medicinal chemistry and computational biology. Recently, we have built an on-line database of compounds with antimicrobial properties, where we provide all-atom force-field parameters and a set of molecular properties, including representative structures extracted from cluster analysis over μs-long molecular dynamics (MD trajectories. In the present work, we used a medium-sized antibiotic from our sample, namely ampicillin, to assess the quality of the conformational ensemble. To this aim, we compared the conformational landscape extracted from previous unbiased MD simulations to those obtained by means of Replica Exchange MD (REMD and those originating from three freely-available conformer generation tools widely adopted in computer-aided drug-design. In addition, for different charge/protonation states of ampicillin, we made available force-field parameters and static/dynamic properties derived from both Density Functional Theory and MD calculations. For the specific system investigated here, we found that: (i the conformational statistics extracted from plain MD simulations is consistent with that obtained from REMD simulations; (ii overall, our MD-based approach performs slightly better than any of the conformer generator tools if one takes into account both the diversity of the generated conformational set and the ability to reproduce experimentally-determined structures.

  2. From Conformal Invariance towards Dynamical Symmetries of the Collisionless Boltzmann Equation

    Directory of Open Access Journals (Sweden)

    Stoimen Stoimenov

    2015-09-01

    Full Text Available Dynamical symmetries of the collisionless Boltzmann transport equation, or Vlasov equation, but under the influence of an external driving force, are derived from non-standard representations of the 2D conformal algebra. In the case without external forces, the symmetry of the conformally-invariant transport equation is first generalized by considering the particle momentum as an independent variable. This new conformal representation can be further extended to include an external force. The construction and possible physical applications are outlined.

  3. Conformal field theory as microscopic dynamics of incompressible Euler and Navier-Stokes equations.

    Science.gov (United States)

    Fouxon, Itzhak; Oz, Yaron

    2008-12-31

    We consider the hydrodynamics of relativistic conformal field theories at finite temperature. We show that the limit of slow motions of the ideal hydrodynamics leads to the nonrelativistic incompressible Euler equation. For viscous hydrodynamics we show that the limit of slow motions leads to the nonrelativistic incompressible Navier-Stokes equation. We explain the physical reasons for the reduction and discuss the implications. We propose that conformal field theories provide a fundamental microscopic viewpoint of the equations and the dynamics governed by them.

  4. Conformal Field Theory as Microscopic Dynamics of Incompressible Euler and Navier-Stokes Equations

    International Nuclear Information System (INIS)

    Fouxon, Itzhak; Oz, Yaron

    2008-01-01

    We consider the hydrodynamics of relativistic conformal field theories at finite temperature. We show that the limit of slow motions of the ideal hydrodynamics leads to the nonrelativistic incompressible Euler equation. For viscous hydrodynamics we show that the limit of slow motions leads to the nonrelativistic incompressible Navier-Stokes equation. We explain the physical reasons for the reduction and discuss the implications. We propose that conformal field theories provide a fundamental microscopic viewpoint of the equations and the dynamics governed by them

  5. Study of conformation and dynamic of surfactant molecules in graphite oxide via NMR

    Energy Technology Data Exchange (ETDEWEB)

    Ai, X.Q. [Jiangsu Second Normal University, College of Physics and Electronic Engineering, Nanjing (China); Ma, L.G. [Nanjing Xiaozhuang University, School of Electronic Engineering, Nanjing (China)

    2016-08-15

    The conformation and dynamic of surfactant in graphite oxide (GO) was investigated by solid-state {sup 13}C magic-angle-spinning NMR and {sup 1}H-{sup 13}C cross-polarization/magic-angle-spinning NMR spectra. The conformation ordering of the alkyl chains in the confined system shows strong dependence on its orientation. While the alkyl chains parallel to the GO layer in lateral monolayer arrangement are in gauche conformation in addition to a small amount of all-trans conformation, those with orientation radiating away from the GO in paraffin bilayer arrangement is in all-trans conformation in addition to some gauche conformation even though high-order diffraction peaks appears. NMR results suggest that the least mobile segment is located at the GO-surfactant interface corresponding to the N-methylene group. Further from it, the mobility of the alkyl chain increases. The terminal methyl and N-methyl carbon groups have the highest mobile. The chains in all-trans conformational state are characterized as more rigid than chains with gauche conformation; each segment of the confined alkyl chains with the lateral monolayer arrangement exhibits less mobility as compared to that with the paraffin bilayer arrangement. (orig.)

  6. Living without supersymmetry—the conformal alternative and a dynamical Higgs boson

    Science.gov (United States)

    Mannheim, Philip D.

    2017-11-01

    We show that the key results of supersymmetry can be achieved via conformal symmetry instead. We propose that the Higgs boson be a dynamical fermion-antifermion bound state rather than an elementary scalar field, so that there is then no quadratically divergent self-energy problem for it and thus no need to invoke supersymmetry to resolve the problem. To obtain such a dynamical Higgs boson we study a conformal invariant gauge theory of interacting fermions and gauge bosons. The conformal invariance of the theory is realized via scaling with anomalous dimensions in the ultraviolet, and by a dynamical symmetry breaking via fermion bilinear condensates in the infrared, a breaking in which the dynamical dimension of the composite operator \\bar{\\psi }\\psi is reduced from three to two. With this reduction in dimension we can augment the gauge theory with a four-fermion interaction made renormalizable by this reduction, and can reinterpret the theory as a renormalizable version of the Nambu-Jona-Lasinio (NJL) model, with the gauge theory sector with its now massive fermion being a mean-field theory and the four-fermion interaction being the residual interaction. It is this residual interaction and not the mean field that then generates dynamical Goldstone and Higgs states, states that, as noted by Baker and Johnson, the gauge theory sector itself does not possess. The Higgs boson is found to be a narrow resonance just above threshold, with its width potentially being a diagnostic that could distinguish a dynamical Higgs boson from an elementary one. We couple the theory to a gravity theory, conformal gravity, that is equally conformal invariant, with the interplay between conformal gravity and the four-fermion interaction taking care of the vacuum energy problem. With conformal gravity being a unitary and renormalizable quantum theory of gravity there is no need for string theory with its supersymmetric underpinnings. With the vacuum energy problem being resolved and

  7. Exploring Platelet Chemokine Antimicrobial Activity: Nuclear Magnetic Resonance Backbone Dynamics of NAP-2 and TC-1▿

    Science.gov (United States)

    Nguyen, Leonard T.; Kwakman, Paulus H. S.; Chan, David I.; Liu, Zhihong; de Boer, Leonie; Zaat, Sebastian A. J.; Vogel, Hans J.

    2011-01-01

    The platelet chemokines neutrophil-activating peptide-2 (NAP-2) and thrombocidin-1 (TC-1) differ by only two amino acids at their carboxy-terminal ends. Nevertheless, they display a significant difference in their direct antimicrobial activities, with the longer NAP-2 being inactive and TC-1 being active. In an attempt to rationalize this difference in activity, we studied the structure and the dynamics of both proteins by nuclear magnetic resonance (NMR) spectroscopy. Using 15N isotope-labeled protein, we confirmed that the two monomeric proteins essentially have the same overall structure in aqueous solution. However, NMR relaxation measurements provided evidence that the negatively charged carboxy-terminal residues of NAP-2 experience a restricted motion, whereas the carboxy-terminal end of TC-1 moves in an unrestricted manner. The same behavior was also seen in molecular dynamic simulations of both proteins. Detailed analysis of the protein motions through model-free analysis, as well as a determination of their overall correlation times, provided evidence for the existence of a monomer-dimer equilibrium in solution, which seemed to be more prevalent for TC-1. This finding was supported by diffusion NMR experiments. Dimerization generates a larger cationic surface area that would increase the antimicrobial activities of these chemokines. Moreover, these data also show that the negatively charged carboxy-terminal end of NAP-2 (which is absent in TC-1) folds back over part of the positively charged helical region of the protein and, in doing so, interferes with the direct antimicrobial activity. PMID:21321145

  8. Molecular modeling of the conformational dynamics of the cellular prion protein

    Science.gov (United States)

    Nguyen, Charles; Colling, Ian; Bartz, Jason; Soto, Patricia

    2014-03-01

    Prions are infectious agents responsible for transmissible spongiform encephalopathies (TSEs), a type of fatal neurodegenerative disease in mammals. Prions propagate biological information by conversion of the non-pathological version of the prion protein to the infectious conformation, PrPSc. A wealth of knowledge has shed light on the nature and mechanism of prion protein conversion. In spite of the significance of this problem, we are far from fully understanding the conformational dynamics of the cellular isoform. To remedy this situation we employ multiple biomolecular modeling techniques such as docking and molecular dynamics simulations to map the free energy landscape and determine what specific regions of the prion protein are most conductive to binding. The overall goal is to characterize the conformational dynamics of the cell form of the prion protein, PrPc, to gain insight into inhibition pathways against misfolding. NE EPSCoR FIRST Award to Patricia Soto.

  9. Non-fluorescent Quenchers to Correlate Single-Molecule Conformational and Compositional Dynamics

    Science.gov (United States)

    Chen, Jin; Tsai, Albert; Petrov, Alexey; Puglisi, Joseph D.

    2015-01-01

    Single-molecule Förster resonance energy transfer (smFRET) is a powerful method to study the conformational dynamics of a biomolecule in real-time. However, studying how interacting ligands correlate with and regulate the conformational dynamics of the biomolecule is extremely challenging due to the availability of a limited number of fluorescent dyes with both high quantum yield and minimal spectral overlap. Here, we report the use of a non-fluorescent quencher (Black Hole Quencher, BHQ) as an acceptor for smFRET. Using a Cy3/BHQ pair, we accurately follow conformational changes of the ribosome during elongation in real time. We demonstrate the application of single-color FRET to correlate the conformational dynamics of the ribosome with the compositional dynamics of tRNA. We use the normal Cy5 FRET acceptor to observe arrival of a fluorescently-labeled tRNA with a concomitant transition of the ribosome from the locked to the unlocked conformation. Our results illustrate the potential of non-fluorescent quenchers in single-molecule correlation studies. PMID:22428667

  10. Conformational dynamics of human protein kinase CK2α and its effect on function and inhibition.

    Science.gov (United States)

    Srivastava, Ashutosh; Hirota, Tsuyoshi; Irle, Stephan; Tama, Florence

    2018-03-01

    Protein kinase, casein kinase II (CK2), is ubiquitously expressed and highly conserved protein kinase that shows constitutive activity. It phosphorylates a diverse set of proteins and plays crucial role in several cellular processes. The catalytic subunit of this enzyme (CK2α) shows remarkable flexibility as evidenced in numerous crystal structures determined till now. Here, using analysis of multiple crystal structures and long timescale molecular dynamics simulations, we explore the conformational flexibility of CK2α. The enzyme shows considerably higher flexibility in the solution as compared to that observed in crystal structure ensemble. Multiple conformations of hinge region, located near the active site, were observed during the dynamics. We further observed that among these multiple conformations, the most populated conformational state was inadequately represented in the crystal structure ensemble. The catalytic spine, was found to be less dismantled in this state as compared to the "open" hinge/αD state crystal structures. The comparison of dynamics in unbound (Apo) state and inhibitor (CX4945) bound state exhibits inhibitor induced suppression in the overall dynamics of the enzyme. This is especially true for functionally important glycine-rich loop above the active site. Together, this work gives novel insights into the dynamics of CK2α in solution and relates it to the function. This work also explains the effect of inhibitor on the dynamics of CK2α and paves way for development of better inhibitors. © 2017 Wiley Periodicals, Inc.

  11. Backbone amide linker strategy

    DEFF Research Database (Denmark)

    Shelton, Anne Pernille Tofteng; Jensen, Knud Jørgen

    2013-01-01

    In the backbone amide linker (BAL) strategy, the peptide is anchored not at the C-terminus but through a backbone amide, which leaves the C-terminal available for various modifications. This is thus a very general strategy for the introduction of C-terminal modifications. The BAL strategy...... to assemble the final peptide. One useful application of this strategy is in the synthesis of C-terminal peptide aldehydes. The C-terminal aldehyde is masked as an acetal during synthesis and then conveniently demasked in the final cleavage step to generate the free aldehyde. Another application...

  12. Comparison of the backbone dynamics of wild-type Hydrogenobacter thermophilus cytochrome c{sub 552} and its b-type variant

    Energy Technology Data Exchange (ETDEWEB)

    Tozawa, Kaeko; Ferguson, Stuart J.; Redfield, Christina, E-mail: christina.redfield@bioch.ox.ac.uk [University of Oxford, Department of Biochemistry (United Kingdom); Smith, Lorna J., E-mail: lorna.smith@chem.ox.ac.uk [University of Oxford, Department of Chemistry (United Kingdom)

    2015-06-15

    Cytochrome c{sub 552} from the thermophilic bacterium Hydrogenobacter thermophilus is a typical c-type cytochrome which binds heme covalently via two thioether bonds between the two heme vinyl groups and two cysteine thiol groups in a CXXCH sequence motif. This protein was converted to a b-type cytochrome by substitution of the two cysteine residues by alanines (Tomlinson and Ferguson in Proc Natl Acad Sci USA 97:5156–5160, 2000a). To probe the significance of the covalent attachment of the heme in the c-type protein, {sup 15}N relaxation and hydrogen exchange studies have been performed for the wild-type and b-type proteins. The two variants share very similar backbone dynamic properties, both proteins showing high {sup 15}N order parameters in the four main helices, with reduced values in an exposed loop region (residues 18–21), and at the C-terminal residue Lys80. Some subtle changes in chemical shift and hydrogen exchange protection are seen between the wild-type and b-type variant proteins, not only for residues at and neighbouring the mutation sites, but also for some residues in the heme binding pocket. Overall, the results suggest that the main role of the covalent linkages between the heme group and the protein chain must be to increase the stability of the protein.

  13. Conformal symmetry and non-relativistic second-order fluid dynamics

    International Nuclear Information System (INIS)

    Chao Jingyi; Schäfer, Thomas

    2012-01-01

    We study the constraints imposed by conformal symmetry on the equations of fluid dynamics at second order in the gradients of the hydrodynamic variables. At zeroth order, conformal symmetry implies a constraint on the equation of state, E 0 =2/3 P, where E 0 is the energy density and P is the pressure. At first order, conformal symmetry implies that the bulk viscosity must vanish. We show that at second order, conformal invariance requires that two-derivative terms in the stress tensor must be traceless, and that it determines the relaxation of dissipative stresses to the Navier–Stokes form. We verify these results by solving the Boltzmann equation at second order in the gradient expansion. We find that only a subset of the terms allowed by conformal symmetry appear. - Highlights: ► We derive conformal constraints for the stress tensor of a scale invariant fluid. ► We determine the relaxation time in kinetic theory. ► We compute the rate of entropy production in second-order fluid dynamics.

  14. Molecular dynamics simulations of poly (ethylene oxide) hydration and conformation in solutions

    Science.gov (United States)

    Dahal, Udaya; Dormidontova, Elena

    Polyethylene oxide (PEO) is one of the most actively used polymers, especially in biomedical applications due to its high hydrophilicity, biocompatibility and potency to inhibit protein adsorption. PEO solubility and conformation in water depends on its capability to form hydrogen bonds. Using atomistic molecular dynamics simulations we investigated the details of water packing around PEO chain and characterized the type and lifetime of hydrogen bonds in aqueous and mixed solvent solutions. The observed polymer chain conformation varies from an extended coil in pure water to collapsed globule in hexane and a helical-like conformation in pure isobutyric acid or isobutyric acid -water mixture in agreement with experimental observations. We'll discuss the implications of protic solvent arrangement and stability of hydrogen bonds on PEO chain conformation and mobility. This research is supported by NSF (DMR-1410928).

  15. Role of conformational dynamics in kinetics of an enzymatic cycle in a nonequilibrium steady state

    Science.gov (United States)

    Min, Wei; Xie, X. Sunney; Bagchi, Biman

    2009-08-01

    Enzyme is a dynamic entity with diverse time scales, ranging from picoseconds to seconds or even longer. Here we develop a rate theory for enzyme catalysis that includes conformational dynamics as cycling on a two-dimensional (2D) reaction free energy surface involving an intrinsic reaction coordinate (X) and an enzyme conformational coordinate (Q). The validity of Michaelis-Menten (MM) equation, i.e., substrate concentration dependence of enzymatic velocity, is examined under a nonequilibrium steady state. Under certain conditions, the classic MM equation holds but with generalized microscopic interpretations of kinetic parameters. However, under other conditions, our rate theory predicts either positive (sigmoidal-like) or negative (biphasic-like) kinetic cooperativity due to the modified effective 2D reaction pathway on X-Q surface, which can explain non-MM dependence previously observed on many monomeric enzymes that involve slow or hysteretic conformational transitions. Furthermore, we find that a slow conformational relaxation during product release could retain the enzyme in a favorable configuration, such that enzymatic turnover is dynamically accelerated at high substrate concentrations. The effect of such conformation retainment in a nonequilibrium steady state is evaluated.

  16. Radiosurgery of multiple brain metastases with single-isocenter dynamic conformal arcs (SIDCA)

    International Nuclear Information System (INIS)

    Huang, Yimei; Chin, Karen; Robbins, Jared R.; Kim, Jinkoo; Li, Haisen; Amro, Hanan; Chetty, Indrin J.; Gordon, James; Ryu, Samuel

    2014-01-01

    Purpose: To propose single-isocenter dynamic conformal arcs (SIDCA), a novel technique for radiosurgery of multiple brain metastases, and to compare SIDCA with volumetric modulated arc therapy (VMAT) and multiple-isocenter dynamic conformal arcs (MIDCA) for plan quality. Methods and materials: SIDCA, MIDCA, and VMAT plans were created on 6 patients with 3–5 metastases. Plans were evaluated using Radiation Therapy Oncology Group conformity index (RCI), Paddick conformity index (PCI), gradient index (GI), volumes that received more than 100% (V 100% ), 50% (V 50% ), 25% (V 25% ) and 10% (V 10% ) of prescription dose, total monitor units (MUs), and delivery time (DT). Results: SIDCA achieved conformal plans (RCI = 1.38 ± 0.12, PCI = 0.72 ± 0.06) with steep dose fall-off (GI = 3.97 ± 0.51). MIDCA plans had comparable plan quality and MUs as SIDCA, but 52% longer DT. The VMAT plans had better conformity (RCI = 1.15 ± 0.09, p < 0.01 and PCI = 0.86 ± 0.06, p < 0.01) than SIDCA, worse GI (4.34 ± 0.46, p < 0.01), higher V 25% (p = 0.05) and V 10% (p = 0.02), 49% less MUs and 46% shorter DT. Conclusions: All three techniques achieved conformal plans with steep dose fall-off from targets. SIDCA plans had similar plan quality as MIDCA but more efficient to delivery. SIDCA plans had lower peripheral dose spread than VMAT; VMAT plans had better conformity and faster delivery time than SIDCA

  17. Unraveling the differential structural stability and dynamics features of T7 endolysin partially folded conformations.

    Science.gov (United States)

    Sharma, Meenakshi; Kumar, Dinesh; Poluri, Krishna Mohan

    2018-04-01

    Characterization of partially collapsed protein conformations at atomic level is a daunting task due to their inherent flexibility and conformational heterogeneity. T7 bacteriophage endolysin (T7L) is a single-domain amidase that facilitates the lysis of Gram-negative bacteria. T7L exhibits a pH-dependent structural transition from native state to partially folded (PF) conformation. In the pH range 5-3, T7L PF states display differential ANS binding characteristics. CD, fluorescence, NMR spectroscopy and lysis assays were used to investigate the structure-stability- dynamics relationships of T7L PF conformations. Structural studies indicated a partial loss of secondary/tertiary structures compared to its native state. The loss in the tertiary structure and the hydrophobic core opening increases upon decrease of pH from 5 to 3. Thermal denaturation experiments delineated that the pH 5 conformation is thermally irreversible in contrast to pH 3, depicting that hydrophobic core opening is essential for thermal reversibility. Further, urea dependent unfolding features of PF state at pH 5 and 4 evidenced for a collapsed conformation at intermediate urea concentrations. Residue level studies revealed that α1-helix and β3-β4 segment of T7L are the major contributors for such a structural collapse and inherent dynamics. The results suggested that the low pH PF states of T7L are heterogeneous and exhibits differential structural, unfolding, thermal reversibility, and dynamic features. Unraveling the structure-stability characteristics of different endolysin conformations is essential for designing novel chimeric and engineered phage endolysins as broadband antimicrobial agents over a varied pH range. Copyright © 2018 Elsevier B.V. All rights reserved.

  18. Fine tuning of sub-millisecond conformational dynamics controls metabotropic glutamate receptors agonist efficacy.

    Science.gov (United States)

    Olofsson, Linnea; Felekyan, Suren; Doumazane, Etienne; Scholler, Pauline; Fabre, Ludovic; Zwier, Jurriaan M; Rondard, Philippe; Seidel, Claus A M; Pin, Jean-Philippe; Margeat, Emmanuel

    2014-10-17

    Efficient cell-to-cell communication relies on the accurate signalling of cell surface receptors. Understanding the molecular bases of their activation requires the characterization of the dynamic equilibrium between active and resting states. Here, we monitor, using single-molecule Förster resonance energy transfer, the kinetics of the reorientation of the extracellular ligand-binding domain of the metabotropic glutamate receptor (mGluR), a class C G-protein-coupled receptor. We demonstrate that most receptors oscillate between a resting- and an active-conformation on a sub-millisecond timescale. Interestingly, we demonstrate that differences in agonist efficacies stem from differing abilities to shift the conformational equilibrium towards the fully active state, rather than from the stabilization of alternative static conformations, which further highlights the dynamic nature of mGluRs and revises our understanding of receptor activation and allosteric modulation.

  19. Effects of carbon nanofiller characteristics on PTT chain conformation and dynamics: A computational study

    International Nuclear Information System (INIS)

    Asadinezhad, Ahmad; Kelich, Payam

    2017-01-01

    Highlights: • Poly (trimethylene terephthalate) (PTT) conformation adopts a folded shape near nanofiller surface. • Graphene and carbon nanotube with different size and chemistry were simulated. • Graphene functionalization induces stronger confinement on PTT chain conformation. • PTT chain motion alters in dynamics mode as it becomes adsorbed onto nanofillers. • PTT reveals further changes near graphene than carbon nanotube surface. - Abstract: The effects of nanofiller chemistry and geometry on static and dynamic properties of an aromatic polyester, poly (trimethylene terephthalate), were addressed thanks to long-run classical molecular dynamics simulation. Two carbon nanofillers, graphene and carbon nanotube, were employed, where graphene was used in pristine and functionalized forms and carbon nanotube was used in two different diameters. The nanofiller geometry and chemistry were found to exert significant effects on conformation and dynamic behavior of PTT chain at the interface within the time scale the simulation was performed. It was found that PTT chain underwent interaction of van der Waals type with nanofiller via two subsequent phases, adsorption and orientation. The former stage, with definite characteristic time, involved translation of polymer chain toward interface while the latter was controlled by vibrational motions of chain atoms. The consequence of interaction was an increase in conformational order of polymer chain by transition to folded shape being favorable for any subsequent structural ordering (crystallization). The interaction of polymer with nanofiller gave rise to a reduction in overall mobility of polymer chain characterized by crossover from normal diffusive motion to subdiffusive mode.

  20. Dynamic Conformations of Nucleosome Arrays in Solution from Small-Angle X-ray Scattering

    Energy Technology Data Exchange (ETDEWEB)

    Howell, Steven C. [George Washington Univ., Washington, DC (United States)

    2016-01-31

    We set out to determine quantitative information regarding the dynamic conformation of nucleosome arrays in solution using experimental SAXS. Toward this end, we developed a CG simulation algorithm for dsDNA which rapidly generates ensembles of structures through Metropolis MC sampling of a Markov chain.

  1. Imatinib (Gleevec@) conformations observed in single crystals, protein-Imatinib co-crystals and molecular dynamics: Implications for drug selectivity

    Science.gov (United States)

    Golzarroshan, B.; Siddegowda, M. S.; Li, Hong qi; Yathirajan, H. S.; Narayana, B.; Rathore, R. S.

    2012-06-01

    Structure and dynamics of the Leukemia drug, Imatinib, were examined using X-ray crystallography and molecular dynamics studies. Comparison of conformations observed in single crystals with several reported co-crystals of protein-drug complexes suggests existence of two conserved conformations of Imatinib, extended and compact (or folded), corresponding to two binding modes of interaction with the receptor. Furthermore, these conformations are conserved throughout a dynamics simulation. The present study attempts to draw a parallel on conformations and binding patterns of interactions, obtained from small-molecule single-crystal and macromolecule co-crystal studies, and provides structural insights for understanding the high selectivity of this drug molecule.

  2. CCR5 Conformations Are Dynamic and Modulated by Localization, Trafficking and G Protein Association

    Science.gov (United States)

    Flegler, Ayanna J.; Cianci, Gianguido C.; Hope, Thomas J.

    2014-01-01

    CCR5 acts as the principal coreceptor during HIV-1 transmission and early stages of infection. Efficient HIV-1 entry requires a series of processes, many dependent on the conformational state of both viral envelope protein and cellular receptor. Monoclonal antibodies (MAbs) are able to identify different CCR5 conformations, allowing for their use as probes to distinguish CCR5 populations. Not all CCR5 MAbs are able to reduce HIV-1 infection, suggesting the use of select CCR5 populations for entry. In the U87.CD4.CCR5-GFP cell line, we used such HIV-1-restricting MAbs to probe the relation between localization, trafficking and G protein association for individual CCR5 conformations. We find that CCR5 conformations not only exhibit different localization and abundance patterns throughout the cell, but that they also display distinct sensitivities to endocytosis inhibition. Using chemokine analogs that vary in their HIV-1 inhibitory mechanisms, we also illustrate that responses to ligand engagement are conformation-specific. Additionally, we provide supporting evidence for the select sensitivity of conformations to G protein association. Characterizing the link between the function and dynamics of CCR5 populations has implications for understanding their selective targeting by HIV-1 and for the development of inhibitors that will block CCR5 utilization by the virus. PMID:24586501

  3. Single Molecule Cluster Analysis Identifies Signature Dynamic Conformations along the Splicing Pathway

    Science.gov (United States)

    Blanco, Mario R.; Martin, Joshua S.; Kahlscheuer, Matthew L.; Krishnan, Ramya; Abelson, John; Laederach, Alain; Walter, Nils G.

    2016-01-01

    The spliceosome is the dynamic RNA-protein machine responsible for faithfully splicing introns from precursor messenger RNAs (pre-mRNAs). Many of the dynamic processes required for the proper assembly, catalytic activation, and disassembly of the spliceosome as it acts on its pre-mRNA substrate remain poorly understood, a challenge that persists for many biomolecular machines. Here, we developed a fluorescence-based Single Molecule Cluster Analysis (SiMCAn) tool to dissect the manifold conformational dynamics of a pre-mRNA through the splicing cycle. By clustering common dynamic behaviors derived from selectively blocked splicing reactions, SiMCAn was able to identify signature conformations and dynamic behaviors of multiple ATP-dependent intermediates. In addition, it identified a conformation adopted late in splicing by a 3′ splice site mutant, invoking a mechanism for substrate proofreading. SiMCAn presents a novel framework for interpreting complex single molecule behaviors that should prove widely useful for the comprehensive analysis of a plethora of dynamic cellular machines. PMID:26414013

  4. Refined solution structure and backbone dynamics of 15N-labeled C12A-p8MTCP studied by NMR relaxation

    Energy Technology Data Exchange (ETDEWEB)

    Barthe, Philippe; Chiche, Laurent; Declerck, Nathalie; Delsuc, Marc-Andre [Universite de Montpellier I, Faculte de Pharmacie, Centre de Biochimie Structurale, CNRS-UMR 9955, INSERM-U414 (France); Lefevre, Jean-Francois [Universite Louis Pasteur, CNRS UPR-9003, ESBS (France); Malliavin, Therese [Universite de Montpellier I, Faculte de Pharmacie, Centre de Biochimie Structurale, CNRS-UMR 9955, INSERM-U414 (France); Mispelter, Joel [Centre Universitaire Bat 112, INSERM-U350, Institut Curie, Biologie (France); Stern, Marc-Henri [Hopital Saint-Louis, Unite INSERM-U462 (France); Lhoste, Jean-Marc; Roumestand, Christian [Universite de Montpellier I, Faculte de Pharmacie, Centre de Biochimie Structurale, CNRS-UMR 9955, INSERM-U414 (France)

    1999-12-15

    MTCP1 (for Mature-T-Cell Proliferation) was the first gene unequivocally identified in the group of uncommon leukemias with a mature phenotype. The three-dimensional solution structure of the human p8{sup MTCP} protein encoded by the MTCP1 oncogene has been previously determined by homonuclear proton two-dimensional NMR methods at 600 MHz: it consists of an original scaffold comprising three {alpha}-helices, associated with a new cysteine motif. Two of the helices are covalently paired by two disulfide bridges, forming an {alpha}-hairpin which resembles an antiparallel coiled-coil. The third helix is orientated roughly parallel to the plane defined by the {alpha}-antiparallel motif and appears less well defined. In order to gain more insight into the details of this new scaffold, we uniformly labeled with nitrogen-15 a mutant of this protein (C12A-p8{sup MTCP1}) in which the unbound cysteine at position 12 has been replaced by an alanine residue, thus allowing reproducibly high yields of recombinant protein. The refined structure benefits from 211 additional NOEs, extracted from {sup 15}N-edited 3D experiments, and from a nearly complete set of {phi} angular restraints allowing the estimation of the helical content of the structured part of the protein. Moreover, measurements of {sup 15} N spin relaxation times and heteronuclear {sup 15} N{sup 1}HNOEs provided additional insights into the dynamics of the protein backbone. The analysis of the linear correlation between J(0) and J({omega}) was used to interpret relaxation parameters. It appears that the apparent relative disorder seen in helix III is not simply due to a lack of experimental constraints, but associated with substantial contributions of sub-nanosecond motions in this segment.

  5. Backbone dynamics and solution structure refinement of the 15N-labeled human oncogenic protein p13MTCP1: Comparison with X-ray data

    Energy Technology Data Exchange (ETDEWEB)

    Guignard, Laurent; Padilla, Andre [Universite de Montpellier I, Faculte de Pharmacie, Centre de Biochimie Structurale, CNRS-UMR 9955, INSERM-U414 (France); Mispelter, Joel [Unite INSERM U350, Institut Curie, Biologie (France); Yang, Y.-S. [Universite de Montpellier I, Faculte de Pharmacie, Centre de Biochimie Structurale, CNRS-UMR 9955, INSERM-U414 (France); Stern, Marc-Henri [Hopital Saint-Louis, Unite INSERM U462 (France); Lhoste, Jean-Marc; Roumestand, Christian [Universite de Montpellier I, Faculte de Pharmacie, Centre de Biochimie Structurale, CNRS-UMR 9955, INSERM-U414 (France)

    2000-07-15

    Two related oncogenes, TCL1 and MTCP1, are overexpressed in certain T-cell prolymphocytic leukemias as a result of chromosomal rearrangements that involve the translocation of one T-cell receptor gene to either chromosome 14q32 or Xq28, respectively. The human oncoprotein p13{sup MTCP1} is coded by the MTCP1 gene and its primary sequence is highly and only homologous to that of p14{sup TCL1}, the product of TCL1. These two proteins likely represent the first members of a new family of oncogenic proteins. A previous model of the three-dimensional solution structure of p13{sup MTCP1} was determined recently using exclusively homonuclear proton two-dimensional NMR methods and, almost simultaneously, high-resolution crystal structures of p13{sup MTCP1} and p14{sup TCL1} appeared in the literature. In order to gain more insight into the details of the solution structure, we uniformly labeled p13{sup MTCP1} with nitrogen-15. The refined structure benefits from 520 additional NOEs, extracted from either {sup 15}N-edited 3D experiments or homonuclear 2D NOESY recorded at 800 MHz, and from a nearly complete set of {phi} angular restraints. Measurements of {sup 15}N spin relaxation times and heteronuclear {sup 15}N{l_brace}{sup 1}H{r_brace}NOEs at two magnetic field strengths provided additional insights into the dynamics of the protein backbone. On the basis of these new results, a putative binding surface for this particular class of oncogenes is discussed.

  6. Fluorescence probe of polypeptide conformational dynamics in gas phase and in solution

    Science.gov (United States)

    Iavarone, Anthony T.; Meinen, Jan; Schulze, Susanne; Parks, Joel H.

    2006-07-01

    Fluorescence measurements of polypeptides derivatized with the fluorescent dye BODIPY TMR have been used to probe the polypeptide conformational dynamics as a function of temperature and charge state. Measurements of (BODIPY TMR)-[Pro]n-Arg-Trp and (BODIPY TMR)-[Gly-Ser]m-Arg-Trp have been performed for charge states 1+ and 2+ of n = 4 and 10 and m = 2 and 5. The 2+ charge states of both of these polypeptides exhibit similar temperature dependences for equal chain lengths (n = 4, m = 2 and n = 10, m = 5) and suggest conformations dominated by Coulomb repulsion. In the absence of such Coulomb repulsion, the 1+ charge state conformations appear to be characterized by the flexibility of the polypeptide chain for which [Gly-Ser]m > [Pro]n. Comparisons of these gas phase polypeptide measurements with corresponding measurements in solution provide a direct measure of the effects of solvent on the conformational dynamics. The change in fluorescence as a function of temperature in the gas phase is two orders of magnitude greater than that in solution, a dramatic result we attribute to the restrictions on intramolecular dynamics imposed by diffusion-limited kinetics and the lack of shielding by solvent. Measurements were also made of unsolvated Pron peptides without the tryptophan (Trp) residue to isolate the interaction of the fluorescent dye with charges.

  7. Orientation-dependent backbone-only residue pair scoring functions for fixed backbone protein design

    Directory of Open Access Journals (Sweden)

    Bordner Andrew J

    2010-04-01

    Full Text Available Abstract Background Empirical scoring functions have proven useful in protein structure modeling. Most such scoring functions depend on protein side chain conformations. However, backbone-only scoring functions do not require computationally intensive structure optimization and so are well suited to protein design, which requires fast score evaluation. Furthermore, scoring functions that account for the distinctive relative position and orientation preferences of residue pairs are expected to be more accurate than those that depend only on the separation distance. Results Residue pair scoring functions for fixed backbone protein design were derived using only backbone geometry. Unlike previous studies that used spherical harmonics to fit 2D angular distributions, Gaussian Mixture Models were used to fit the full 3D (position only and 6D (position and orientation distributions of residue pairs. The performance of the 1D (residue separation only, 3D, and 6D scoring functions were compared by their ability to identify correct threading solutions for a non-redundant benchmark set of protein backbone structures. The threading accuracy was found to steadily increase with increasing dimension, with the 6D scoring function achieving the highest accuracy. Furthermore, the 3D and 6D scoring functions were shown to outperform side chain-dependent empirical potentials from three other studies. Next, two computational methods that take advantage of the speed and pairwise form of these new backbone-only scoring functions were investigated. The first is a procedure that exploits available sequence data by averaging scores over threading solutions for homologs. This was evaluated by applying it to the challenging problem of identifying interacting transmembrane alpha-helices and found to further improve prediction accuracy. The second is a protein design method for determining the optimal sequence for a backbone structure by applying Belief Propagation

  8. 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

  9. On the analysis and comparison of conformer-specific essential dynamics upon ligand binding to a protein

    Science.gov (United States)

    Grosso, Marcos; Kalstein, Adrian; Parisi, Gustavo; Roitberg, Adrian E.; Fernandez-Alberti, Sebastian

    2015-06-01

    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.

  10. Covalent dye attachment influences the dynamics and conformational properties of flexible peptides.

    Directory of Open Access Journals (Sweden)

    Manuel P Luitz

    Full Text Available Fluorescence spectroscopy techniques like Förster resonance energy transfer (FRET and fluorescence correlation spectroscopy (FCS have become important tools for the in vitro and in vivo investigation of conformational dynamics in biomolecules. These methods rely on the distance-dependent quenching of the fluorescence signal of a donor fluorophore either by a fluorescent acceptor fluorophore (FRET or a non-fluorescent quencher, as used in FCS with photoinduced electron transfer (PET. The attachment of fluorophores to the molecule of interest can potentially alter the molecular properties and may affect the relevant conformational states and dynamics especially of flexible biomolecules like intrinsically disordered proteins (IDP. Using the intrinsically disordered S-peptide as a model system, we investigate the impact of terminal fluorescence labeling on the molecular properties. We perform extensive molecular dynamics simulations on the labeled and unlabeled peptide and compare the results with in vitro PET-FCS measurements. Experimental and simulated timescales of end-to-end fluctuations were found in excellent agreement. Comparison between simulations with and without labels reveal that the π-stacking interaction between the fluorophore labels traps the conformation of S-peptide in a single dominant state, while the unlabeled peptide undergoes continuous conformational rearrangements. Furthermore, we find that the open to closed transition rate of S-peptide is decreased by at least one order of magnitude by the fluorophore attachment. Our approach combining experimental and in silico methods provides a benchmark for the simulations and reveals the significant effect that fluorescence labeling can have on the conformational dynamics of small biomolecules, at least for inherently flexible short peptides. The presented protocol is not only useful for comparing PET-FCS experiments with simulation results but provides a strategy to minimize the

  11. 1990s: High Capacity Backbones

    Indian Academy of Sciences (India)

    First page Back Continue Last page Overview Graphics. 1990s: High Capacity Backbones. Backbone capacities increased from 2.5 Gb/s to 100s of Gb/s during the 1990's. Wavelength division multiplexing with 160 waves of 10 Gb/s was commercially available. Several high-capacity backbones built in the US and Europe.

  12. The conformation and dynamic behaviour of tetrathiacalix[4]arenes functionalized by hydrazide and hydrazone groups

    Science.gov (United States)

    Syakaev, Victor V.; Podyachev, Sergey N.; Gubaidullin, Aidar T.; Sudakova, Svetlana N.; Konovalov, Alexander I.

    2008-08-01

    The 1H, 13C and 15N NMR data, conformation and dynamic behaviour of the new tetrathiacalix[4]arenes functionalized by hydrazide and hydrazone groups are reported and compared with the result of earlier investigations of 4- tert-butylphenoxyacetylhydrazones. The unusual fact of formation of N, N'-diacetylhydrazine bridge and factors leading to its formation in the cone conformer of calixarene has been discussed. The barriers of rotation of hydrazone fragments of tetrathiacalix[4]arenes were determined by NMR-measurements at various temperatures. The structure of 1,3- alternate conformer of 5,11,17,23-tetra- tert-butyl-25,26,27,28-tetrakis[hydrazinocarbonylmethyl]-2,8,14,20-tetrathiacalix[4]arene in solution is compared with crystal structure obtained by the X-ray analysis.

  13. How accurately do current force fields predict experimental peptide conformations? An adiabatic free energy dynamics study.

    Science.gov (United States)

    Tzanov, Alexandar T; Cuendet, Michel A; Tuckerman, Mark E

    2014-06-19

    The quality of classical biomolecular simulations is inevitably limited by two problems: the accuracy of the force field used and the comprehensiveness of configuration space sampling. In this work we tackle the sampling problem by carrying out driven adiabatic free energy dynamics to obtain converged free energy surfaces of dipeptides in the gas phase and in solution using selected dihedral angles as collective variables. To calculate populations of conformational macrostates observed in experiment, we introduce a fuzzy clustering algorithm in collective-variable space, which delineates macrostates without prior definition of arbitrary boundaries. With this approach, we calculate the conformational preferences of small peptides with six biomolecular force fields chosen from among the most recent and widely used. We assess the accuracy of each force field against recently published Raman or IR-UV spectroscopy measurements of conformer populations for the dipeptides in solution or in the gas phase.

  14. Conformational and dynamic differences between actin filaments polymerized from ATP- or ADP-actin monomers.

    Science.gov (United States)

    Nyitrai, M; Hild, G; Hartvig, N; Belágyi, J; Somogyi, B

    2000-12-29

    Conformational and dynamic properties of actin filaments polymerized from ATP- or ADP-actin monomers were compared by using fluorescence spectroscopic methods. The fluorescence intensity of IAEDANS attached to the Cys(374) residue of actin was smaller in filaments from ADP-actin than in filaments from ATP-actin monomers, which reflected a nucleotide-induced conformational difference in subdomain 1 of the monomer. Radial coordinate calculations revealed that this conformational difference did not modify the distance of Cys(374) from the longitudinal filament axis. Temperature-dependent fluorescence resonance energy transfer measurements between donor and acceptor molecules on Cys(374) of neighboring actin protomers revealed that the inter-monomer flexibility of filaments assembled from ADP-actin monomers were substantially greater than the one of filaments from ATP-actin monomers. Flexibility was reduced by phalloidin in both types of filaments.

  15. On the relationship between NMR-derived amide order parameters and protein backbone entropy changes.

    Science.gov (United States)

    Sharp, Kim A; O'Brien, Evan; Kasinath, Vignesh; Wand, A Joshua

    2015-05-01

    Molecular dynamics simulations are used to analyze the relationship between NMR-derived squared generalized order parameters of amide NH groups and backbone entropy. Amide order parameters (O(2) NH ) are largely determined by the secondary structure and average values appear unrelated to the overall flexibility of the protein. However, analysis of the more flexible subset (O(2) NH  entropy than that reported by the side chain methyl axis order parameters, O(2) axis . A calibration curve for backbone entropy vs. O(2) NH is developed, which accounts for both correlations between amide group motions of different residues, and correlations between backbone and side chain motions. This calibration curve can be used with experimental values of O(2) NH changes obtained by NMR relaxation measurements to extract backbone entropy changes, for example, upon ligand binding. In conjunction with our previous calibration for side chain entropy derived from measured O(2) axis values this provides a prescription for determination of the total protein conformational entropy changes from NMR relaxation measurements. © 2015 Wiley Periodicals, Inc.

  16. Conformal House

    DEFF Research Database (Denmark)

    Ryttov, Thomas; Sannino, Francesco

    2010-01-01

    fixed point. As a consistency check we recover the previously investigated conformal windows bounds when restricting to a single matter representation. The earlier conformal windows can be imagined to be part now of the new conformal house. We predict the nonperturbative anomalous dimensions...... at the infrared fixed points. We further investigate the effects of adding mass terms to the condensates on the conformal house chiral dynamics and construct the simplest instanton induced effective Lagrangian terms....

  17. The Conformational Dynamics of Cas9 Governing DNA Cleavage Are Revealed by Single-Molecule FRET

    Directory of Open Access Journals (Sweden)

    Mengyi Yang

    2018-01-01

    Full Text Available Summary: Off-target binding and cleavage by Cas9 pose major challenges in its application. How the conformational dynamics of Cas9 govern its nuclease activity under on- and off-target conditions remains largely unknown. Here, using intra-molecular single-molecule fluorescence resonance energy transfer measurements, we revealed that Cas9 in apo, sgRNA-bound, and dsDNA/sgRNA-bound forms spontaneously transits among three major conformational states, mainly reflecting significant conformational mobility of the catalytic HNH domain. We also uncovered surprising long-range allosteric communication between the HNH domain and the RNA/DNA heteroduplex at the PAM-distal end to ensure correct positioning of the catalytic site, which demonstrated that a unique proofreading mechanism served as the last checkpoint before DNA cleavage. Several Cas9 residues were likely to mediate the allosteric communication and proofreading step. Modulating interactions between Cas9 and heteroduplex at the PAM-distal end by introducing mutations on these sites provides an alternative route to improve and optimize the CRISPR/Cas9 toolbox. : Yang et al. revealed significant conformational dynamics of Cas9 at global and local scales using single-molecule FRET. They uncovered surprising long-range allosteric communication between the HNH nuclease domain and the RNA/DNA heteroduplex at the PAM-distal end that serves as a proofreading checkpoint to govern the nuclease activity and specificity of Cas9. Keywords: CRISPR, Cas9, single-molecule, FRET, conformational dynamics, proofreading, off-target, allosteric communication, genome editing

  18. Mobility and Conformational Dynamics of large DNA diffusing through Cytoskeletal Networks

    Science.gov (United States)

    Regan, Kathryn; Ricketts, Shea; Wulstein, Devynn; McGorty, Ryan; Robertson-Anderson, Rae M.

    The high concentrations of proteins crowding cells greatly influence intracellular DNA dynamics. These crowders, ranging from small mobile proteins to large cytoskeletal filaments such as semiflexible actin and rigid microtubules, can hinder diffusion and induce conformational changes in DNA. The rigidity, mobility, and concentration of crowders all play a role in DNA transport, yet previous studies have mainly focused on the effect of small mobile crowders on transport. At the same time the rigid cytoskeleton has been identified as a key factor suppressing viral transfection and gene delivery. Here, we use fluorescence microscopy and custom single-molecule conformational tracking algorithms to measure center-of-mass transport and time-varying conformational sizes and shapes of single 115 kbp DNA molecules diffusing in networks of actin filaments and microtubules. We determine the dependence of protein concentration (6 - 23 μM) and rigidity (actin vs microtubules) on DNA dynamics. Corresponding measurements with monomeric actin and tubulin identify the roles that network rigidity versus excluded volume play in transport. Initial results show that crowding by microtubules induces anomalous transport and larger, slower conformational fluctuations of DNA. Funding from AFOSR Young Investigator Program (FA95550-12-1-0315).

  19. Molecular dynamics simulations of conformation changes of HIV-1 regulatory protein on graphene

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Daohui; Li, Libo; He, Daohang; Zhou, Jian, E-mail: jianzhou@scut.edu.cn

    2016-07-30

    Graphical abstract: Preferential adsorption of Vpr13-33 on graphene accompanied by early conformational change from α-helix to β-sheet structures was observed by molecular simulations. This work presents the molecular mechanism of graphene-induced peptide conformational alteration and sheds light on developing graphene-based materials to inhibit HIV. - Highlights: • Graphene induced early structural transition of Vpr13-33 is studied by MD simulations. • Both π-π stacking and hydrophobic interactions orchestrate the peptide adsorption. • Vpr has an increased propensity of β-sheet content on graphene surface. • To develop graphene-based materials to inhibit HIV is possible. - Abstract: The fragment of viral protein R (Vpr), Vpr13-33, plays an important role in regulating nuclear importing of HIV genes through channel formation in which it adopts a leucine-zipper-like alpha-helical conformation. A recent experimental study reported that helical Vpr13-33 would transform to β-sheet or random coil structures and aggregate on the surface of graphene or graphene oxide through hydrophobic interactions. Due to experimental limitations, however, there is still a considerable lack of understanding on the adsorption dynamics at the early stage of the conformational transition at water-graphene interface and the underlying driving force at molecular level. In this study, atomistic molecular dynamics simulations were used to explore the conformation transition phenomena. Vpr13-33 kept α-helical structure in solution, but changed to β-sheet structure when strongly adsorbed onto graphene. Preferential adsorption of Vpr13-33 on graphene is dominated by hydrophobic interactions. The cluster analysis identified the most significant populated conformation and the early stage of structure conversion from α-helical to β-sheet was found, but the full β-sheet propagation was not observed. Free energy landscape analysis further complemented the transformation analysis of

  20. Molecular dynamics simulations of conformation changes of HIV-1 regulatory protein on graphene

    International Nuclear Information System (INIS)

    Zhao, Daohui; Li, Libo; He, Daohang; Zhou, Jian

    2016-01-01

    Graphical abstract: Preferential adsorption of Vpr13-33 on graphene accompanied by early conformational change from α-helix to β-sheet structures was observed by molecular simulations. This work presents the molecular mechanism of graphene-induced peptide conformational alteration and sheds light on developing graphene-based materials to inhibit HIV. - Highlights: • Graphene induced early structural transition of Vpr13-33 is studied by MD simulations. • Both π-π stacking and hydrophobic interactions orchestrate the peptide adsorption. • Vpr has an increased propensity of β-sheet content on graphene surface. • To develop graphene-based materials to inhibit HIV is possible. - Abstract: The fragment of viral protein R (Vpr), Vpr13-33, plays an important role in regulating nuclear importing of HIV genes through channel formation in which it adopts a leucine-zipper-like alpha-helical conformation. A recent experimental study reported that helical Vpr13-33 would transform to β-sheet or random coil structures and aggregate on the surface of graphene or graphene oxide through hydrophobic interactions. Due to experimental limitations, however, there is still a considerable lack of understanding on the adsorption dynamics at the early stage of the conformational transition at water-graphene interface and the underlying driving force at molecular level. In this study, atomistic molecular dynamics simulations were used to explore the conformation transition phenomena. Vpr13-33 kept α-helical structure in solution, but changed to β-sheet structure when strongly adsorbed onto graphene. Preferential adsorption of Vpr13-33 on graphene is dominated by hydrophobic interactions. The cluster analysis identified the most significant populated conformation and the early stage of structure conversion from α-helical to β-sheet was found, but the full β-sheet propagation was not observed. Free energy landscape analysis further complemented the transformation analysis of

  1. Conformational dependence of hemoglobin reactivity under high viscosity conditions: the role of solvent slaved dynamics.

    Science.gov (United States)

    Samuni, Uri; Roche, Camille J; Dantsker, David; Friedman, Joel M

    2007-10-24

    The concept of protein dynamic states is introduced. This concept is based on (i) protein dynamics being organized hierarchically with respect to solvent slaving and (ii) which tier of dynamics is operative over the time window of a given measurement. The protein dynamic state concept is used to analyze the kinetic phases derived from the recombination of carbon monoxide to sol-gel-encapsulated human adult hemoglobin (HbA) and select recombinant mutants. The temperature-dependent measurements are made under very high viscosity conditions obtained by bathing the samples in an excess of glycerol. The results are consistent with a given tier of solvent slaved dynamics becoming operative at a time delay (with respect to the onset of the measurement) that is primarily solvent- and temperature-dependent. However, the functional consequences of the dynamics are protein- and conformation-specific. The kinetic traces from both equilibrium populations and trapped allosteric intermediates show a consistent progression that exposes the role of both conformation and hydration in the control of reactivity. Iron-zinc symmetric hybrid forms of HbA are used to show the dramatic difference between the kinetic patterns for T state alpha and beta subunits. The overall results support a model for allostery in HbA in which the ligand-binding-induced transition from the deoxy T state to the high -affinity R state proceeds through a progression of T state intermediates.

  2. S and T Parameters from a Light Nonstandard Higgs versus Near Conformal Dynamics

    DEFF Research Database (Denmark)

    Foadi, Roshan; Sannino, Francesco

    2013-01-01

    We determine the contribution to the $S$ and $T$ parameters coming from extensions of the standard model featuring a light nonstandard-like Higgs particle. We neatly separate, using the Landau gauge, the contribution from the purely nonstandard Higgs sector, from the one due to the interplay...... of this sector with the standard model. If the nonstandard Higgs sector derives from a new type of near conformal dynamics, the formalism allows to precisely link the intrinsic underlying contribution with the experimentally relevant parameters....

  3. Designing molecular dynamics simulations to shift populations of the conformational states of calmodulin.

    Directory of Open Access Journals (Sweden)

    Ayse Ozlem Aykut

    Full Text Available We elucidate the mechanisms that lead to population shifts in the conformational states of calcium-loaded calmodulin (Ca(2+-CaM. We design extensive molecular dynamics simulations to classify the effects that are responsible for adopting occupied conformations available in the ensemble of NMR structures. Electrostatic interactions amongst the different regions of the protein and with its vicinal water are herein mediated by lowering the ionic strength or the pH. Amino acid E31, which is one of the few charged residues whose ionization state is highly sensitive to pH differences in the physiological range, proves to be distinctive in its control of population shifts. E31A mutation at low ionic strength results in a distinct change from an extended to a compact Ca(2+-CaM conformation within tens of nanoseconds, that otherwise occur on the time scales of microseconds. The kinked linker found in this particular compact form is observed in many of the target-bound forms of Ca(2+-CaM, increasing the binding affinity. This mutation is unique in controlling C-lobe dynamics by affecting the fluctuations between the EF-hand motif helices. We also monitor the effect of the ionic strength on the conformational multiplicity of Ca(2+-CaM. By lowering the ionic strength, the tendency of nonspecific anions in water to accumulate near the protein surface increases, especially in the vicinity of the linker. The change in the distribution of ions in the vicinal layer of water allows N- and C- lobes to span a wide variety of relative orientations that are otherwise not observed at physiological ionic strength. E31 protonation restores the conformations associated with physiological environmental conditions even at low ionic strength.

  4. Ca2+ and Mg2+ modulate conformational dynamics and stability of downstream regulatory element antagonist modulator.

    Science.gov (United States)

    Pham, Khoa; Dhulipala, Gangadhar; Gonzalez, Walter G; Gerstman, Bernard S; Regmi, Chola; Chapagain, Prem P; Miksovska, Jaroslava

    2015-05-01

    Downstream Regulatory Element Antagonist Modulator (DREAM) belongs to the family of neuronal calcium sensors (NCS) that transduce the intracellular changes in Ca(2+) concentration into a variety of responses including gene expression, regulation of Kv channel activity, and calcium homeostasis. Despite the significant sequence and structural similarities with other NCS members, DREAM shows several features unique among NCS such as formation of a tetramer in the apo-state, and interactions with various intracellular biomacromolecules including DNA, presenilin, Kv channels, and calmodulin. Here we use spectroscopic techniques in combination with molecular dynamics simulation to study conformational changes induced by Ca(2+) /Mg(2+) association to DREAM. Our data indicate a minor impact of Ca(2+) association on the overall structure of the N- and C-terminal domains, although Ca(2+) binding decreases the conformational heterogeneity as evident from the decrease in the fluorescence lifetime distribution in the Ca(2+) bound forms of the protein. Time-resolved fluorescence data indicate that Ca(2+) binding triggers a conformational transition that is characterized by more efficient quenching of Trp residue. The unfolding of DREAM occurs through an partially unfolded intermediate that is stabilized by Ca(2+) association to EF-hand 3 and EF-hand 4. The native state is stabilized with respect to the partially unfolded state only in the presence of both Ca(2+) and Mg(2+) suggesting that, under physiological conditions, Ca(2+) free DREAM exhibits a high conformational flexibility that may facilitate its physiological functions. © 2015 The Protein Society.

  5. Polarization and Segregation through Conformity Pressure and Voluntary Migration: Simulation Analysis of Co-Evolutionary Dynamics

    Directory of Open Access Journals (Sweden)

    Dai Zusai

    2017-11-01

    Full Text Available While conformity pressures people to assimilate in a community, an individual occasionally migrates among communities when the individual feels discomfort. These two factors cause segregation and cultural diversity within communities in the society. By embedding a migration dynamic into Kuran and Sandholm’s model (2008 of preference evolution, we build an agent-based model to see how the variance of preferences in the entire society quantitatively changes over time. We find from the Monte-Carlo simulations that, while preferences assimilate within a community, self-selected migrations enlarge the diversity of preferences over communities in the society. We further study how the arrival rate of migration opportunities and the degree of conformity pressures affect the variance of preferences.

  6. Conformational dynamics of dry lamellar crystals of sugar based lipids: an atomistic simulation study.

    Directory of Open Access Journals (Sweden)

    Vijayan ManickamAchari

    Full Text Available The rational design of a glycolipid application (e.g. drug delivery with a tailored property depends on the detailed understanding of its structure and dynamics. Because of the complexity of sugar stereochemistry, we have undertaken a simulation study on the conformational dynamics of a set of synthetic glycosides with different sugar groups and chain design, namely dodecyl β-maltoside, dodecyl β-cellobioside, dodecyl β-isomaltoside and a C12C10 branched β-maltoside under anhydrous conditions. We examined the chain structure in detail, including the chain packing, gauche/trans conformations and chain tilting. In addition, we also investigated the rotational dynamics of the headgroup and alkyl chains. Monoalkylated glycosides possess a small amount of gauche conformers (∼20% in the hydrophobic region of the lamellar crystal (LC phase. In contrast, the branched chain glycolipid in the fluid Lα phase has a high gauche population of up to ∼40%. Rotational diffusion analysis reveals that the carbons closest to the headgroup have the highest correlation times. Furthermore, its value depends on sugar type, where the rotational dynamics of an isomaltose was found to be 11-15% and more restrained near the sugar, possibly due to the chain disorder and partial inter-digitation compared to the other monoalkylated lipids. Intriguingly, the present simulation demonstrates the chain from the branched glycolipid bilayer has the ability to enter into the hydrophilic region. This interesting feature of the anhydrous glycolipid bilayer simulation appears to arise from a combination of lipid crowding and the amphoteric nature of the sugar headgroups.

  7. Direct observation of backbone planarization via side-chain alignment in single bulky-substituted polythiophenes

    Science.gov (United States)

    Raithel, Dominic; Simine, Lena; Pickel, Sebastian; Schötz, Konstantin; Panzer, Fabian; Baderschneider, Sebastian; Schiefer, Daniel; Lohwasser, Ruth; Köhler, Jürgen; Thelakkat, Mukundan; Sommer, Michael; Köhler, Anna; Rossky, Peter J.; Hildner, Richard

    2018-03-01

    The backbone conformation of conjugated polymers affects, to a large extent, their optical and electronic properties. The usually flexible substituents provide solubility and influence the packing behavior of conjugated polymers in films or in bad solvents. However, the role of the side chains in determining and potentially controlling the backbone conformation, and thus the optical and electronic properties on the single polymer level, is currently under debate. Here, we investigate directly the impact of the side chains by studying the bulky-substituted poly(3-(2,5-dioctylphenyl)thiophene) (PDOPT) and the common poly(3-hexylthiophene) (P3HT), both with a defined molecular weight and high regioregularity, using low-temperature single-chain photoluminescence (PL) spectroscopy and quantum-classical simulations. Surprisingly, the optical transition energy of PDOPT is significantly (˜2,000 cm‑1 or 0.25 eV) red-shifted relative to P3HT despite a higher static and dynamic disorder in the former. We ascribe this red shift to a side-chain induced backbone planarization in PDOPT, supported by temperature-dependent ensemble PL spectroscopy. Our atomistic simulations reveal that the bulkier 2,5-dioctylphenyl side chains of PDOPT adopt a clear secondary helical structural motif and thus protect conjugation, i.e., enforce backbone planarity, whereas, for P3HT, this is not the case. These different degrees of planarity in both thiophenes do not result in different conjugation lengths, which we found to be similar. It is rather the stronger electronic coupling between the repeating units in the more planar PDOPT which gives rise to the observed spectral red shift as well as to a reduced calculated electron‑hole polarization.

  8. Conformational entropy changes upon lactose binding to the carbohydrate recognition domain of galectin-3

    International Nuclear Information System (INIS)

    Diehl, Carl; Genheden, Samuel; Modig, Kristofer; Ryde, Ulf; Akke, Mikael

    2009-01-01

    The conformational entropy of proteins can make significant contributions to the free energy of ligand binding. NMR spin relaxation enables site-specific investigation of conformational entropy, via order parameters that parameterize local reorientational fluctuations of rank-2 tensors. Here we have probed the conformational entropy of lactose binding to the carbohydrate recognition domain of galectin-3 (Gal3), a protein that plays an important role in cell growth, cell differentiation, cell cycle regulation, and apoptosis, making it a potential target for therapeutic intervention in inflammation and cancer. We used 15 N spin relaxation experiments and molecular dynamics simulations to monitor the backbone amides and secondary amines of the tryptophan and arginine side chains in the ligand-free and lactose-bound states of Gal3. Overall, we observe good agreement between the experimental and computed order parameters of the ligand-free and lactose-bound states. Thus, the 15 N spin relaxation data indicate that the molecular dynamics simulations provide reliable information on the conformational entropy of the binding process. The molecular dynamics simulations reveal a correlation between the simulated order parameters and residue-specific backbone entropy, re-emphasizing that order parameters provide useful estimates of local conformational entropy. The present results show that the protein backbone exhibits an increase in conformational entropy upon binding lactose, without any accompanying structural changes

  9. Active Polymers — Emergent Conformational and Dynamical Properties: A Brief Review

    Science.gov (United States)

    Winkler, Roland G.; Elgeti, Jens; Gompper, Gerhard

    2017-10-01

    Active matter exhibits a wealth of emerging nonequilibrium behaviours. A paradigmatic example is the interior of cells, where active components, such as the cytoskeleton, are responsible for its structural organization and the dynamics of the various components. Of particular interest are the properties of polymers and filaments. The intimate coupling of thermal and active noise, hydrodynamic interactions, and polymer conformations implies the emergence of novel structural and dynamical features. In this article, we review recent theoretical and simulation developments and results for the structural and dynamical properties of polymers exposed to activity. Two- and three-dimensional filaments are considered propelled by different mechanisms such as active Brownian particles or hydrodynamically-coupled force dipoles.

  10. Activation of Hsp90 Enzymatic Activity and Conformational Dynamics through Rationally Designed Allosteric Ligands.

    Science.gov (United States)

    Sattin, Sara; Tao, Jiahui; Vettoretti, Gerolamo; Moroni, Elisabetta; Pennati, Marzia; Lopergolo, Alessia; Morelli, Laura; Bugatti, Antonella; Zuehlke, Abbey; Moses, Mike; Prince, Thomas; Kijima, Toshiki; Beebe, Kristin; Rusnati, Marco; Neckers, Len; Zaffaroni, Nadia; Agard, David A; Bernardi, Anna; Colombo, Giorgio

    2015-09-21

    Hsp90 is a molecular chaperone of pivotal importance for multiple cell pathways. ATP-regulated internal dynamics are critical for its function and current pharmacological approaches block the chaperone with ATP-competitive inhibitors. Herein, a general approach to perturb Hsp90 through design of new allosteric ligands aimed at modulating its functional dynamics is proposed. Based on the characterization of a first set of 2-phenylbenzofurans showing stimulatory effects on Hsp90 ATPase and conformational dynamics, new ligands were developed that activate Hsp90 by targeting an allosteric site, located 65 Å from the active site. Specifically, analysis of protein responses to first-generation activators was exploited to guide the design of novel derivatives with improved ability to stimulate ATP hydrolysis. The molecules' effects on Hsp90 enzymatic, conformational, co-chaperone and client-binding properties were characterized through biochemical, biophysical and cellular approaches. These designed probes act as allosteric activators of the chaperone and affect the viability of cancer cell lines for which proper functioning of Hsp90 is necessary. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. Collective Dynamics of Belief Evolution under Cognitive Coherence and Social Conformity.

    Science.gov (United States)

    Rodriguez, Nathaniel; Bollen, Johan; Ahn, Yong-Yeol

    2016-01-01

    Human history has been marked by social instability and conflict, often driven by the irreconcilability of opposing sets of beliefs, ideologies, and religious dogmas. The dynamics of belief systems has been studied mainly from two distinct perspectives, namely how cognitive biases lead to individual belief rigidity and how social influence leads to social conformity. Here we propose a unifying framework that connects cognitive and social forces together in order to study the dynamics of societal belief evolution. Each individual is endowed with a network of interacting beliefs that evolves through interaction with other individuals in a social network. The adoption of beliefs is affected by both internal coherence and social conformity. Our framework may offer explanations for how social transitions can arise in otherwise homogeneous populations, how small numbers of zealots with highly coherent beliefs can overturn societal consensus, and how belief rigidity protects fringe groups and cults against invasion from mainstream beliefs, allowing them to persist and even thrive in larger societies. Our results suggest that strong consensus may be insufficient to guarantee social stability, that the cognitive coherence of belief-systems is vital in determining their ability to spread, and that coherent belief-systems may pose a serious problem for resolving social polarization, due to their ability to prevent consensus even under high levels of social exposure. We argue that the inclusion of cognitive factors into a social model could provide a more complete picture of collective human dynamics.

  12. Retrieving Backbone String Neighbors Provides Insights Into Structural Modeling of Membrane Proteins*

    Science.gov (United States)

    Sun, Jiang-Ming; Li, Tong-Hua; Cong, Pei-Sheng; Tang, Sheng-Nan; Xiong, Wen-Wei

    2012-01-01

    Identification of protein structural neighbors to a query is fundamental in structure and function prediction. Here we present BS-align, a systematic method to retrieve backbone string neighbors from primary sequences as templates for protein modeling. The backbone conformation of a protein is represented by the backbone string, as defined in Ramachandran space. The backbone string of a query can be accurately predicted by two innovative technologies: a knowledge-driven sequence alignment and encoding of a backbone string element profile. Then, the predicted backbone string is employed to align against a backbone string database and retrieve a set of backbone string neighbors. The backbone string neighbors were shown to be close to native structures of query proteins. BS-align was successfully employed to predict models of 10 membrane proteins with lengths ranging between 229 and 595 residues, and whose high-resolution structural determinations were difficult to elucidate both by experiment and prediction. The obtained TM-scores and root mean square deviations of the models confirmed that the models based on the backbone string neighbors retrieved by the BS-align were very close to the native membrane structures although the query and the neighbor shared a very low sequence identity. The backbone string system represents a new road for the prediction of protein structure from sequence, and suggests that the similarity of the backbone string would be more informative than describing a protein as belonging to a fold. PMID:22415040

  13. Retrieving backbone string neighbors provides insights into structural modeling of membrane proteins.

    Science.gov (United States)

    Sun, Jiang-Ming; Li, Tong-Hua; Cong, Pei-Sheng; Tang, Sheng-Nan; Xiong, Wen-Wei

    2012-07-01

    Identification of protein structural neighbors to a query is fundamental in structure and function prediction. Here we present BS-align, a systematic method to retrieve backbone string neighbors from primary sequences as templates for protein modeling. The backbone conformation of a protein is represented by the backbone string, as defined in Ramachandran space. The backbone string of a query can be accurately predicted by two innovative technologies: a knowledge-driven sequence alignment and encoding of a backbone string element profile. Then, the predicted backbone string is employed to align against a backbone string database and retrieve a set of backbone string neighbors. The backbone string neighbors were shown to be close to native structures of query proteins. BS-align was successfully employed to predict models of 10 membrane proteins with lengths ranging between 229 and 595 residues, and whose high-resolution structural determinations were difficult to elucidate both by experiment and prediction. The obtained TM-scores and root mean square deviations of the models confirmed that the models based on the backbone string neighbors retrieved by the BS-align were very close to the native membrane structures although the query and the neighbor shared a very low sequence identity. The backbone string system represents a new road for the prediction of protein structure from sequence, and suggests that the similarity of the backbone string would be more informative than describing a protein as belonging to a fold.

  14. Hadron spectroscopy and dynamics from light-front holography and conformal symmetry

    Directory of Open Access Journals (Sweden)

    de Téramond Guy F.

    2014-06-01

    Full Text Available To a first semiclassical approximation one can reduce the multi-parton light-front problem in QCD to an effective one-dimensional quantum field theory, which encodes the fundamental conformal symmetry of the classical QCD Lagrangian. This procedure leads to a relativistic light-front wave equation for arbitrary spin which incorporates essential spectroscopic and non-perturbative dynamical features of hadron physics. The mass scale for confinement and higher dimensional holographic mapping to AdS space are also emergent properties of this framework.

  15. The Conformational Dynamics of Cas9 Governing DNA Cleavage Are Revealed by Single-Molecule FRET.

    Science.gov (United States)

    Yang, Mengyi; Peng, Sijia; Sun, Ruirui; Lin, Jingdi; Wang, Nan; Chen, Chunlai

    2018-01-09

    Off-target binding and cleavage by Cas9 pose major challenges in its application. How the conformational dynamics of Cas9 govern its nuclease activity under on- and off-target conditions remains largely unknown. Here, using intra-molecular single-molecule fluorescence resonance energy transfer measurements, we revealed that Cas9 in apo, sgRNA-bound, and dsDNA/sgRNA-bound forms spontaneously transits among three major conformational states, mainly reflecting significant conformational mobility of the catalytic HNH domain. We also uncovered surprising long-range allosteric communication between the HNH domain and the RNA/DNA heteroduplex at the PAM-distal end to ensure correct positioning of the catalytic site, which demonstrated that a unique proofreading mechanism served as the last checkpoint before DNA cleavage. Several Cas9 residues were likely to mediate the allosteric communication and proofreading step. Modulating interactions between Cas9 and heteroduplex at the PAM-distal end by introducing mutations on these sites provides an alternative route to improve and optimize the CRISPR/Cas9 toolbox. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  16. New binding site conformations of the dengue virus NS3 protease accessed by molecular dynamics simulation.

    Directory of Open Access Journals (Sweden)

    Hugo de Almeida

    Full Text Available Dengue fever is caused by four distinct serotypes of the dengue virus (DENV1-4, and is estimated to affect over 500 million people every year. Presently, there are no vaccines or antiviral treatments for this disease. Among the possible targets to fight dengue fever is the viral NS3 protease (NS3PRO, which is in part responsible for viral processing and replication. It is now widely recognized that virtual screening campaigns should consider the flexibility of target protein by using multiple active conformational states. The flexibility of the DENV NS3PRO could explain the relatively low success of previous virtual screening studies. In this first work, we explore the DENV NS3PRO conformational states obtained from molecular dynamics (MD simulations to take into account protease flexibility during the virtual screening/docking process. To do so, we built a full NS3PRO model by multiple template homology modeling. The model comprised the NS2B cofactor (essential to the NS3PRO activation, a glycine flexible link and the proteolytic domain. MD simulations had the purpose to sample, as closely as possible, the ligand binding site conformational landscape prior to inhibitor binding. The obtained conformational MD sample was clustered into four families that, together with principal component analysis of the trajectory, demonstrated protein flexibility. These results allowed the description of multiple binding modes for the Bz-Nle-Lys-Arg-Arg-H inhibitor, as verified by binding plots and pair interaction analysis. This study allowed us to tackle protein flexibility in our virtual screening campaign against the dengue virus NS3 protease.

  17. A variational conformational dynamics approach to the selection of collective variables in metadynamics

    Science.gov (United States)

    McCarty, James; Parrinello, Michele

    2017-11-01

    In this paper, we combine two powerful computational techniques, well-tempered metadynamics and time-lagged independent component analysis. The aim is to develop a new tool for studying rare events and exploring complex free energy landscapes. Metadynamics is a well-established and widely used enhanced sampling method whose efficiency depends on an appropriate choice of collective variables. Often the initial choice is not optimal leading to slow convergence. However by analyzing the dynamics generated in one such run with a time-lagged independent component analysis and the techniques recently developed in the area of conformational dynamics, we obtain much more efficient collective variables that are also better capable of illuminating the physics of the system. We demonstrate the power of this approach in two paradigmatic examples.

  18. Two-dimensional NMR investigations of the dynamic conformations of phospholipids and liquid crystals

    Energy Technology Data Exchange (ETDEWEB)

    Hong, Mei [Univ. of California, Berkeley, CA (United States). Applied Science and Technology

    1996-05-01

    Two-dimensional 13C, 1H, and 31P nuclear magnetic resonance (NMR) techniques are developed and used to study molecular structure and dynamics in liquid-crystalline systems, primarily phospholipids and nematic liquid crystals. NMR spectroscopy characterizes molecular conformation in terms of orientations and distances of molecular segments. In anisotropically mobile systems, this is achieved by measuring motionally-averaged nuclear dipolar couplings and chemical shift anisotropies. The short-range couplings yield useful bond order parameters, while the long-range interactions constrain the overall conformation. In this work, techniques for probing proton dipolar local fields are further developed to obtain highlyresolved dipolar couplings between protons and rare spins. By exploiting variable-angle sample spinning techniques, orientation-sensitive NMR spectra are resolved according to sitespecific isotropic chemical shifts. Moreover, the signs and magnitudes of various short-range dipolar couplings are obtained. They are used in novel theoretical analyses that provide information about segmental orientations and their distributions. Such information is obtained in a model-independent fashion or with physically reasonable assumptions. The structural investigation of phospholipids is focused on the dynam

  19. Thermal fluctuations of haemoglobin from different species: adaptation to temperature via conformational dynamics

    Science.gov (United States)

    Stadler, A. M.; Garvey, C. J.; Bocahut, A.; Sacquin-Mora, S.; Digel, I.; Schneider, G. J.; Natali, F.; Artmann, G. M.; Zaccai, G.

    2012-01-01

    Thermodynamic stability, configurational motions and internal forces of haemoglobin (Hb) of three endotherms (platypus, Ornithorhynchus anatinus; domestic chicken, Gallus gallus domesticus and human, Homo sapiens) and an ectotherm (salt water crocodile, Crocodylus porosus) were investigated using circular dichroism, incoherent elastic neutron scattering and coarse-grained Brownian dynamics simulations. The experimental results from Hb solutions revealed a direct correlation between protein resilience, melting temperature and average body temperature of the different species on the 0.1 ns time scale. Molecular forces appeared to be adapted to permit conformational fluctuations with a root mean square displacement close to 1.2 Å at the corresponding average body temperature of the endotherms. Strong forces within crocodile Hb maintain the amplitudes of motion within a narrow limit over the entire temperature range in which the animal lives. In fully hydrated powder samples of human and chicken, Hb mean square displacements and effective force constants on the 1 ns time scale showed no differences over the whole temperature range from 10 to 300 K, in contrast to the solution case. A complementary result of the study, therefore, is that one hydration layer is not sufficient to activate all conformational fluctuations of Hb in the pico- to nanosecond time scale which might be relevant for biological function. Coarse-grained Brownian dynamics simulations permitted to explore residue-specific effects. They indicated that temperature sensing of human and chicken Hb occurs mainly at residues lining internal cavities in the β-subunits. PMID:22696485

  20. Cosmological Consequences of Nearly Conformal Dynamics at the TeV scale

    CERN Document Server

    Konstandin, Thomas

    2011-01-01

    Nearly conformal dynamics at the TeV scale as motivated by the hierarchy problem can be characterized by a stage of significant supercooling at the electroweak epoch. This has important cosmological consequences. In particular, a common assumption about the history of the universe is that the reheating temperature is high, at least high enough to assume that TeV-mass particles were once in thermal equilibrium. However, as we discuss in this paper, this assumption is not well justified in some models of strong dynamics at the TeV scale. We then need to reexamine how to achieve baryogenesis in these theories as well as reconsider how the dark matter abundance is inherited. We argue that baryonic and dark matter abundances can be explained naturally in these setups where reheating takes place by bubble collisions at the end of the strongly first-order phase transition characterizing conformal symmetry breaking, even if the reheating temperature is below the electroweak scale $\\sim 100$ GeV. We also discuss infla...

  1. pKa of the essential Glu54 and backbone conformation for subunit c from the H+-coupled F1F0 ATP synthase from an alkaliphilic Bacillus.

    Science.gov (United States)

    Rivera-Torres, Iván O; Krueger-Koplin, Ray D; Hicks, David B; Cahill, Sean M; Krulwich, Terry A; Girvin, Mark E

    2004-09-24

    The conformation of the ATP synthase c-subunit and the pKa of its essential E54 residue were characterized in alkaliphilic Bacillus pseudofirmus OF4. The c-subunit folds as a helix-loop-helix, with inter-helical contacts demonstrated by paramagnetic relaxation effects. The E54 pKa of 7.7 is significantly higher than in non-alkaliphiles, which likely prevents proton loss from the c-rotor at high pH. The E54 pKa was unchanged in a mutant, cP51A, that has a severe ATP synthesis defect at high pH only. cP51 must have some structural role that accounts for the mutant defect, such as different subunit-subunit interactions at high pH.

  2. Dynamic Optimization and Conformity in Health Behavior and Life Enjoyment over the Life Cycle

    Directory of Open Access Journals (Sweden)

    Hernan Daniel Bejarano

    2015-06-01

    Full Text Available This article examines individual and social influences on investments in health and enjoyment from immediate consumption. Our lab experiment mimics the problem of health investment over a lifetime (Grossman 1972a, 1972b. Incentives to find the appropriate expenditures on life enjoyment and health are given by making in each period come period a function of previous health investments. In order to model social effects in the experiment, we randomly assigned individuals to chat/observation groups. Groups were permitted to freely chat between repeated lifetimes. Two treatments were employed: In the Independent-rewards treatment, an individual’s rewards from investments in life enjoyment depend only on his choice and in the Interdependent-rewards treatment; rewards not only depend on an individual’s choices but also on their similarity to the choices of the others in their group, generating a premium on conformity. The principal hypothesis is that gains from conformity increase variance in health behavior among groups and can lead to suboptimal performance. We tested three predictions and each was supported by the data: the Interdependent-rewards treatment 1 decreased within-group variance, 2 increased between-group variance, and 3 increased the likelihood of behavior far from the optimum with respect to the dynamic problem. We also test and find support for a series of subsidiary hypotheses. We found: 4 Subjects engaged in helpful chat in both treatments; 5 there was significant heterogeneity among both subjects and groups in chat frequencies; and 6 chat was most common early in the experiment, and 7 the interdependent rewards treatment increased strategic chat frequency. Incentives for conformity appear to promote prosocial behavior, but also increase variance among groups, leading to convergence on suboptimal strategies for some groups. We discuss these results in light of the growing literature focusing on social networks and health outcomes.

  3. Dynamic optimization and conformity in health behavior and life enjoyment over the life cycle.

    Science.gov (United States)

    Bejarano, Hernán D; Kaplan, Hillard; Rassenti, Stephen

    2015-01-01

    This article examines individual and social influences on investments in health and enjoyment from immediate consumption. Our lab experiment mimics the problem of health investment over a lifetime (Grossman, 1972a,b). Incentives to find the appropriate expenditures on life enjoyment and health are given by making in each period come period a function of previous health investments. In order to model social effects in the experiment, we randomly assigned individuals to chat/observation groups. Groups were permitted to freely chat between repeated lifetimes. Two treatments were employed: In the Independent-rewards treatment, an individual's rewards from investments in life enjoyment depend only on his choice and in the Interdependent-rewards treatment; rewards not only depend on an individual's choices but also on their similarity to the choices of the others in their group, generating a premium on conformity. The principal hypothesis is that gains from conformity increase variance in health behavior among groups and can lead to suboptimal performance. We tested three predictions and each was supported by the data: the Interdependent-rewards treatment (1) decreased within-group variance, (2) increased between-group variance, and (3) increased the likelihood of behavior far from the optimum with respect to the dynamic problem. We also test and find support for a series of subsidiary hypotheses. We found: (4) Subjects engaged in helpful chat in both treatments; (5) there was significant heterogeneity among both subjects and groups in chat frequencies; and (6) chat was most common early in the experiment, and (7) the interdependent rewards treatment increased strategic chat frequency. Incentives for conformity appear to promote prosocial behavior, but also increase variance among groups, leading to convergence on suboptimal strategies for some groups. We discuss these results in light of the growing literature focusing on social networks and health outcomes.

  4. Isolate-Specific Differences in the Conformational Dynamics and Antigenicity of HIV-1 gp120

    Science.gov (United States)

    Davenport, Thaddeus M.; Guttman, Miklos; Guo, Wenjin; Cleveland, Brad; Kahn, Maria; Hu, Shiu-Lok

    2013-01-01

    The HIV-1 envelope glycoprotein (Env) mediates viral entry into host cells and is the sole target of neutralizing antibodies. Much of the sequence diversity in the HIV-1 genome is concentrated within Env, particularly within its gp120 surface subunit. While dramatic functional diversity exists among HIV-1 Env isolates—observable even in the context of monomeric gp120 proteins as differences in antigenicity and immunogenicity—we have little understanding of the structural features that distinguish Env isolates and lead to isolate-specific functional differences, as crystal structures of truncated gp120 “core” proteins from diverse isolates reveal a high level of structural conservation. Because gp120 proteins are used as prospective vaccine immunogens, it is critical to understand the structural factors that influence their reactivity with antibodies. Here, we studied four full-length, glycosylated gp120 monomers from diverse HIV-1 isolates by using small-angle X-ray scattering (SAXS) to probe the overall subunit morphology and hydrogen/deuterium-exchange with mass spectrometry (HDX-MS) to characterize the local structural order of each gp120. We observed that while the overall subunit architecture was similar among isolates by SAXS, dramatic isolate-specific differences in the conformational stability of gp120 were evident by HDX-MS. These differences persisted even with the CD4 receptor bound. Furthermore, surface plasmon resonance (SPR) and enzyme-linked immunosorbance assays (ELISAs) showed that disorder was associated with poorer recognition by antibodies targeting conserved conformational epitopes. These data provide additional insight into the structural determinants of gp120 antigenicity and suggest that conformational dynamics should be considered in the selection and design of optimized Env immunogens. PMID:23903848

  5. Characterizing highly dynamic conformational states: The transcription bubble in RNAP-promoter open complex as an example

    Science.gov (United States)

    Lerner, Eitan; Ingargiola, Antonino; Weiss, Shimon

    2018-03-01

    Bio-macromolecules carry out complicated functions through structural changes. To understand their mechanism of action, the structure of each step has to be characterized. While classical structural biology techniques allow the characterization of a few "structural snapshots" along the enzymatic cycle (usually of stable conformations), they do not cover all (and often fast interconverting) structures in the ensemble, where each may play an important functional role. Recently, several groups have demonstrated that structures of different conformations in solution could be solved by measuring multiple distances between different pairs of residues using single-molecule Förster resonance energy transfer (smFRET) and using them as constrains for hybrid/integrative structural modeling. However, this approach is limited in cases where the conformational dynamics is faster than the technique's temporal resolution. In this study, we combine existing tools that elucidate sub-millisecond conformational dynamics together with hybrid/integrative structural modeling to study the conformational states of the transcription bubble in the bacterial RNA polymerase-promoter open complex (RPo). We measured microsecond alternating laser excitation-smFRET of differently labeled lacCONS promoter dsDNA constructs. We used a combination of burst variance analysis, photon-by-photon hidden Markov modeling, and the FRET-restrained positioning and screening approach to identify two conformational states for RPo. The experimentally derived distances of one conformational state match the known crystal structure of bacterial RPo. The experimentally derived distances of the other conformational state have characteristics of a scrunched RPo. These findings support the hypothesis that sub-millisecond dynamics in the transcription bubble are responsible for transcription start site selection.

  6. Conformational Ensembles Explored Dynamically from Disordered Peptides Targeting Chemokine Receptor CXCR4

    Directory of Open Access Journals (Sweden)

    Marian Vincenzi

    2015-05-01

    Full Text Available This work reports on the design and the synthesis of two short linear peptides both containing a few amino acids with disorder propensity and an allylic ester group at the C-terminal end. Their structural properties were firstly analyzed by means of experimental techniques in solution such as CD and NMR methods that highlighted peptide flexibility. These results were further confirmed by MD simulations that demonstrated the ability of the peptides to assume conformational ensembles. They revealed a network of transient and dynamic H-bonds and interactions with water molecules. Binding assays with a well-known drug-target, i.e., the CXCR4 receptor, were also carried out in an attempt to verify their biological function and the possibility to use the assays to develop new specific targets for CXCR4. Moreover, our data indicate that these peptides represent useful tools for molecular recognition processes in which a flexible conformation is required in order to obtain an interaction with a specific target.

  7. Conformational ensembles explored dynamically from disordered peptides targeting chemokine receptor CXCR4.

    Science.gov (United States)

    Vincenzi, Marian; Costantini, Susan; Scala, Stefania; Tesauro, Diego; Accardo, Antonella; Leone, Marilisa; Colonna, Giovanni; Guillon, Jean; Portella, Luigi; Trotta, Anna Maria; Ronga, Luisa; Rossi, Filomena

    2015-05-28

    This work reports on the design and the synthesis of two short linear peptides both containing a few amino acids with disorder propensity and an allylic ester group at the C-terminal end. Their structural properties were firstly analyzed by means of experimental techniques in solution such as CD and NMR methods that highlighted peptide flexibility. These results were further confirmed by MD simulations that demonstrated the ability of the peptides to assume conformational ensembles. They revealed a network of transient and dynamic H-bonds and interactions with water molecules. Binding assays with a well-known drug-target, i.e., the CXCR4 receptor, were also carried out in an attempt to verify their biological function and the possibility to use the assays to develop new specific targets for CXCR4. Moreover, our data indicate that these peptides represent useful tools for molecular recognition processes in which a flexible conformation is required in order to obtain an interaction with a specific target.

  8. Adsorbed Conformations of PCE Superplasticizers in Cement Pore Solution Unraveled by Molecular Dynamics Simulations.

    Science.gov (United States)

    Hirata, Tsuyoshi; Ye, Jun; Branicio, Paulo; Zheng, Jianwei; Lange, Alex; Plank, Johann; Sullivan, Michael

    2017-11-30

    The conformations of polycarboxylate ether (PCE) type superplasticizer polymers adsorbed on the surface of MgO in cement pore solution are simulated by molecular dynamics (MD). Three types of PCEs commonly applied to concrete are simulated, namely a methacrylate type PCE (PCEM-P), an allyl ether type PCE (PCEA-P), and an isoprenyl ether type PCE (PCEI-P) with ethylene oxide (EO) unit numbers (P) of 25, 34 and 25, respectively. It is observed that the adsorbed layer thickness is inversely proportional to the experimentally measured adsorbed amount at the initial paste flow of 26 ± 0.5 cm. Simulation results indicate that the adsorbed layer thickness is sensitive to the initial polymer orientations against the model MgO surface. I.e., polymer molecules initially placed parallel/perpendicularly against the MgO surface gradually forms a train shaped or a loop and tail adsorption profile, respectively. As a result, the loop and tail shaped conformation gives a higher layer thickness.

  9. Probing Conformational Dynamics of Tau Protein by Hydrogen/Deuterium Exchange Mass Spectrometry

    Science.gov (United States)

    Huang, Richard Y.-C.; Iacob, Roxana E.; Sankaranarayanan, Sethu; Yang, Ling; Ahlijanian, Michael; Tao, Li; Tymiak, Adrienne A.; Chen, Guodong

    2018-01-01

    Fibrillization of the microtubule-associated protein tau has been recognized as one of the signature pathologies of the nervous system in Alzheimer's disease, progressive supranuclear palsy, and other tauopathies. The conformational transition of tau in the fibrillization process, tau monomer to soluble aggregates to fibrils in particular, remains unclear. Here we report on the use of hydrogen/deuterium exchange mass spectrometry (HDX-MS) in combination with other biochemical approaches, including Thioflavin S fluorescence measurements, enzyme-linked immunosorbent assay (ELISA), and Western blotting to understand the heparin-induced tau's fibrillization. HDX-MS studies including anti-tau antibody epitope mapping experiments provided molecular level details of the full-length tau's conformational dynamics and its regional solvent accessibility upon soluble aggregates formation. The results demonstrate that R3 region in the full-length tau's microtubule binding repeat region (MTBR) is stabilized in the aggregation process, leaving both N and C terminal regions to be solvent exposed in the soluble aggregates and fibrils. The findings also illustrate the practical utility of orthogonal analytical methodologies for the characterization of protein higher order structure. [Figure not available: see fulltext.

  10. Elucidation of the conformational dynamics of multi-body systems by construction of Markov state models.

    Science.gov (United States)

    Zhu, Lizhe; Sheong, Fu Kit; Zeng, Xiangze; Huang, Xuhui

    2016-11-09

    Constructing Markov State Models (MSMs) based on short molecular dynamics simulations is a powerful computational technique to complement experiments in predicting long-time kinetics of biomolecular processes at atomic resolution. Even though the MSM approach has been widely applied to study one-body processes such as protein folding and enzyme conformational changes, the majority of biological processes, e.g. protein-ligand recognition, signal transduction, and protein aggregation, essentially involve multiple entities. Here we review the attempts at constructing MSMs for multi-body systems, point out the challenges therein and discuss recent algorithmic progresses that alleviate these challenges. In particular, we describe an automatic kinetics based partitioning method that achieves optimal definition of the conformational states in a multi-body system, and discuss a novel maximum-likelihood approach that efficiently estimates the slow uphill kinetics utilizing pre-computed equilibrium populations of all states. We expect that these new algorithms and their combinations may boost investigations of important multi-body biological processes via the efficient construction of MSMs.

  11. NATO Advanced Study Institute on Photophysical and Photochemical Tools in Polymer Science : Conformation, Dynamics, Morphology

    CERN Document Server

    1986-01-01

    In 1980 the New York Academy of Sciences sponsored a three-day conference on luminescence in biological and synthetic macromolecules. After that meeting, Professor Frans DeSchryver and I began to discuss the possibility of organizing a different kind of meeting, with time for both informal and in-depth discussions, to examine certain aspects of the application of fluorescence and phosphorescence spectroscopy to polymers. Our ideas developed through discussions with many others, particularly Professor Lucien Monnerie. By 1983, when we submitted our proposal to NATO for an Advanced Study Institute, the area had grown enormous ly. It is interesting in retrospect to look back on the points which emerged from these discussions as the basis around which the scientific program would be organized and the speakers chosen. We decided early on to focus on applications of these methods to provide information about polymer molecules and polymer systems: The topics would all relate to the conformation and dynamics of macro...

  12. Backbone assignment of the binary complex of the full length Sulfolobus solfataricus DNA polymerase IV and DNA.

    Science.gov (United States)

    Lee, Eunjeong; Fowler, Jason D; Suo, Zucai; Wu, Zhengrong

    2017-04-01

    Sulfolobus solfataricus DNA polymerase IV (Dpo4), a model Y-family DNA polymerase, bypasses a wide range of DNA lesions in vitro and in vivo. In this paper, we report the backbone chemical shift assignments of the full length Dpo4 in its binary complex with a 14/14-mer DNA substrate. Upon DNA binding, several β-stranded regions in the isolated catalytic core and little finger/linker fragments of Dpo4 become more structured. This work serves as a foundation for our ongoing investigation of conformational dynamics of Dpo4 and future determination of the first solution structures of a DNA polymerase and its binary and ternary complexes.

  13. Molecular dynamics coupled with a virtual system for effective conformational sampling.

    Science.gov (United States)

    Hayami, Tomonori; Kasahara, Kota; Nakamura, Haruki; Higo, Junichi

    2018-02-21

    An enhanced conformational sampling method is proposed: virtual-system coupled canonical molecular dynamics (VcMD). Although VcMD enhances sampling along a reaction coordinate, this method is free from estimation of a canonical distribution function along the reaction coordinate. This method introduces a virtual system that does not necessarily obey a physical law. To enhance sampling the virtual system couples with a molecular system to be studied. Resultant snapshots produce a canonical ensemble. This method was applied to a system consisting of two short peptides in an explicit solvent. Conventional molecular dynamics simulation, which is ten times longer than VcMD, was performed along with adaptive umbrella sampling. Free-energy landscapes computed from the three simulations mutually converged well. The VcMD provided quicker association/dissociation motions of peptides than the conventional molecular dynamics did. The VcMD method is applicable to various complicated systems because of its methodological simplicity. © 2018 Wiley Periodicals, Inc. © 2018 Wiley Periodicals, Inc.

  14. Mapping the Conformational Dynamics of E-selectin upon Interaction with its Ligands

    KAUST Repository

    Aleisa, Fajr A

    2013-05-15

    Selectins are key adhesion molecules responsible for initiating a multistep process that leads a cell out of the blood circulation and into a tissue or organ. The adhesion of cells (expressing ligands) to the endothelium (expressing the selectin i.e.,E-selectin) occurs through spatio-temporally regulated interactions that are mediated by multiple intra- and inter-cellular components. The mechanism of cell adhesion is investigated primarily using ensemble-based experiments, which provides indirect information about how individual molecules work in such a complex system. Recent developments in single-molecule (SM) fluorescence detection allow for the visualization of individual molecules with a good spatio-temporal resolution nanometer spatial resolution and millisecond time resolution). Furthermore, advanced SM fluorescence techniques such as Förster Resonance Energy Transfer (FRET) and super-resolution microscopy provide unique opportunities to obtain information about nanometer-scale conformational dynamics of proteins as well as nano-scale architectures of biological samples. Therefore, the state-of-the-art SM techniques are powerful tools for investigating complex biological system such as the mechanism of cell adhesion. In this project, several constructs of fluorescently labeled E-selectin will be used to study the conformational dynamics of E-selectin binding to its ligand(s) using SM-FRET and combination of SM-FRET and force microscopy. These studies will be beneficial to fully understand the mechanistic details of cell adhesion and migration of cells using the established model system of hematopoietic stem cells (HSCs) adhesion to the selectin expressing endothelial cells (such as the E-selectin expressing endothelial cells in the bone marrow).

  15. Direct evidence for conformational dynamics in major histocompatibility complex class I molecules.

    Science.gov (United States)

    van Hateren, Andy; Anderson, Malcolm; Bailey, Alistair; Werner, Jörn M; Skipp, Paul; Elliott, Tim

    2017-12-08

    Major histocompatibility complex class I molecules (MHC I) help protect jawed vertebrates by binding and presenting immunogenic peptides to cytotoxic T lymphocytes. Peptides are selected from a large diversity present in the endoplasmic reticulum. However, only a limited number of peptides complement the polymorphic MHC specificity determining pockets in a way that leads to high-affinity peptide binding and efficient antigen presentation. MHC I molecules possess an intrinsic ability to discriminate between peptides, which varies in efficiency between allotypes, but the mechanism of selection is unknown. Elucidation of the selection mechanism is likely to benefit future immune-modulatory therapies. Evidence suggests peptide selection involves transient adoption of alternative, presumably higher energy conformations than native peptide-MHC complexes. However, the instability of peptide-receptive MHC molecules has hindered characterization of such conformational plasticity. To investigate the dynamic nature of MHC, we refolded MHC proteins with peptides that can be hydrolyzed by UV light and thus released. We compared the resultant peptide-receptive MHC molecules with non-hydrolyzed peptide-loaded MHC complexes by monitoring the exchange of hydrogen for deuterium in solution. We found differences in hydrogen-deuterium exchange between peptide-loaded and peptide-receptive molecules that were negated by the addition of peptide to peptide-receptive MHC molecules. Peptide hydrolysis caused significant increases in hydrogen-deuterium exchange in sub-regions of the peptide-binding domain and smaller increases elsewhere, including in the α3 domain and the non-covalently associated β 2 -microglobulin molecule, demonstrating long-range dynamic communication. Comparing two MHC allotypes revealed allotype-specific differences in hydrogen-deuterium exchange, consistent with the notion that MHC I plasticity underpins peptide selection. © 2017 by The American Society for

  16. Adding diverse noncanonical backbones to rosetta: enabling peptidomimetic design.

    Directory of Open Access Journals (Sweden)

    Kevin Drew

    Full Text Available Peptidomimetics are classes of molecules that mimic structural and functional attributes of polypeptides. Peptidomimetic oligomers can frequently be synthesized using efficient solid phase synthesis procedures similar to peptide synthesis. Conformationally ordered peptidomimetic oligomers are finding broad applications for molecular recognition and for inhibiting protein-protein interactions. One critical limitation is the limited set of design tools for identifying oligomer sequences that can adopt desired conformations. Here, we present expansions to the ROSETTA platform that enable structure prediction and design of five non-peptidic oligomer scaffolds (noncanonical backbones, oligooxopiperazines, oligo-peptoids, [Formula: see text]-peptides, hydrogen bond surrogate helices and oligosaccharides. This work is complementary to prior additions to model noncanonical protein side chains in ROSETTA. The main purpose of our manuscript is to give a detailed description to current and future developers of how each of these noncanonical backbones was implemented. Furthermore, we provide a general outline for implementation of new backbone types not discussed here. To illustrate the utility of this approach, we describe the first tests of the ROSETTA molecular mechanics energy function in the context of oligooxopiperazines, using quantum mechanical calculations as comparison points, scanning through backbone and side chain torsion angles for a model peptidomimetic. Finally, as an example of a novel design application, we describe the automated design of an oligooxopiperazine that inhibits the p53-MDM2 protein-protein interaction. For the general biological and bioengineering community, several noncanonical backbones have been incorporated into web applications that allow users to freely and rapidly test the presented protocols (http://rosie.rosettacommons.org. This work helps address the peptidomimetic community's need for an automated and expandable

  17. Molecular dynamics simulations reveal the conformational dynamics of Arabidopsis thaliana BRI1 and BAK1 receptor-like kinases.

    Science.gov (United States)

    Moffett, Alexander S; Bender, Kyle W; Huber, Steven C; Shukla, Diwakar

    2017-07-28

    The structural motifs responsible for activation and regulation of eukaryotic protein kinases in animals have been studied extensively in recent years, and a coherent picture of their activation mechanisms has begun to emerge. In contrast, non-animal eukaryotic protein kinases are not as well understood from a structural perspective, representing a large knowledge gap. To this end, we investigated the conformational dynamics of two key Arabidopsis thaliana receptor-like kinases, brassinosteroid-insensitive 1 (BRI1) and BRI1-associated kinase 1 (BAK1), through extensive molecular dynamics simulations of their fully phosphorylated kinase domains. Molecular dynamics simulations calculate the motion of each atom in a protein based on classical approximations of interatomic forces, giving researchers insight into protein function at unparalleled spatial and temporal resolutions. We found that in an otherwise "active" BAK1 the αC helix is highly disordered, a hallmark of deactivation, whereas the BRI1 αC helix is moderately disordered and displays swinging behavior similar to numerous animal kinases. An analysis of all known sequences in the A. thaliana kinome found that αC helix disorder may be a common feature of plant kinases. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  18. Conformational dynamics of cathepsin D and binding to a small-molecule BACE1 inhibitor.

    Science.gov (United States)

    Ellis, Christopher R; Tsai, Cheng-Chieh; Lin, Fang-Yu; Shen, Jana

    2017-06-05

    BACE1 is a major therapeutic target for prevention and treatment of Alzheimer's disease. Developing inhibitors that can selectively target BACE1 in favor of other proteases, especially cathepsin D (CatD), has presented significant challenges. Here, we investigate the conformational dynamics and protonation states of BACE1 and CatD using continuous constant pH molecular dynamics with pH replica-exchange sampling protocol. Despite similar structure, BACE1 and CatD exhibit markedly different active site dynamics. BACE1 displays pH-dependent flap dynamics that controls substrate accessibility, while the CatD flap is relatively rigid and remains open in the pH range 2.5-6. Interestingly, although each protease hydrolyzes peptide bonds, the protonation states of the catalytic dyads are different within the active pH range. The acidic and basic components of the BACE1 catalytic dyad are clear, while either aspartic acid of the CatD catalytic dyad could play the role of acid or base. Finally, we investigate binding of the inhibitor LY2811376 developed by Eli Lilly to BACE1 and CatD. Surprisingly, in the enzyme active pH range, LY2811376 forms a stronger salt bridge with the catalytic dyad in CatD than in BACE1, which might explain the retinal toxicity of the inhibitor related to off-target inhibition of CatD. This work highlights the complexity and challenge in structure-based drug design where receptor-ligand binding induces protonation state change in both the protein and the inhibitor. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  19. Conformity, Anticonformity and Polarization of Opinions: Insights from a Mathematical Model of Opinion Dynamics

    Directory of Open Access Journals (Sweden)

    Tyll Krueger

    2017-07-01

    Full Text Available Understanding and quantifying polarization in social systems is important because of many reasons. It could for instance help to avoid segregation and conflicts in the society or to control polarized debates and predict their outcomes. In this paper, we present a version of the q-voter model of opinion dynamics with two types of responses to social influence: conformity (like in the original q-voter model and anticonformity. We put the model on a social network with the double-clique topology in order to check how the interplay between those responses impacts the opinion dynamics in a population divided into two antagonistic segments. The model is analyzed analytically, numerically and by means of Monte Carlo simulations. Our results show that the system undergoes two bifurcations as the number of cross-links between cliques changes. Below the first critical point, consensus in the entire system is possible. Thus, two antagonistic cliques may share the same opinion only if they are loosely connected. Above that point, the system ends up in a polarized state.

  20. Dosimetric effect on pediatric conformal treatment plans using dynamic jaw with Tomotherapy HDA

    Energy Technology Data Exchange (ETDEWEB)

    Han, Eun Young, E-mail: eyhan@uams.edu [Department of Radiation Oncology, University of Arkansas Medical Sciences, Little Rock, AR (United States); Kim, Dong-Wook [Department of Radiation Oncology, Kyung Hee University Hospital, Seoul (Korea, Republic of); Zhang, Xin; Penagaricano, Jose; Liang, Xiaoying; Hardee, Matthew; Morrill, Steve; Ratanatharathorn, Vaneerat [Department of Radiation Oncology, University of Arkansas Medical Sciences, Little Rock, AR (United States)

    2015-10-01

    It is important to minimize the radiation dose delivered to healthy tissues in pediatric cancer treatment because of the risk of secondary malignancies. Tomotherapy HDA provides a dynamic jaw (DJ) delivery mode that creates a sharper penumbra at the craniocaudal ends of a target in addition to a fixed jaw (FJ) delivery mode. The purpose of this study was to evaluate its dosimetric effect on the pediatric cancer cases. We included 6 pediatric cases in this study. The dose profiles and plan statistics—target dose conformity, uniformity, organ-at-risk (OAR) mean dose, beam-on time, and integral dose—were compared for each case. Consequently, the target dose coverage and uniformity were similar for different jaw settings. The OAR dose sparing depended on its relative location to the target and disease sites. For example, in the head and neck cancer cases, the brain stem dose using DJ 2.5 was reduced by more than two-fold (2.4 Gy vs. 6.3 Gy) than that obtained with FJ 2.5. The integral dose with DJ 2.5 decreased by more than 9% compared with that with FJ 2.5. Thus, using dynamic jaw in pediatric cases could be critical to reduce a probability of a secondary malignancy.

  1. Conformation Analysis of T1 Lipase on Alcohols Solvent using Molecular Dynamics Simulation

    Science.gov (United States)

    Putri, A. M.; Sumaryada, T.; Wahyudi, S. T.

    2017-07-01

    Biodiesel usually is produced commercially via a transesterification reaction of vegetable oil with alcohol and alkali catalyst. The alkali catalyst has some drawbacks, such as the soap formation during the reaction. T1 Lipase enzyme had been known as a thermostable biocatalyst which is able to produce biodiesel through a cleaner process. In this paper the performance of T1 lipase enzyme as catalyst for transesterification reaction in pure ethanol, methanol, and water solvents were studied using a Molecular Dynamics (MD) Simulation at temperature of 300 K for 10 nanoseconds. The results have shown that in general the conformation of T1 lipase enzyme in methanol is more dynamics as shown by the value of root mean square deviation (RMSD), root mean squared fluctuation (RMSF), and radius of gyration. The highest solvent accessible surface area (SASA) total was also found in methanol due to the contribution of non-polar amino acid in the interior of the protein. Analysis of MD simulation has also revealed that the enzyme structure tend to be more rigid in ethanol environment. The analysis of electrostatic interactions have shown that Glu359-Arg270 salt-bridge pair might hold the key of thermostability of T1 lipase enzyme as shown by its strong and stable binding in all three solvents.

  2. Nucleotide-mediated conformational changes of monomeric actin and Arp3 studied by molecular dynamics simulations.

    Science.gov (United States)

    Dalhaimer, Paul; Pollard, Thomas D; Nolen, Brad J

    2008-02-08

    Members of the actin family of proteins exhibit different biochemical properties when ATP, ADP-P(i), ADP, or no nucleotide is bound. We used molecular dynamics simulations to study the effect of nucleotides on the behavior of actin and actin-related protein 3 (Arp3). In all of the actin simulations, the nucleotide cleft stayed closed, as in most crystal structures. ADP was much more mobile within the cleft than ATP, despite the fact that both nucleotides adopt identical conformations in actin crystal structures. The nucleotide cleft of Arp3 opened in most simulations with ATP, ADP, and no bound nucleotide. Deletion of a C-terminal region of Arp3 that extends beyond the conserved actin sequence reduced the tendency of the Arp3 cleft to open. When the Arp3 cleft opened, we observed multiple instances of partial release of the nucleotide. Cleft opening in Arp3 also allowed us to observe correlated movements of the phosphate clamp, cleft mouth, and barbed-end groove, providing a way for changes in the nucleotide state to be relayed to other parts of Arp3. The DNase binding loop of actin was highly flexible regardless of the nucleotide state. The conformation of Ser14/Thr14 in the P1 loop was sensitive to the presence of the gamma-phosphate, but other changes observed in crystal structures were not correlated with the nucleotide state on nanosecond timescales. The divalent cation occupied three positions in the nucleotide cleft, one of which was not previously observed in actin or Arp2/3 complex structures. In sum, these simulations show that subtle differences in structures of actin family proteins have profound effects on their nucleotide-driven behavior.

  3. Decay of an active GPCR: Conformational dynamics govern agonist rebinding and persistence of an active, yet empty, receptor state.

    Science.gov (United States)

    Schafer, Christopher T; Fay, Jonathan F; Janz, Jay M; Farrens, David L

    2016-10-18

    Here, we describe two insights into the role of receptor conformational dynamics during agonist release (all-trans retinal, ATR) from the visual G protein-coupled receptor (GPCR) rhodopsin. First, we show that, after light activation, ATR can continually release and rebind to any receptor remaining in an active-like conformation. As with other GPCRs, we observe that this equilibrium can be shifted by either promoting the active-like population or increasing the agonist concentration. Second, we find that during decay of the signaling state an active-like, yet empty, receptor conformation can transiently persist after retinal release, before the receptor ultimately collapses into an inactive conformation. The latter conclusion is based on time-resolved, site-directed fluorescence labeling experiments that show a small, but reproducible, lag between the retinal leaving the protein and return of transmembrane helix 6 (TM6) to the inactive conformation, as determined from tryptophan-induced quenching studies. Accelerating Schiff base hydrolysis and subsequent ATR dissociation, either by addition of hydroxylamine or introduction of mutations, further increased the time lag between ATR release and TM6 movement. These observations show that rhodopsin can bind its agonist in equilibrium like a traditional GPCR, provide evidence that an active GPCR conformation can persist even after agonist release, and raise the possibility of targeting this key photoreceptor protein by traditional pharmaceutical-based treatments.

  4. Molecular dynamics analysis of conformational change of paramyxovirus F protein during the initial steps of membrane fusion

    International Nuclear Information System (INIS)

    Martín-García, Fernando; Mendieta-Moreno, Jesús Ignacio; Mendieta, Jesús; Gómez-Puertas, Paulino

    2012-01-01

    Highlights: ► Initial conformational change of paramyxovirus F protein is caused only by mechanical forces. ► HRA region undergoes a structural change from a beta + alpha conformation to an extended coil and then to an all-alpha conformation. ► HRS domains of F protein form three single α-helices prior to generation of the coiled coil. -- Abstract: The fusion of paramyxovirus to the cell membrane is mediated by fusion protein (F protein) present in the virus envelope, which undergoes a dramatic conformational change during the process. Unlike hemagglutinin in orthomyxovirus, this change is not mediated by an alteration of environmental pH, and its cause remains unknown. Steered molecular dynamics analysis leads us to suggest that the conformational modification is mediated only by stretching mechanical forces once the transmembrane fusion peptide of the protein is anchored to the cell membrane. Such elongating forces will generate major secondary structure rearrangement in the heptad repeat A region of the F protein; from β-sheet conformation to an elongated coil and then spontaneously to an α-helix. In addition, it is proposed that the heptad repeat A region adopts a final three-helix coiled coil and that this structure appears after the formation of individual helices in each monomer.

  5. Domain decomposition-based structural condensation of large protein structures for understanding their conformational dynamics.

    Science.gov (United States)

    Kim, Jae In; Na, Sungsoo; Eom, Kilho

    2011-01-15

    Normal mode analysis (NMA) with coarse-grained model, such as elastic network model (ENM), has allowed the quantitative understanding of protein dynamics. As the protein size is increased, there emerges the expensive computational process to find the dynamically important low-frequency normal modes due to diagonalization of massive Hessian matrix. In this study, we have provided the domain decomposition-based structural condensation method that enables the efficient computations on low-frequency motions. Specifically, our coarse-graining method is established by coupling between model condensation (MC; Eom et al., J Comput Chem 2007, 28, 1400) and component mode synthesis (Kim et al., J Chem Theor Comput 2009, 5, 1931). A protein structure is first decomposed into substructural units, and then each substructural unit is coarse-grained by MC. Once the NMA is implemented to coarse-grained substructural units, normal modes and natural frequencies for each coarse-grained substructural unit are assembled by using geometric constraints to provide the normal modes and natural frequencies for whole protein structure. It is shown that our coarse-graining method enhances the computational efficiency for analysis of large protein complexes. It is clearly suggested that our coarse-graining method provides the B-factors of 100 large proteins, quantitatively comparable with those obtained from original NMA, with computational efficiency. Moreover, the collective behaviors and/or the correlated motions for model proteins are well delineated by our suggested coarse-grained models, quantitatively comparable with those computed from original NMA. It is implied that our coarse-grained method enables the computationally efficient studies on conformational dynamics of large protein complex.

  6. Photon-counting single-molecule spectroscopy for studying conformational dynamics and macromolecular interactions

    Energy Technology Data Exchange (ETDEWEB)

    Laurence, Ted Alfred [Univ. of California, Berkeley, CA (United States)

    2002-01-01

    Single-molecule methods have the potential to provide information about conformational dynamics and molecular interactions that cannot be obtained by other methods. Removal of ensemble averaging provides several benefits, including the ability to detect heterogeneous populations and the ability to observe asynchronous reactions. Single-molecule diffusion methodologies using fluorescence resonance energy transfer (FRET) are developed to monitor conformational dynamics while minimizing perturbations introduced by interactions between molecules and surfaces. These methods are used to perform studies of the folding of Chymotrypsin Inhibitor 2, a small, single-domain protein, and of single-stranded DNA (ssDNA) homopolymers. Confocal microscopy is used in combination with sensitive detectors to detect bursts of photons from fluorescently labeled biomolecules as they diffuse through the focal volume. These bursts are analyzed to extract fluorescence resonance energy transfer (FRET) efficiency. Advances in data acquisition and analysis techniques that are providing a more complete picture of the accessible molecular information are discussed. Photon Arrival-time Interval Distribution (PAID) analysis is a new method for monitoring macromolecular interactions by fluorescence detection with simultaneous determination of coincidence, brightness, diffusion time, and occupancy (proportional to concentration) of fluorescently-labeled molecules undergoing diffusion in a confocal detection volume. This method is based on recording the time of arrival of all detected photons, and then plotting the two-dimensional histogram of photon pairs, where one axis is the time interval between each pair of photons 1 and 2, and the second axis is the number of other photons detected in the time interval between photons 1 and 2. PAID is related to Fluorescence Correlation Spectroscopy (FCS) by a collapse of this histogram onto the time interval axis. PAID extends auto- and cross-correlation FCS

  7. Photon-counting single-molecule spectroscopy for studying conformational dynamics and macromolecular interactions

    International Nuclear Information System (INIS)

    Laurence, Ted Alfred

    2002-01-01

    Single-molecule methods have the potential to provide information about conformational dynamics and molecular interactions that cannot be obtained by other methods. Removal of ensemble averaging provides several benefits, including the ability to detect heterogeneous populations and the ability to observe asynchronous reactions. Single-molecule diffusion methodologies using fluorescence resonance energy transfer (FRET) are developed to monitor conformational dynamics while minimizing perturbations introduced by interactions between molecules and surfaces. These methods are used to perform studies of the folding of Chymotrypsin Inhibitor 2, a small, single-domain protein, and of single-stranded DNA (ssDNA) homopolymers. Confocal microscopy is used in combination with sensitive detectors to detect bursts of photons from fluorescently labeled biomolecules as they diffuse through the focal volume. These bursts are analyzed to extract fluorescence resonance energy transfer (FRET) efficiency. Advances in data acquisition and analysis techniques that are providing a more complete picture of the accessible molecular information are discussed. Photon Arrival-time Interval Distribution (PAID) analysis is a new method for monitoring macromolecular interactions by fluorescence detection with simultaneous determination of coincidence, brightness, diffusion time, and occupancy (proportional to concentration) of fluorescently-labeled molecules undergoing diffusion in a confocal detection volume. This method is based on recording the time of arrival of all detected photons, and then plotting the two-dimensional histogram of photon pairs, where one axis is the time interval between each pair of photons 1 and 2, and the second axis is the number of other photons detected in the time interval between photons 1 and 2. PAID is related to Fluorescence Correlation Spectroscopy (FCS) by a collapse of this histogram onto the time interval axis. PAID extends auto- and cross-correlation FCS

  8. On dynamical realizations of l-conformal Galilei and Newton–Hooke algebras

    Directory of Open Access Journals (Sweden)

    Anton Galajinsky

    2015-07-01

    Full Text Available In two recent papers (Aizawa et al., 2013 [15] and (Aizawa et al., 2015 [16], representation theory of the centrally extended l-conformal Galilei algebra with half-integer l has been applied so as to construct second order differential equations exhibiting the corresponding group as kinematical symmetry. It was suggested to treat them as the Schrödinger equations which involve Hamiltonians describing dynamical systems without higher derivatives. The Hamiltonians possess two unusual features, however. First, they involve the standard kinetic term only for one degree of freedom, while the remaining variables provide contributions linear in momenta. This is typical for Ostrogradsky's canonical approach to the description of higher derivative systems. Second, the Hamiltonian in the second paper is not Hermitian in the conventional sense. In this work, we study the classical limit of the quantum Hamiltonians and demonstrate that the first of them is equivalent to the Hamiltonian describing free higher derivative nonrelativistic particles, while the second can be linked to the Pais–Uhlenbeck oscillator whose frequencies form the arithmetic sequence ωk=(2k−1, k=1,…,n. We also confront the higher derivative models with a genuine second order system constructed in our recent work (Galajinsky and Masterov, 2013 [5] which is discussed in detail for l=32.

  9. On dynamical realizations of l-conformal Galilei and Newton-Hooke algebras

    Science.gov (United States)

    Galajinsky, Anton; Masterov, Ivan

    2015-07-01

    In two recent papers (Aizawa et al., 2013 [15]) and (Aizawa et al., 2015 [16]), representation theory of the centrally extended l-conformal Galilei algebra with half-integer l has been applied so as to construct second order differential equations exhibiting the corresponding group as kinematical symmetry. It was suggested to treat them as the Schrödinger equations which involve Hamiltonians describing dynamical systems without higher derivatives. The Hamiltonians possess two unusual features, however. First, they involve the standard kinetic term only for one degree of freedom, while the remaining variables provide contributions linear in momenta. This is typical for Ostrogradsky's canonical approach to the description of higher derivative systems. Second, the Hamiltonian in the second paper is not Hermitian in the conventional sense. In this work, we study the classical limit of the quantum Hamiltonians and demonstrate that the first of them is equivalent to the Hamiltonian describing free higher derivative nonrelativistic particles, while the second can be linked to the Pais-Uhlenbeck oscillator whose frequencies form the arithmetic sequence ωk = (2 k - 1), k = 1, …, n. We also confront the higher derivative models with a genuine second order system constructed in our recent work (Galajinsky and Masterov, 2013 [5]) which is discussed in detail for l =3/2.

  10. Comparison of Chain Conformation of Poly(vinyl alcohol) in Solutions and Melts from Quantum Chemistry Based Molecular Dynamics Simulations

    Science.gov (United States)

    Jaffe, Richard; Han, Jie; Matsuda, Tsunetoshi; Yoon, Do; Langhoff, Stephen R. (Technical Monitor)

    1997-01-01

    Confirmations of 2,4-dihydroxypentane (DHP), a model molecule for poly(vinyl alcohol), have been studied by quantum chemistry (QC) calculations and molecular dynamics (MD) simulations. QC calculations at the 6-311G MP2 level show the meso tt conformer to be lowest in energy followed by the racemic tg, due to intramolecular hydrogen bond between the hydroxy groups. The Dreiding force field has been modified to reproduce the QC conformer energies for DHP. MD simulations using this force field have been carried out for DHP molecules in the gas phase, melt, and CHCl3 and water solutions. Extensive intramolecular hydrogen bonding is observed for the gas phase and CHCl3 solution, but not for the melt or aqueous solution, Such a condensed phase effect due to intermolecular interactions results in a drastic change in chain conformations, in agreement with experiments.

  11. Evaluation of the dose distribution of dynamic conical conformal therapy using a C-arm mounted accelerator

    International Nuclear Information System (INIS)

    Nakagawa, Keiichi; Aoki, Yukimasa; Ohtomo, Kuni

    2001-01-01

    Conformal radiation therapy, which is widely utilized in Japan as a standard, highly precise technique has limited advantage in dose confinement because of its coplanar beam entry. An improved form of conformal therapy is delivered by a linac mounted on a C-arm rotatable gantry. The linac head was designed to move along the C-arm with a maximum angle of 60 degrees. Simultaneous rotation of the gantry creates a Dynamic Conical irradiation technique. Dynamic Conical Conformal Therapy (Dyconic Therapy) was developed by combining the technique with continuous MLC motion based on beam's eye views of the target volume. Dose distributions were measured in a phantom using film densitometry and compared with conventional conformal radiation therapy. The measurements showed that the dose distribution conformed to the target shape identified by CT. In addition, the dose distribution for a cancer patient was evaluated through the use of DVHs generated by a treatment planning system. These measurements showed that the dose distribution along the patient's long axis conformed to the shape of the target volume. DVH analysis, however, did not indicate superiority of the present technique over the conventional technique. Angulation of the C-arm gantry allowed the primary beam to strike a larger area of the therapy room. This necessitated adding shielding to the walls and ceiling of the treatment room. It was confirmed that the leakage radiation was reduced to a negligible level by adding an iron plate 20 cm thick to several places on the side walls, by adding an iron plate 9 cm thick to several places on the ceiling, and by increasing the thickness of the concrete ceiling from 70 to 140 cm. The possible usefulness of Dyconic Therapy was confirmed. (author)

  12. Backbone upgrades and DEC equipment replacement

    Science.gov (United States)

    Vancamp, Warren

    1991-01-01

    The NASA Science Internet (NSI) dual protocol backbone is outlined. It includes DECnet link upgrades to match TCP/IP link performance. It also includes the integration of backbone resources and central management. The phase 1 transition process is outlined.

  13. Cross-Correlated Relaxation of Dipolar Coupling and Chemical-Shift Anisotropy in Magic-Angle Spinning R1ρ NMR Measurements: Application to Protein Backbone Dynamics Measurements

    Science.gov (United States)

    Kurauskas, Vilius; Weber, Emmanuelle; Hessel, Audrey; Ayala, Isabel; Marion, Dominique; Schanda, Paul

    2016-01-01

    Transverse relaxation rate measurements in MAS solid-state NMR provide information about molecular motions occurring on nanoseconds-to-milliseconds (ns-ms) time scales. The measurement of heteronuclear (13C, 15N) relaxation rate constants in the presence of a spin-lock radio-frequency field (R1ρ relaxation) provides access to such motions, and an increasing number of studies involving R1ρ relaxation in proteins has been reported. However, two factors that influence the observed relaxation rate constants have so far been neglected, namely (i) the role of CSA/dipolar cross-correlated relaxation (CCR), and (ii) the impact of fast proton spin flips (i.e. proton spin diffusion and relaxation). We show that CSA/D CCR in R1ρ experiments is measurable, and that this cross-correlated relaxation rate constant depends on ns-ms motions, and can thus itself provide insight into dynamics. We find that proton spin-diffusion attenuates this cross-correlated relaxation, due to its decoupling effect on the doublet components. For measurements of dynamics, the use of R1ρ rate constants has practical advantages over the use of CCR rates, and the present manuscript reveals factors that have so far been disregarded and which are important for accurate measurements and interpretation. PMID:27500976

  14. Dynamics and ligand-induced conformational changes in human prolyl oligopeptidase analyzed by hydrogen/deuterium exchange mass spectrometry

    OpenAIRE

    Tsirigotaki, Alexandra; Elzen, van, Roos; Veken, van der, Pieter; Lambeir, Anne-Marie; Economou, Anastassios

    2017-01-01

    Abstract: Prolyl oligopeptidase (PREP) is conserved in many organisms across life. It is involved in numerous processes including brain function and neuropathology, that require more than its strict proteolytic role. It consists of a seven-bladed beta-propeller juxtaposed to a catalytic alpha/beta-hydrolase domain. The conformational dynamics of PREP involved in domain motions and the gating mechanism that allows substrate accessibility remain elusive. Here we used Hydrogen Deuterium eXchange...

  15. The EF loop in green proteorhodopsin affects conformation and photocycle dynamics.

    Science.gov (United States)

    Mehler, Michaela; Scholz, Frank; Ullrich, Sandra J; Mao, Jiafei; Braun, Markus; Brown, Lynda J; Brown, Richard C D; Fiedler, Sarah A; Becker-Baldus, Johanna; Wachtveitl, Josef; Glaubitz, Clemens

    2013-07-16

    The proteorhodopsin family consists of retinal proteins of marine bacterial origin with optical properties adjusted to their local environments. For green proteorhodopsin, a highly specific mutation in the EF loop, A178R, has been found to cause a surprisingly large redshift of 20 nm despite its distance from the chromophore. Here, we analyze structural and functional consequences of this EF loop mutation by time-resolved optical spectroscopy and solid-state NMR. We found that the primary photoreaction and the formation of the K-like photo intermediate is almost pH-independent and slower compared to the wild-type, whereas the decay of the K-intermediate is accelerated, suggesting structural changes within the counterion complex upon mutation. The photocycle is significantly elongated mainly due to an enlarged lifetime of late photo intermediates. Multidimensional MAS-NMR reveals mutation-induced chemical shift changes propagating from the EF loop to the chromophore binding pocket, whereas dynamic nuclear polarization-enhanced (13)C-double quantum MAS-NMR has been used to probe directly the retinylidene conformation. Our data show a modified interaction network between chromophore, Schiff base, and counterion complex explaining the altered optical and kinetic properties. In particular, the mutation-induced distorted structure in the EF loop weakens interactions, which help reorienting helix F during the reprotonation step explaining the slower photocycle. These data lead to the conclusion that the EF loop plays an important role in proton uptake from the cytoplasm but our data also reveal a clear interaction pathway between the EF loop and retinal binding pocket, which might be an evolutionary conserved communication pathway in retinal proteins. Copyright © 2013 Biophysical Society. Published by Elsevier Inc. All rights reserved.

  16. Conformational Analysis of a High-Mannose-Type Oligosaccharide Displaying Glucosyl Determinant Recognised by Molecular Chaperones Using NMR-Validated Molecular Dynamics Simulation.

    Science.gov (United States)

    Suzuki, Tatsuya; Kajino, Megumi; Yanaka, Saeko; Zhu, Tong; Yagi, Hirokazu; Satoh, Tadashi; Yamaguchi, Takumi; Kato, Koichi

    2017-02-16

    Exploration of the conformational spaces of flexible oligosaccharides is essential to gain deeper insights into their functional mechanisms. Here we characterised dynamic conformation of a high-mannose-type dodecasaccharide with a terminal glucose residue, a critical determinant recognised by molecular chaperones. The dodecasaccharide was prepared by our developed chemoenzymatic technique, which uses 13 C labelling and lanthanide tagging to detect conformation-dependent paramagnetic effects by NMR spectroscopy. The NMR-validated molecular dynamics simulation produced the dynamic conformational ensemble of the dodecasaccharide. This determined its spatial distribution as well as the glycosidic linkage conformation of the terminal glucose determinant. Moreover, comparison of our results with previously reported crystallographic data indicates that the chaperone binding to its target oligosaccharides involves an induced-fit mechanism. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. Impact of an extruded nucleotide on cleavage activity and dynamic catalytic core conformation of the hepatitis delta virus ribozyme

    Czech Academy of Sciences Publication Activity Database

    Šefčíková, J.; Krasovská, Maryna V.; Špačková, Naďa; Šponer, Jiří; Walter, N.G.

    2007-01-01

    Roč. 85, 5-6 (2007), s. 392-406 ISSN 0006-3525 R&D Projects: GA ČR(CZ) GA203/05/0388; GA ČR(CZ) GA203/05/0009; GA AV ČR(CZ) 1QS500040581; GA MŠk(CZ) LC512 Institutional research plan: CEZ:AV0Z50040702 Keywords : conformational dynamics * hepatitis delta virus * molecular dynamics Subject RIV: BO - Biophysics Impact factor: 2.389, year: 2007

  18. A hierarchical virtual backbone construction protocol for mobile ad hoc networks

    Directory of Open Access Journals (Sweden)

    Bharti Sharma

    2016-07-01

    Full Text Available We propose a hierarchical backbone construction protocol for mobile ad hoc networks. Our protocol is based on the idea of using an efficient extrema finding method to create clusters comprising the nodes that are within certain prespecified wireless hop distance. Afterward, we apply our ‘diameter’ algorithm among clusters to identify the dominating nodes that are, finally, connected via multi-hop virtual links to construct the backbone. We present the analytic as well as simulation study of our algorithm and also a method for the dynamic maintenance of constructed backbone. In the end, we illustrate the use of the virtual backbone with the help of an interesting application.

  19. Conformational dynamics of L-lysine, L-arginine, L-ornithine binding protein reveals ligand-dependent plasticity.

    Science.gov (United States)

    Silva, Daniel-Adriano; Domínguez-Ramírez, Lenin; Rojo-Domínguez, Arturo; Sosa-Peinado, Alejandro

    2011-07-01

    The molecular basis of multiple ligand binding affinity for amino acids in periplasmic binding proteins (PBPs) and in the homologous domain for class C G-protein coupled receptors is an unsolved question. Here, using unrestrained molecular dynamic simulations, we studied the ligand binding mechanism present in the L-lysine, L-arginine, L-ornithine binding protein. We developed an analysis based on dihedral angles for the description of the conformational changes upon ligand binding. This analysis has an excellent correlation with each of the two main movements described by principal component analysis (PCA) and it's more convenient than RMSD measurements to describe the differences in the conformational ensembles observed. Furthermore, an analysis of hydrogen bonds showed specific interactions for each ligand studied as well as the ligand interaction with the aromatic residues Tyr-14 and Phe-52. Using uncharged histidine tautomers, these interactions are not observed. On the basis of these results, we propose a model in which hydrogen bond interactions place the ligand in the correct orientation to induce a cation-π interaction with Tyr-14 and Phe-52 thereby stabilizing the closed state. Our results also show that this protein adopts slightly different closed conformations to make available specific hydrogen bond interactions for each ligand thus, allowing a single mechanism to attain multiple ligand specificity. These results shed light on the experimental evidence for ligand-dependent conformational plasticity not explained by the previous crystallographic data. Copyright © 2011 Wiley-Liss, Inc.

  20. Virtual screening for potential inhibitors of Mcl-1 conformations sampled by normal modes, molecular dynamics, and nuclear magnetic resonance

    Directory of Open Access Journals (Sweden)

    Glantz-Gashai Y

    2017-06-01

    Full Text Available Yitav Glantz-Gashai,* Tomer Meirson,* Eli Reuveni, Abraham O Samson Faculty of Medicine in the Galilee, Bar Ilan University, Safed, Israel *These authors contributed equally to this work Abstract: Myeloid cell leukemia-1 (Mcl-1 is often overexpressed in human cancer and is an important target for developing antineoplastic drugs. In this study, a data set containing 2.3 million lead-like molecules and a data set of all the US Food and Drug Administration (FDA-approved drugs are virtually screened for potential Mcl-1 ligands using Protein Data Bank (PDB ID 2MHS. The potential Mcl-1 ligands are evaluated and computationally docked on to three conformation ensembles generated by normal mode analysis (NMA, molecular dynamics (MD, and nuclear magnetic resonance (NMR, respectively. The evaluated potential Mcl-1 ligands are then compared with their clinical use. Remarkably, half of the top 30 potential drugs are used clinically to treat cancer, thus partially validating our virtual screen. The partial validation also favors the idea that the other half of the top 30 potential drugs could be used in the treatment of cancer. The normal mode-, MD-, and NMR-based conformation greatly expand the conformational sampling used herein for in silico identification of potential Mcl-1 inhibitors. Keywords: virtual screening, Mcl-1, molecular dynamics, NMR, normal modes

  1. Single-molecule diffusion and conformational dynamics by spatial integration of temporal fluctuations

    KAUST Repository

    Serag, Maged F.

    2014-10-06

    Single-molecule localization and tracking has been used to translate spatiotemporal information of individual molecules to map their diffusion behaviours. However, accurate analysis of diffusion behaviours and including other parameters, such as the conformation and size of molecules, remain as limitations to the method. Here, we report a method that addresses the limitations of existing single-molecular localization methods. The method is based on temporal tracking of the cumulative area occupied by molecules. These temporal fluctuations are tied to molecular size, rates of diffusion and conformational changes. By analysing fluorescent nanospheres and double-stranded DNA molecules of different lengths and topological forms, we demonstrate that our cumulative-area method surpasses the conventional single-molecule localization method in terms of the accuracy of determined diffusion coefficients. Furthermore, the cumulative-area method provides conformational relaxation times of structurally flexible chains along with diffusion coefficients, which together are relevant to work in a wide spectrum of scientific fields.

  2. Fluorescence of the single tryptophan of cutinase: temperature and pH effect on protein conformation and dynamics.

    Science.gov (United States)

    Martinho, J M G; Santos, A M; Fedorov, A; Baptista, R P; Taipa, M A; Cabral, J M S

    2003-07-01

    The cutinase from Fusarium solani pisi is an enzyme with a single L-tryptophan (Trp) involved in a hydrogen bond with an alanine (Ala) residue and located close to a cystine formed by a disulfide bridge between two cysteine (Cys) residues. The Cys strongly quenches the fluorescence of Trp by both static and dynamic quenching mechanisms. The Trp fluorescence intensity increases by about fourfold on protein melting because of the disruption of the Ala-Trp hydrogen bond that releases the Trp from the vicinity of the cystine residue. The Trp forms charge-transfer complexes with the disulfide bridge, which is disrupted by UV light irradiation of the protein. This results in a 10-fold increase of the Trp fluorescence quantum yield because of the suppression of the static quenching by the cystine residue. The Trp fluorescence anisotropy decays are similar to those in other proteins and were interpreted in terms of the wobbling-in-cone model. The long relaxation time is attributed to the Brownian rotational correlation time of the protein as a whole below the protein-melting temperature and to protein-backbone dynamics above it. The short relaxation time is related to the local motion of the Trp, whose mobility increases on protein denaturation.

  3. Low energy dynamics from deformed conformal symmetry in quantum 4D N=2 SCFTs

    International Nuclear Information System (INIS)

    Kuzenko, S.M.; McArthur, I.N.; Theisen, S.

    2003-01-01

    We determine the one-loop deformation of the conformal symmetry of a general N=2 superconformally invariant Yang-Mills theory. The deformation is computed for several explicit examples which have a realization as world-volume theories on a stack of D3 branes. These include: (i) N=4 SYM with gauge groups SU(N), USp(2N) and SO(N); (ii) USp(2N) gauge theory with one hypermultiplet in the traceless antisymmetric representation and four hypermultiplets in the fundamental; (iii) quiver gauge theory with gauge group SU(N)xSU(N) and two hypermultiplets in the bifundamental representations (N,N-bar) and (N-bar,N). The existence of quantum corrections to the conformal transformations imposes restrictions on the effective action which we study on a subset of the Coulomb branch corresponding to the separation of one brane from the stack. In the N=4 case, the one-loop corrected transformations provide a realization of the conformal algebra; this deformation is shown to be one-loop exact. For the other two models, higher-loop corrections are necessary to close the algebra. Requiring closure, we infer the two-loop conformal deformation

  4. Children's Gender Identity Development: The Dynamic Negotiation Process between Conformity and Authenticity

    Science.gov (United States)

    Brinkman, Britney G; Rabenstein, Kelly L.; Rosén, Lee A.; Zimmerman, Toni S.

    2014-01-01

    In the current study, 45 girls and 41 boys participated in focus groups following a program designed to teach them about social justice. The children articulated the discrepancy between their own gender identity and gender role stereotypes and discussed potential problems with conforming to gender role expectations as well as consequences of…

  5. Revisiting imidazolium based ionic liquids: Effect of the conformation bias of the [NTf2] anion studied by molecular dynamics simulations

    Science.gov (United States)

    Neumann, Jan; Golub, Benjamin; Odebrecht, Lisa-Marie; Ludwig, Ralf; Paschek, Dietmar

    2018-05-01

    We study ionic liquids composed of 1-alkyl-3-methylimidazolium cations and bis(trifluoromethyl-sulfonyl)imide anions ([CnMIm][NTf2]) with varying chain-length n = 2, 4, 6, 8 by using molecular dynamics simulations. We show that a reparametrization of the dihedral potentials as well as charges of the [NTf2] anion leads to an improvement of the force field model introduced by Köddermann, Paschek, and Ludwig [ChemPhysChem 8, 2464 (2007)] (KPL-force field). A crucial advantage of the new parameter set is that the minimum energy conformations of the anion (trans and gauche), as deduced from ab initio calculations and Raman experiments, are now both well represented by our model. In addition, the results for [CnMIm][NTf2] show that this modification leads to an even better agreement between experiment and molecular dynamics simulation as demonstrated for densities, diffusion coefficients, vaporization enthalpies, reorientational correlation times, and viscosities. Even though we focused on a better representation of the anion conformation, also the alkyl chain-length dependence of the cation behaves closer to the experiment. We strongly encourage to use the new NGOLP (Neumann, Golub, Odebrecht, Ludwig, Paschek) force field for the [NTf2] anion instead of the earlier KPL parameter set for computer simulations aiming to describe the thermodynamics, dynamics, and also structure of imidazolium-based ionic liquids.

  6. Gauge/gravity duality, jets in strongly coupled plasma, and far-from-equilibrium dynamics in conformal field theories

    Science.gov (United States)

    Chesler, Paul M.

    We study dynamics in conformal field theories with gravitational duals. Attention is focused on heavy and light quark jets as well as far-from-equilibrium dynamics. The stress-energy tensor of a heavy quark moving through a strongly coupled N = 4 supersymmetric Yang-Mills plasma is evaluated using gauge/gravity duality. The accuracy with which the resulting wake, in position space, is reproduced by hydrodynamics is examined. Remarkable agreement is found between hydrodynamics and the complete result down to distances less than 2/ T away from the quark. We also compute the penetration depth of a light quark moving through a N = 4 supersymmetric Yang-Mills plasma using a combination of analytic and numerical techniques. We find that the maximum distance a quark with energy E can travel through a plasma is given by Dxmax E= C/T E/Tl 1/3 with C ≈ 0.5. For the study of dynamics far-from-equilibrium, we consider the creation and evolution of boost invariant anisotropic, strongly coupled conformal plasma. In the dual gravitational description, this corresponds to horizon formation in a geometry driven to be anisotropic by a time-dependent change in boundary conditions.

  7. Dynamics and ligand-induced conformational changes in human prolyl oligopeptidase analyzed by hydrogen/deuterium exchange mass spectrometry.

    Science.gov (United States)

    Tsirigotaki, Alexandra; Elzen, Roos Van; Veken, Pieter Van Der; Lambeir, Anne-Marie; Economou, Anastassios

    2017-05-26

    Prolyl oligopeptidase (PREP) is conserved in many organisms across life. It is involved in numerous processes including brain function and neuropathology, that require more than its strict proteolytic role. It consists of a seven-bladed β-propeller juxtaposed to a catalytic α/β-hydrolase domain. The conformational dynamics of PREP involved in domain motions and the gating mechanism that allows substrate accessibility remain elusive. Here we used Hydrogen Deuterium eXchange Mass Spectrometry (HDX-MS) to derive the first near-residue resolution analysis of global PREP dynamics in the presence or absence of inhibitor bound in the active site. Clear roles are revealed for parts that would be critical for the activation mechanism. In the free state, the inter-domain interface is loose, providing access to the catalytic site. Inhibitor binding "locks" the two domains together exploiting prominent interactions between the loop of the first β-propeller blade and its proximal helix from the α/β-hydrolase domain. Loop A, thought to drive gating, is partially stabilized but remains flexible and dynamic. These findings provide a conformational guide for further dissection of the gating mechanism of PREP, that would impact drug development. Moreover, they offer a structural framework against which to study proteolysis-independent interactions with disordered proteins like α-synuclein involved in neurodegenerative disease.

  8. Evidence of Allosteric Enzyme Regulation via Changes in Conformational Dynamics: A Hydrogen/Deuterium Exchange Investigation of Dihydrodipicolinate Synthase.

    Science.gov (United States)

    Sowole, Modupeola A; Simpson, Sarah; Skovpen, Yulia V; Palmer, David R J; Konermann, Lars

    2016-09-27

    Dihydrodipicolinate synthase is a tetrameric enzyme of the diaminopimelate pathway in bacteria and plants. The protein catalyzes the condensation of pyruvate (Pyr) and aspartate semialdehyde en route to the end product lysine (Lys). Dihydrodipicolinate synthase from Campylobacter jejuni (CjDHDPS) is allosterically inhibited by Lys. CjDHDPS is a promising antibiotic target, as highlighted by the recent development of a potent bis-lysine (bisLys) inhibitor. The mechanism whereby Lys and bisLys allosterically inhibit CjDHDPS remains poorly understood. In contrast to the case for other allosteric enzymes, crystallographically detectable conformational changes in CjDHDPS upon inhibitor binding are very minor. Also, it is difficult to envision how Pyr can access the active site; the available X-ray data seemingly imply that each turnover step requires diffusion-based mass transfer through a narrow access channel. This study employs hydrogen/deuterium exchange mass spectrometry for probing the structure and dynamics of CjDHDPS in a native solution environment. The deuteration kinetics reveal that the most dynamic protein regions are in the direct vicinity of the substrate access channel. This finding is consistent with the view that transient opening/closing fluctuations facilitate access of the substrate to the active site. Under saturating conditions, both Lys and bisLys cause dramatically reduced dynamics in the inhibitor binding region. In addition, rigidification extends to regions close to the substrate access channel. This finding strongly suggests that allosteric inhibitors interfere with conformational fluctuations that are required for CjDHDPS substrate turnover. In particular, our data imply that Lys and bisLys suppress opening/closing events of the access channel, thereby impeding diffusion of the substrate into the active site. Overall, this work illustrates why allosteric control does not have to be associated with crystallographically detectable large

  9. Analyzing conformational dynamics of single P-glycoprotein transporters by Förster resonance energy transfer using hidden Markov models.

    Science.gov (United States)

    Zarrabi, Nawid; Ernst, Stefan; Verhalen, Brandy; Wilkens, Stephan; Börsch, Michael

    2014-03-15

    Single-molecule Förster resonance energy (smFRET) transfer has become a powerful tool for observing conformational dynamics of biological macromolecules. Analyzing smFRET time trajectories allows to identify the state transitions occuring on reaction pathways of molecular machines. Previously, we have developed a smFRET approach to monitor movements of the two nucleotide binding domains (NBDs) of P-glycoprotein (Pgp) during ATP hydrolysis driven drug transport in solution. One limitation of this initial work was that single-molecule photon bursts were analyzed by visual inspection with manual assignment of individual FRET levels. Here a fully automated analysis of Pgp smFRET data using hidden Markov models (HMM) for transitions up to 9 conformational states is applied. We propose new estimators for HMMs to integrate the information of fluctuating intensities in confocal smFRET measurements of freely diffusing lipid bilayer bound membrane proteins in solution. HMM analysis strongly supports that under conditions of steady state turnover, conformational states with short NBD distances and short dwell times are more populated compared to conditions without nucleotide or transport substrate present. Copyright © 2013 Elsevier Inc. All rights reserved.

  10. Mitochondrial dynamics and optical conformation changes in DsRed as studied by Fourier imaging correlation spectroscopy

    Science.gov (United States)

    Senning, Eric Nicolas

    Novel experiments that probe the dynamics of intracellular species, including the center-of-mass displacements and internal conformational transitions of biological macromolecules, have the potential to reveal the complex biochemical mechanisms operating within the cell. This work presents the implementation and development of Fourier imaging correlation spectroscopy (FICS), a phase-selective approach to fluorescence spectroscopy that measures the collective coordinate fluctuations of fluorescently labeled microscopic particles. In FICS experiments, a spatially modulated optical grating excites a fluorescently labeled sample. Phase-synchronous detection of the fluorescence, with respect to the phase of the exciting optical grating, can be used to monitor the fluctuations of partially averaged spatial coordinates. These data are then analyzed by two-point and four-point time correlation functions to provide a statistically meaningful understanding of the dynamics under observation. FICS represents a unique route to elevate signal levels, while acquiring detailed information about molecular coordinate trajectories. Mitochondria of mammalian cells are known to associate with cytoskeletal proteins, and their motions are affected by the stability of microtubules and microfilaments. Within the cell it is possible to fluorescently label the mitochondria and study its dynamic behavior with FICS. The dynamics of S. cerevisiae yeast mitochondria are characterized at four discrete length scales (ranging from 0.6--1.19 mum) and provide detailed information about the influence of specific cytoskeletal elements. Using the microtubule and microfilament destabilizing agents, Nocodazole and Latrunculin A, it is determined that microfilaments are required for normal yeast mitochondrial motion while microtubules have no effect. Experiments with specific actin mutants revealed that actin is responsible for enhanced mobility on length scales greater than 0.6 mum. The versatility of

  11. The broadband microwave spectra of the monoterpenoids thymol and carvacrol: Conformational landscape and internal dynamics

    Energy Technology Data Exchange (ETDEWEB)

    Schmitz, D.; Shubert, V. A. [Max Planck Institute for the Structure and Dynamics of Matter, Hamburg (Germany); The Center for Free-Electron Laser Science, Hamburg (Germany); Giuliano, B. M. [Center for Astrobiology, INTA-CSIC, Torrejón de Ardoz, Madrid (Spain); Schnell, M., E-mail: melanie.schnell@mpsd.mpg.de [Max Planck Institute for the Structure and Dynamics of Matter, Hamburg (Germany); The Center for Free-Electron Laser Science, Hamburg (Germany); The Hamburg Centre for Ultrafast Imaging, Universität Hamburg, Hamburg (Germany)

    2014-07-21

    The rotational spectra of the monoterpenoids thymol and carvacrol are reported in the frequency range 2–8.5 GHz, obtained with broadband Fourier-transform microwave spectroscopy. For carvacrol four different conformations were identified in the cold conditions of the molecular jet, whereas only three conformations were observed for thymol. The rotational constants and other molecular parameters are reported and compared with quantum chemical calculations. For both molecules, line splittings due to methyl group internal rotation were observed and the resulting barrier heights could be determined. The experimental barrier heights, 4.0863(25) kJ/mol for trans-carvacrol-A, 4.4024(16) kJ/mol for trans-carvacrol-B, and 0.3699(11) kJ/mol for trans-thymol-A, are compared with similar molecules.

  12. Conformational Dynamics of hSGLT1 during Na+/Glucose Cotransport

    DEFF Research Database (Denmark)

    Loo, D. D.; Hirayama, B. A.; Karakossian, M. H.

    2006-01-01

    This study examines the conformations of the Na+/glucose cotransporter (SGLT1) during sugar transport using charge and fluorescence measurements on the human SGLT1 mutant G507C expressed in Xenopus oocytes. The mutant exhibited similar steady-state and presteady-state kinetics as wild-type SGLT1....... voltage (Q-V) and fluorescence vs. voltage ( F-V) relations (for medium and slow components) obeyed Boltzmann relations with similar parameters: z (apparent valence of voltage sensor) 1; and V0.5 (midpoint voltage) between -15 and -40 mV. Sugar induced an inward current (Na+/glucose cotransport......) was totally abolished, whereas Fmax was only reduced 50%. Phlorizin reduced both Qmax and Fmax (Ki 0.4 µM), with no changes in V0.5's or relaxation time constants. Simulations using an eight-state kinetic model indicate that external sugar increases the occupancy probability of inward-facing conformations...

  13. Conformational dynamics in the selectivity filter of KcsA in response to potassium ion concentration.

    Science.gov (United States)

    Bhate, Manasi P; Wylie, Benjamin J; Tian, Lin; McDermott, Ann E

    2010-08-13

    Conformational change in the selectivity filter of KcsA as a function of ambient potassium concentration is studied with solid-state NMR. This highly conserved region of the protein is known to chelate potassium ions selectively. We report solid-state NMR chemical shift fingerprints of two distinct conformations of the selectivity filter; significant changes are observed in the chemical shifts of key residues in the filter as the potassium ion concentration is changed from 50 mM to 1 muM. Potassium ion titration studies reveal that the site-specific K(d) for K(+) binding at the key pore residue Val76 is on the order of approximately 7 muM and that a relatively high sample hydration is necessary to observe the low-K(+) conformer. Simultaneous detection of both conformers at low ambient potassium concentration suggests that the high-K(+) and low-K(+) states are in slow exchange on the NMR timescale (k(ex)evacuating both inner sites simultaneously differ from prior observations in detergent in solution, but agree well with measurements by electrophysiology and appear to result from our use of a hydrated bilayer environment. These observations strongly support a common assumption that the low-K(+) state is not involved in ion transmission, and that during transmission one of the two inner sites is always occupied. On the other hand, these kinetic and thermodynamic characteristics of the evacuation of the inner sites certainly could be compatible with participation in a control mechanism at low ion concentration such as C-type inactivation, a process that is coupled to activation and involves closing of the outer mouth of the channel. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

  14. Low energy dynamics from deformed conformal symmetry in quantum 4D N = 2 SCFTs

    CERN Document Server

    Kuzenko, S M; Theisen, Stefan J

    2003-01-01

    We determine the one-loop deformation of the conformal symmetry of a general N}=2 superconformally invariant Yang-Mills theory. The deformation is computed for several explicit examples which have a realization as world-volume theories on a stack of D3 branes. These include (i) N=4 SYM with gauge groups SU(N), USp(2N) and SO(N); (ii) USp(2N) gauge theory with one hypermultiplet in the traceless antisymmetric representation and four hypermultiplets in the fundamental; (iii) quiver gauge theory with gauge group SU(N)xSU(N) and two hypermultiplets in the bifundamental representations (N,\\bar N) and (bar N,N). The existence of quantum corrections to the conformal transformations imposes restrictions on the effective action which we study on a subset of the Coulomb branch corresponding to the separation of one brane from the stack. In the N=4 case, the one-loop corrected transformations provide a realization of the conformal algebra; this deformation is shown to be one-loop exact. For the other two models, higher-...

  15. Finite-Size Conformational Transitions: A Unifying Concept Underlying Chromosome Dynamics

    International Nuclear Information System (INIS)

    Caré, Bertrand R.; Victor, Jean-Marc; Lesne, Annick; Carrivain, Pascal; Forné, Thierry

    2014-01-01

    Investigating average thermodynamic quantities is not sufficient to understand conformational transitions of a finite-size polymer. We propose that such transitions are better described in terms of the probability distribution of some finite-size order parameter, and the evolution of this distribution as a control parameter varies. We demonstrate this claim for the coil-globule transition of a linear polymer and its mapping onto a two-state model. In a biological context, polymer models delineate the physical constraints experienced by the genome at different levels of organization, from DNA to chromatin to chromosome. We apply our finite-size approach to the formation of plectonemes in a DNA segment submitted to an applied torque and the ensuing helix-coil transition that can be numerically observed, with a coexistence of the helix and coil states in a range of parameters. Polymer models are also essential to analyze recent in vivo experiments providing the frequency of pairwise contacts between genomic loci. The probability distribution of these contacts yields quantitative information on the conformational fluctuations of chromosome regions. The changes observed in the shape of the distribution when the cell type or the physiological conditions vary may reveal an epigenetic modulation of the conformational constraints experienced by the chromosomes. (condensed matter: structural, mechanical, and thermal properties)

  16. Conformational Dynamics of the Receptor Protein Galactose/Glucose Binding Protein

    Science.gov (United States)

    Messina, Troy; Talaga, David

    2006-03-01

    We have performed time-correlated single photon counting (TCSPC) anisotropy and Stokes Shift measurements on bulk solutions of galactose/glucose binding protein. Site-directed mutagenesis was used to provide a single cysteine amino acid near the sugar-binding center of the protein (glutamine 26 to cysteine -- Q26C). The cysteine was covalently labeled with the environmentally-sensitive fluorophore acrylodan, and a long-lived ruthenium complex was covalently attached to the N-terminus to provide a fluorescent reference. The TCSPC data were analyzed using global convolute-and-compare fitting routines over the entire glucose titration and temperature range to provide minimal reduced chi-squared values and the highest time resolution possible. Using a standard ligand-binding model, the resulting distributions show that the closed (ligand-bound) conformation exists even at zero glucose concentration. At 20^oC, the relative abundance of this conformation is as high as 40%. The temperature dependence of this conformational study will be discussed and related to the ligand-binding free energy surface.

  17. Excited state conformational dynamics in carotenoids: dark intermediates and excitation energy transfer.

    Science.gov (United States)

    Beck, Warren F; Bishop, Michael M; Roscioli, Jerome D; Ghosh, Soumen; Frank, Harry A

    2015-04-15

    A consideration of the excited state potential energy surfaces of carotenoids develops a new hypothesis for the nature of the conformational motions that follow optical preparation of the S2 (1(1)Bu(+)) state. After an initial displacement from the Franck-Condon geometry along bond length alternation coordinates, it is suggested that carotenoids pass over a transition-state barrier leading to twisted conformations. This hypothesis leads to assignments for several dark intermediate states encountered in femtosecond spectroscopic studies. The Sx state is assigned to the structure reached upon the onset of torsional motions near the transition state barrier that divides planar and twisted structures on the S2 state potential energy surface. The X state, detected recently in two-dimensional electronic spectra, corresponds to a twisted structure well past the barrier and approaching the S2 state torsional minimum. Lastly, the S(∗) state is assigned to a low lying S1 state structure with intramolecular charge transfer character (ICT) and a pyramidal conformation. It follows that the bent and twisted structures of carotenoids that are found in photosynthetic light-harvesting proteins yield excited-state structures that favor the development of an ICT character and optimized energy transfer yields to (bacterio)chlorophyll acceptors. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. Stabilizing the weak scale with conformal dynamics: A survey of model building approaches

    Science.gov (United States)

    Galloway, Jamison Robert

    The Standard Model of particle physics stands as the most accurate description we have of our observed phenomena. It accommodates the experimental data collected to date, and provides an economical and predictive framework for understanding nature on small scales. The model can in fact be consistently extrapolated to the smallest length scales we can imagine, where the concept of spacetime itself is believed to require modification. As such, the Standard Model stands as a truly monumental achievement of scientific pursuits. The successes of the model, however, present some equally profound questions. The model, for instance, can in fact be extrapolated to very high scales, but only at the cost of introducing a highly unstable hierarchy. This thesis addresses the possibilities afforded by conformal field theories in addressing this problem. There are three classes of models discussed: four-dimensional composite models, five-dimensional composite models, and unparticle models. The foundations of each scenario are reviewed, and new approaches to solving some of their problems are presented. In each case, conformality plays a central role. Generically this is due to the fact that nontrivial scale dependence is at the heart of conformal field theories: we will see the common occurrence of large anomalous dimensions in strongly-coupled conformal field theories, which allow a softening of the dependence of relatively low-energy physics on unknown physics at higher energies. Finding a mechanism to achieve a stable separation of low-scale physics presents many challenges, but typically gives concrete predictions for new phenomena to be observed at the Large Hadron Collider, which recently became the world's highest energy particle accelerator. What will be revealed there in coming years is still very uncertain, so knowing in advance how each theoretical construction will be manifested physically is the immediate concern of particle physicists. The goal of this work is to

  19. Modification of the histone tetramer at the H3-H3 interface impacts tetrasome conformations and dynamics

    Science.gov (United States)

    Ordu, Orkide; Kremser, Leopold; Lusser, Alexandra; Dekker, Nynke H.

    2018-03-01

    Nucleosomes consisting of a short piece of deoxyribonucleic acid (DNA) wrapped around an octamer of histone proteins form the fundamental unit of chromatin in eukaryotes. Their role in DNA compaction comes with regulatory functions that impact essential genomic processes such as replication, transcription, and repair. The assembly of nucleosomes obeys a precise pathway in which tetramers of histones H3 and H4 bind to the DNA first to form tetrasomes, and two dimers of histones H2A and H2B are subsequently incorporated to complete the complex. As viable intermediates, we previously showed that tetrasomes can spontaneously flip between a left-handed and right-handed conformation of DNA-wrapping. To pinpoint the underlying mechanism, here we investigated the role of the H3-H3 interface for tetramer flexibility in the flipping process at the single-molecule level. Using freely orbiting magnetic tweezers, we studied the assembly and structural dynamics of individual tetrasomes modified at the cysteines close to this interaction interface by iodoacetamide (IA) in real time. While such modification did not affect the structural properties of the tetrasomes, it caused a 3-fold change in their flipping kinetics. The results indicate that the IA-modification enhances the conformational plasticity of tetrasomes. Our findings suggest that subnucleosomal dynamics may be employed by chromatin as an intrinsic and adjustable mechanism to regulate DNA supercoiling.

  20. Interconverting conformations of variants of the human amyloidogenic protein beta2-microglobulin quantitatively characterized by dynamic capillary electrophoresis and computer simulation

    DEFF Research Database (Denmark)

    Heegaard, Niels H H; Jørgensen, Thomas J D; Cheng, Lei

    2006-01-01

    Capillary electrophoretic separation profiles of cleaved variants of beta2-microglobulin (beta2m) reflect the conformational equilibria existing in solutions of these proteins. The characterization of these equilibria is of interest since beta2m is responsible for amyloid formation in dialysis...... a unified theory for dynamic chromatography and dynamic electrophoresis. The results are correlated with the outcome of independent experiments based on mass spectrometric measurement of H/D exchange. This study illustrates that dynamic capillary electrophoresis is suitable for the investigation...... of the interconversion of protein conformations of amyloidogenic molecules and is not only restricted to ideal model compounds....

  1. Conformational Dynamics and Binding Free Energies of Inhibitors of BACE-1: From the Perspective of Protonation Equilibria.

    Directory of Open Access Journals (Sweden)

    M Olivia Kim

    2015-10-01

    Full Text Available BACE-1 is the β-secretase responsible for the initial amyloidogenesis in Alzheimer's disease, catalyzing hydrolytic cleavage of substrate in a pH-sensitive manner. The catalytic mechanism of BACE-1 requires water-mediated proton transfer from aspartyl dyad to the substrate, as well as structural flexibility in the flap region. Thus, the coupling of protonation and conformational equilibria is essential to a full in silico characterization of BACE-1. In this work, we perform constant pH replica exchange molecular dynamics simulations on both apo BACE-1 and five BACE-1-inhibitor complexes to examine the effect of pH on dynamics and inhibitor binding properties of BACE-1. In our simulations, we find that solution pH controls the conformational flexibility of apo BACE-1, whereas bound inhibitors largely limit the motions of the holo enzyme at all levels of pH. The microscopic pKa values of titratable residues in BACE-1 including its aspartyl dyad are computed and compared between apo and inhibitor-bound states. Changes in protonation between the apo and holo forms suggest a thermodynamic linkage between binding of inhibitors and protons localized at the dyad. Utilizing our recently developed computational protocol applying the binding polynomial formalism to the constant pH molecular dynamics (CpHMD framework, we are able to obtain the pH-dependent binding free energy profiles for various BACE-1-inhibitor complexes. Our results highlight the importance of correctly addressing the binding-induced protonation changes in protein-ligand systems where binding accompanies a net proton transfer. This work comprises the first application of our CpHMD-based free energy computational method to protein-ligand complexes and illustrates the value of CpHMD as an all-purpose tool for obtaining pH-dependent dynamics and binding free energies of biological systems.

  2. Dynamics of the His79-heme Alkaline Transition of Yeast Iso-1-cytochrome c Probed by Conformationally-gated Electron Transfer with Co(II)bis(terpyridine)†

    Science.gov (United States)

    Cherney, Melisa M.; Junior, Carolyn C.; Bergquist, Bryan B.; Bowler, Bruce E.

    2013-01-01

    Alkaline conformers of cytochrome c may be involved in both its electron transport and apoptotic functions. We use cobalt(II)bis(terpyridine), Co(terpy)22+, as a reagent for conformationally-gated electron transfer (gated ET) experiments to study the alkaline conformational transition of K79H variants of yeast iso-1-cytochrome c expressed in Escherichia coli, WT*K79H, with alanine at position 72, and Saccharomyces cerevisiae, yK79H, with trimethyllysine (Tml) at position 72. Co(terpy)22+ is well-suited to the 100 ms to 1 s time scale of the His79-mediated alkaline conformational transition of these variants. Reduction of the His79-heme alkaline conformer by Co(terpy)22+ occurs primarily by gated ET, which involves conversion to the native state followed by reduction, with a small fraction of the His79- heme alkaline conformer directly reduced by Co(terpy)22+. The gated ET experiments show that the mechanism of formation of the His79-heme alkaline conformer involves only two ionizable groups. In previous work, we showed that the mechanism of the His73-mediated alkaline conformational transition requires three ionizable groups. Thus, the mechanism of heme crevice opening depends upon the position of the ligand mediating the process. The microscopic rate constants provided by gated ET studies show that mutation of Tml72 (yK79H variant) in the heme crevice loop to Ala72 (WT*K79H variant) affects the dynamics of heme crevice opening through a small destabilization of both the native conformer and the transition state relative to the His79-heme alkaline conformer. Previous pH jump data had indicated that the Tml72→Ala mutation primarily stabilized the transition state for the His79-mediated alkaline conformational transition. PMID:23899348

  3. Conformational dynamics and role of the acidic pocket in ASIC pH-dependent gating.

    Science.gov (United States)

    Vullo, Sabrina; Bonifacio, Gaetano; Roy, Sophie; Johner, Niklaus; Bernèche, Simon; Kellenberger, Stephan

    2017-04-04

    Acid-sensing ion channels (ASICs) are proton-activated Na + channels expressed in the nervous system, where they are involved in learning, fear behaviors, neurodegeneration, and pain sensation. In this work, we study the role in pH sensing of two regions of the ectodomain enriched in acidic residues: the acidic pocket, which faces the outside of the protein and is the binding site of several animal toxins, and the palm, a central channel domain. Using voltage clamp fluorometry, we find that the acidic pocket undergoes conformational changes during both activation and desensitization. Concurrently, we find that, although proton sensing in the acidic pocket is not required for channel function, it does contribute to both activation and desensitization. Furthermore, protonation-mimicking mutations of acidic residues in the palm induce a dramatic acceleration of desensitization followed by the appearance of a sustained current. In summary, this work describes the roles of potential pH sensors in two extracellular domains, and it proposes a model of acidification-induced conformational changes occurring in the acidic pocket of ASIC1a.

  4. Structural analysis of prolyl oligopeptidases using molecular docking and dynamics: insights into conformational changes and ligand binding.

    Directory of Open Access Journals (Sweden)

    Swati Kaushik

    Full Text Available Prolyl oligopeptidase (POP is considered as an important pharmaceutical target for the treatment of numerous diseases. Despite enormous studies on various aspects of POPs structure and function still some of the questions are intriguing like conformational dynamics of the protein and interplay between ligand entry/egress. Here, we have used molecular modeling and docking based approaches to unravel questions like differences in ligand binding affinities in three POP species (porcine, human and A. thaliana. Despite high sequence and structural similarity, they possess different affinities for the ligands. Interestingly, human POP was found to be more specific, selective and incapable of binding to a few planar ligands which showed extrapolation of porcine POP in human context is more complicated. Possible routes for substrate entry and product egress were also investigated by detailed analyses of molecular dynamics (MD simulations for the three proteins. Trajectory analysis of bound and unbound forms of three species showed differences in conformational dynamics, especially variations in β-propeller pore size, which was found to be hidden by five lysine residues present on blades one and seven. During simulation, β-propeller pore size was increased by ∼2 Å in porcine ligand-bound form which might act as a passage for smaller product movement as free energy barrier was reduced, while there were no significant changes in human and A. thaliana POPs. We also suggest that these differences in pore size could lead to fundamental differences in mode of product egress among three species. This analysis also showed some functionally important residues which can be used further for in vitro mutagenesis and inhibitor design. This study can help us in better understanding of the etiology of POPs in several neurodegenerative diseases.

  5. Intramolecular interactions stabilizing compact conformations of the intrinsically disordered kinase-inhibitor domain of Sic1: a molecular dynamics investigation.

    Directory of Open Access Journals (Sweden)

    Matteo eLambrughi

    2012-11-01

    Full Text Available Cyclin-dependent kinase inhibitors (CKIs are key regulatory proteins of the eukaryotic cell cycle, which modulate cyclin-dependent kinase (Cdk activity. CKIs perform their inhibitory effect by the formation of ternary complexes with a target kinase and its cognate cyclin. These regulators generally belong to the class of intrinsically disordered proteins (IDPs, which lack a well-defined and organized three-dimensional structure in their free state, undergoing folding upon binding to specific partners. Unbound IDPs are not merely random-coil structures, but can present intrinsically folded structural units (IFSUs and collapsed conformations. These structural features can be relevant to protein function in vivo.The yeast CKI Sic1 is a 284-amino acid IDP that binds to Cdk1 in complex with the Clb5,6 cyclins, preventing phosphorylation of G1 substrates and, therefore, entrance to the S phase. Sic1 degradation, triggered by multiple phosphorylation events, promotes cell-cycle progression. Previous experimental studies pointed out a propensity of Sic1 and its isolated domains to populate both extended and compact conformations. The present contribution provides models of the compact conformations of the Sic1 kinase-inhibitory domain (KID by all-atom molecular-dynamics simulations in explicit solvent and in the absence of interactors. The results are integrated by spectroscopic and spectrometric data. Helical IFSUs are identified, along with networks of intramolecular interactions. The results identify a group of hub residues and electrostatic interactions which are likely to be involved in the stabilization of globular states.

  6. Steered molecular dynamics simulations of a type IV pilus probe initial stages of a force-induced conformational transition.

    Directory of Open Access Journals (Sweden)

    Joseph L Baker

    2013-04-01

    Full Text Available Type IV pili are long, protein filaments built from a repeating subunit that protrudes from the surface of a wide variety of infectious bacteria. They are implicated in a vast array of functions, ranging from bacterial motility to microcolony formation to infection. One of the most well-studied type IV filaments is the gonococcal type IV pilus (GC-T4P from Neisseria gonorrhoeae, the causative agent of gonorrhea. Cryo-electron microscopy has been used to construct a model of this filament, offering insights into the structure of type IV pili. In addition, experiments have demonstrated that GC-T4P can withstand very large tension forces, and transition to a force-induced conformation. However, the details of force-generation, and the atomic-level characteristics of the force-induced conformation, are unknown. Here, steered molecular dynamics (SMD simulation was used to exert a force in silico on an 18 subunit segment of GC-T4P to address questions regarding the nature of the interactions that lead to the extraordinary strength of bacterial pili. SMD simulations revealed that the buried pilin α1 domains maintain hydrophobic contacts with one another within the core of the filament, leading to GC-T4P's structural stability. At the filament surface, gaps between pilin globular head domains in both the native and pulled states provide water accessible routes between the external environment and the interior of the filament, allowing water to access the pilin α1 domains as reported for VC-T4P in deuterium exchange experiments. Results were also compared to the experimentally observed force-induced conformation. In particular, an exposed amino acid sequence in the experimentally stretched filament was also found to become exposed during the SMD simulations, suggesting that initial stages of the force induced transition are well captured. Furthermore, a second sequence was shown to be initially hidden in the native filament and became exposed upon

  7. Steered molecular dynamics simulations of a type IV pilus probe initial stages of a force-induced conformational transition.

    Science.gov (United States)

    Baker, Joseph L; Biais, Nicolas; Tama, Florence

    2013-04-01

    Type IV pili are long, protein filaments built from a repeating subunit that protrudes from the surface of a wide variety of infectious bacteria. They are implicated in a vast array of functions, ranging from bacterial motility to microcolony formation to infection. One of the most well-studied type IV filaments is the gonococcal type IV pilus (GC-T4P) from Neisseria gonorrhoeae, the causative agent of gonorrhea. Cryo-electron microscopy has been used to construct a model of this filament, offering insights into the structure of type IV pili. In addition, experiments have demonstrated that GC-T4P can withstand very large tension forces, and transition to a force-induced conformation. However, the details of force-generation, and the atomic-level characteristics of the force-induced conformation, are unknown. Here, steered molecular dynamics (SMD) simulation was used to exert a force in silico on an 18 subunit segment of GC-T4P to address questions regarding the nature of the interactions that lead to the extraordinary strength of bacterial pili. SMD simulations revealed that the buried pilin α1 domains maintain hydrophobic contacts with one another within the core of the filament, leading to GC-T4P's structural stability. At the filament surface, gaps between pilin globular head domains in both the native and pulled states provide water accessible routes between the external environment and the interior of the filament, allowing water to access the pilin α1 domains as reported for VC-T4P in deuterium exchange experiments. Results were also compared to the experimentally observed force-induced conformation. In particular, an exposed amino acid sequence in the experimentally stretched filament was also found to become exposed during the SMD simulations, suggesting that initial stages of the force induced transition are well captured. Furthermore, a second sequence was shown to be initially hidden in the native filament and became exposed upon stretching.

  8. Green Network Planning Model for Optical Backbones

    DEFF Research Database (Denmark)

    Gutierrez Lopez, Jose Manuel; Riaz, M. Tahir; Jensen, Michael

    2010-01-01

    Communication networks are becoming more essential for our daily lives and critically important for industry and governments. The intense growth in the backbone traffic implies an increment of the power demands of the transmission systems. This power usage might have a significant negative effect...... on the environment in general. In network planning there are existing planning models focused on QoS provisioning, investment minimization or combinations of both and other parameters. But there is a lack of a model for designing green optical backbones. This paper presents novel ideas to be able to define...... an analytical model to consider environmental aspects in the planning stage of backbones design....

  9. Implementation and evaluation of modified dynamic conformal arc (MDCA) technique for lung SBRT patients following RTOG protocols

    Energy Technology Data Exchange (ETDEWEB)

    Shi, Chengyu, E-mail: shicy1974@gmail.com [St. Vincent' s Medical Center, Bridgeport, CT (United States); Tazi, Adam; Fang, Deborah Xiangdong; Iannuzzi, Christopher [St. Vincent' s Medical Center, Bridgeport, CT (United States)

    2013-10-01

    To implement modified dynamic conformal arc (MDCA) technique and Radiation Therapy Oncology Group (RTOG) protocols in our clinic for stereotactic body radiation therapy (SBRT) treatment of patients with Stage I/II non–small cell lung cancer. Five patients with non–small cell lung cancer have been treated with SBRT. All the patients were immobilized using CIVCO Body Pro-Lok system and scanned using GE 4-slice computed tomography. The MDCA technique that was previously published was adopted as our planning technique, and RTOG protocols for the lung SBRT were followed. The patients were treated on Novalis Tx system with cone-beam computed tomography imaging guidance. All the patient plans passed the RTOG criteria. The conformal index ranges from 0.99 to 1.12 for the planning target volume, and the biological equivalent dose for the planning target volume is overall 100 Gy. Critical structures (lung, spinal cord, brachial plexus, skin, and chest wall) also meet RTOG protocols or published data. A 6-month follow-up of one of the patients shows good local disease control. We have successfully implemented the MDCA technique into our clinic for the lung SBRT program. It shows that the MDCA is useful and efficient for the lung SBRT planning, with the plan quality meeting the RTOG protocols.

  10. Analysis of cytochrome P450 CYP119 ligand-dependent conformational dynamics by two-dimensional NMR and X-ray crystallography.

    Science.gov (United States)

    Basudhar, Debashree; Madrona, Yarrow; Kandel, Sylvie; Lampe, Jed N; Nishida, Clinton R; de Montellano, Paul R Ortiz

    2015-04-17

    Defining the conformational states of cytochrome P450 active sites is critical for the design of agents that minimize drug-drug interactions, the development of isoform-specific P450 inhibitors, and the engineering of novel oxidative catalysts. We used two-dimensional (1)H,(15)N HSQC chemical shift perturbation mapping of (15)N-labeled Phe residues and x-ray crystallography to examine the ligand-dependent conformational dynamics of CYP119. Active site Phe residues were most affected by the binding of azole inhibitors and fatty acid substrates, in agreement with active site localization of the conformational changes. This was supported by crystallography, which revealed movement of the F-G loop with various azoles. Nevertheless, the NMR chemical shift perturbations caused by azoles and substrates were distinguishable. The absence of significant chemical shift perturbations with several azoles revealed binding of ligands to an open conformation similar to that of the ligand-free state. In contrast, 4-phenylimidazole caused pronounced NMR changes involving Phe-87, Phe-144, and Phe-153 that support the closed conformation found in the crystal structure. The same closed conformation is observed by NMR and crystallography with a para-fluoro substituent on the 4-phenylimidazole, but a para-chloro or bromo substituent engendered a second closed conformation. An open conformation is thus favored in solution with many azole ligands, but para-substituted phenylimidazoles give rise to two closed conformations that depend on the size of the para-substituent. The results suggest that ligands selectively stabilize discrete cytochrome P450 conformational states. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  11. External Tank - The Structure Backbone

    Science.gov (United States)

    Welzyn, Kenneth; Pilet, Jeffrey C.; Diecidue-Conners, Dawn; Worden, Michelle; Guillot, Michelle

    2011-01-01

    The External Tank forms the structural backbone of the Space Shuttle in the launch configuration. Because the tank flies to orbital velocity with the Space Shuttle Orbiter, minimization of weight is mandatory, to maximize payload performance. Choice of lightweight materials both for structure and thermal conditioning was necessary. The tank is large, and unique manufacturing facilities, tooling, handling, and transportation operations were required. Weld processes and tooling evolved with the design as it matured through several block changes, to reduce weight. Non Destructive Evaluation methods were used to assure integrity of welds and thermal protection system materials. The aluminum-lithium alloy was used near the end of the program and weld processes and weld repair techniques had to be refined. Development and implementation of friction stir welding was a substantial technology development incorporated during the Program. Automated thermal protection system application processes were developed for the majority of the tank surface. Material obsolescence was an issue throughout the 40 year program. The final configuration and tank weight enabled international space station assembly in a high inclination orbit allowing international cooperation with the Russian Federal Space Agency. Numerous process controls were implemented to assure product quality, and innovative proof testing was accomplished prior to delivery. Process controls were implemented to assure cleanliness in the production environment, to control contaminants, and to preclude corrosion. Each tank was accepted via rigorous inspections, including non-destructive evaluation techniques, proof testing, and all systems testing. In the post STS-107 era, the project focused on ascent debris risk reduction. This was accomplished via stringent process controls, post flight assessment using substantially improved imagery, and selective redesigns. These efforts were supported with a number of test programs to

  12. Future High Capacity Backbone Networks

    DEFF Research Database (Denmark)

    Wang, Jiayuan

    are proposed. The work focuses on energy efficient routing algorithms in a dynamic optical core network environment, with Generalized MultiProtocol Label Switching (GMPLS) as the control plane. Energy ef- ficient routing algorithms for energy savings and CO2 savings are proposed, and their performance...... is studied in details with dynamic network simulations using OPNET. Dynamic routing optimization methods are proposed. The influences of re-routing and load-balancing factors on the algorithm are evaluated with a focus on different re-routing thresholds. Results from dynamic network simulations show that re-routing...... strategies can further lower CO2 emissions compared to basic energy source routing scheme, and that a lower re-routing threshold achieves more savings. The increased blocking probability brought by using rerouting schemes can be compensated by applying load balancing criteria. A trade-off between blocking...

  13. Change of conformation and internal dynamics of supercoiled DNA upon binding of Escherichia coli single-strand binding protein

    International Nuclear Information System (INIS)

    Langowski, J.; Benight, A.S.; Fujimoto, B.S.; Schurr, J.M.; Schomburg, U.

    1985-01-01

    The influence of Escherichia coli single-strand binding (SSB) protein on the conformation and internal dynamics of pBR322 and pUC8 supercoiled DNAs has been investigated by using dynamic light scattering at 632.8 and 351.1 nm and time-resolved fluorescence polarization anisotropy of intercalated ethidium. SSB protein binds to both DNAs up to a stoichiometry that is sufficient to almost completely relax the superhelical turns. Upon saturation binding, the translational diffusion coefficients (D 0 ) of both DNAs decrease by approximately 20%. Apparent diffusion coefficients (D/sub app/) obtained from dynamic light scattering display the well-known increase with K 2 (K = scattering vector), leveling off toward a plateau value (D/sub plat/) at high K 2 . For both DNAs, the difference D/sub plat/ - D 0 increases upon relaxation of supercoils by SSB protein, which indicates a corresponding enhancement of the subunit mobilities in internal motions. Fluorescence polarization anisotropy measurements on free and complexed pBR322 DNA indicate a (predominantly) uniform torsional rigidity for the saturated DNA/SSB protein complex that is significantly reduced compared to the free DNA. These observations are all consistent with the notion that binding of SSB protein is accompanied by a gradual loss of supercoils and saturates when the superhelical twist is largely removed

  14. On the purported "backbone fluorescence" in protein three-dimensional fluorescence spectra

    DEFF Research Database (Denmark)

    Bortolotti, Annalisa; Wong, Yin How; Korsholm, Stine S.

    2016-01-01

    claiming that this fluorescence originates from the protein backbone, contrary to the established knowledge that UV protein emission is due to aromatic amino acids only. Overall, our data clearly demonstrate that the observed emission upon excitation at 220-230 nm is due to the excitation of Tyr and/or Trp......, with subsequent emission from the lowest excited state (i.e. the same as obtained with 280 nm excitation) in agreement with Kasha's rule. Therefore, this fluorescence peak does not provide any information on backbone conformation, but simply reports on the local environment around the aromatic side chains, just...

  15. Exploitation of Conformational Dynamics in Imparting Selective Inhibition for Related Matrix Metalloproteinases.

    Science.gov (United States)

    Mahasenan, Kiran V; Bastian, Maria; Gao, Ming; Frost, Emma; Ding, Derong; Zorina-Lichtenwalter, Katerina; Jacobs, John; Suckow, Mark A; Schroeder, Valerie A; Wolter, William R; Chang, Mayland; Mobashery, Shahriar

    2017-06-08

    Matrix metalloproteinases (MMPs) have numerous physiological functions and share a highly similar catalytic domain. Differential dynamical information on the closely related human MMP-8, -13, and -14 was integrated onto the benzoxazinone molecular template. An in silico library of 28,099 benzoxazinones was generated and evaluated in the context of the molecular-dynamics information. This led to experimental evaluation of 19 synthesized compounds and identification of selective inhibitors, which have potential utility in delineating the physiological functions of MMPs. Moreover, the approach serves as an example of how dynamics of closely related active sites may be exploited to achieve selective inhibition by small molecules and should find applications in other enzyme families with similar active sites.

  16. Comparison of conformal radiation therapy techniques within the dynamic radiotherapy project 'Dynarad'

    NARCIS (Netherlands)

    Mavroidis, P.; Lind, B. K.; van Dijk, J.; Koedooder, K.; de Neve, W.; de Wagter, C.; Planskoy, B.; Rosenwald, J. C.; Proimos, B.; Kappas, C.; Claudia, D.; Benassi, M.; Chierego, G.; Brahme, A.

    2000-01-01

    The objective of the dynamic radiotherapy project 'Dynarad' within the European Community has been to compare and grade treatment techniques that are currently applied or being developed at the participating institutions. Cervical cancer was selected as the tumour site on the grounds that the

  17. Conformational dynamics of bacterial and human cytoplasmic models of the ribosomal A-site

    Czech Academy of Sciences Publication Activity Database

    Panecka, J.; Šponer, Jiří; Trylska, J.

    112C, MAY 2015 (2015), s. 96-110 ISSN 0300-9084 R&D Projects: GA ČR(CZ) GBP305/12/G034; GA MŠk(CZ) ED1.1.00/02.0068 Institutional support: RVO:68081707 Keywords : MOLECULAR-DYNAMICS * DECODING SITE * CRYSTAL-STRUCTURE Subject RIV: BO - Biophysics Impact factor: 3.017, year: 2015

  18. Conformational Sampling by Ab Initio Molecular Dynamics Simulations Improves NMR Chemical Shift Predictions

    Czech Academy of Sciences Publication Activity Database

    Dračínský, Martin; Möller, H. M.; Exner, T. E.

    2013-01-01

    Roč. 9, č. 8 (2013), s. 3806-3815 ISSN 1549-9618 R&D Projects: GA ČR GA13-24880S Institutional support: RVO:61388963 Keywords : ab initio molecular dynamics * NMR spectroscopy * DFT calculations * hydration Subject RIV: CF - Physical ; Theoretical Chemistry Impact factor: 5.310, year: 2013

  19. Assignment of Side-Chain Conformation Using Adiabatic Energy Mapping, Free Energy Perturbation, and Molecular Dynamic Simulations

    DEFF Research Database (Denmark)

    Frimurer, Thomas M.; Günther, Peter H.; Sørensen, Morten Dahl

    1999-01-01

    adiabatic mapping, conformational change, essentialdynamics, free energy simulations, Kunitz type inhibitor *ga3(VI)......adiabatic mapping, conformational change, essentialdynamics, free energy simulations, Kunitz type inhibitor *ga3(VI)...

  20. Investigation of intramolecular dynamics and conformations of α-, β- and γ-synuclein.

    Directory of Open Access Journals (Sweden)

    Vanessa C Ducas

    Full Text Available The synucleins are a family of natively unstructured proteins consisting of α-, β-, and γ-synuclein which are primarily expressed in neurons. They have been linked to a wide variety of pathologies, including neurological disorders, such as Parkinson's disease (α-synuclein and dementia with Lewy bodies (α- and β-synuclein, as well as various types of cancers (γ-synuclein. Self-association is a key pathological feature of many of these disorders, with α-synuclein having the highest propensity to form aggregates, while β-synuclein is the least prone. Here, we used a combination of fluorescence correlation spectroscopy and single molecule Förster resonance energy transfer to compare the intrinsic dynamics of different regions of all three synuclein proteins to investigate any correlation with putative functional or dysfunctional interactions. Despite a relatively high degree of sequence homology, we find that individual regions sample a broad range of diffusion coefficients, differing by almost a factor of four. At low pH, a condition that accelerates aggregation of α-synuclein, on average smaller diffusion coefficients are measured, supporting a hypothesis that slower intrachain dynamics may be correlated with self-association. Moreover, there is a surprising inverse correlation between dynamics and bulkiness of the segments. Aside from this observation, we could not discern any clear relationship between the physico-chemical properties of the constructs and their intrinsic dynamics. This work suggests that while protein dynamics may play a role in modulating self-association or interactions with other binding partners, other factors, particularly the local cellular environment, may be more important.

  1. Characterization of the internal dynamics and conformational space of zinc-bound amyloid β peptides by replica-exchange molecular dynamics simulations.

    Science.gov (United States)

    Xu, Liang; Wang, Xiaojuan; Wang, Xicheng

    2013-07-01

    Amyloid β (Aβ) peptides and metal ions have been associated with the pathogenesis of Alzheimer's disease. The conformational space of Aβ fragments of different length with and without binding of metal ions has been extensively investigated by replica-exchange molecular dynamics (REMD) simulation. However, only trajectories extracted at relatively low temperatures have been used for this analysis. The capability of REMD simulations to characterize the internal dynamics of such intrinsically disordered proteins (IDPs) as Aβ has been overlooked. In this work, we use an approach recently developed by Xue and Skrynnikov (J Am Chem Soc 133:14614-14628, 2011) to calculate NMR observables, including (15)N relaxation rates and (15)N-(1)H nuclear Overhauser enhancement (NOE), from the high-temperature trajectory of REMD simulations for zinc-bound Aβ peptides. The time axis of the trajectory was rescaled to correct for the effect of the high temperature (408 K) compared with the experimental temperature (278 K). Near-quantitative agreement between simulated values and experimental results was obtained. When the structural properties and free-energy surfaces of zinc-bound Aβ(1-40) and Aβ(1-42) were compared at the physiological temperature 310 K it was found that zinc-bound Aβ(1-42) was more rigid than Aβ(1-40) at the C terminus, and its conformational transitions were also more preferred. The self-consistent results derived from trajectories at high and low temperatures demonstrate the capability of REMD simulations to capture the internal dynamics of IDPs.

  2. Conformational dynamics of the human propeller telomeric DNA quadruplex on a microsecond time scale

    Czech Academy of Sciences Publication Activity Database

    Islam, B.; Sgobba, M.; Laughton, C.; Orozco, M.; Šponer, Jiří; Neidle, S.; Haider, S.

    2013-01-01

    Roč. 41, č. 4 (2013), s. 2723-2735 ISSN 0305-1048 R&D Projects: GA ČR(CZ) GAP208/11/1822 Grant - others:GA ČR(CZ) ED1.1.00/02.0068 Program:ED Institutional support: RVO:68081707 Keywords : MOLECULAR-DYNAMICS * CRYSTAL-STRUCTURE * B-DNA Subject RIV: BO - Biophysics Impact factor: 8.808, year: 2013

  3. Effects of N-glycosylation on protein conformation and dynamics: Protein Data Bank analysis and molecular dynamics simulation study.

    Science.gov (United States)

    Lee, Hui Sun; Qi, Yifei; Im, Wonpil

    2015-03-09

    N-linked glycosylation is one of the most important, chemically complex, and ubiquitous post-translational modifications in all eukaryotes. The N-glycans that are covalently linked to proteins are involved in numerous biological processes. There is considerable interest in developments of general approaches to predict the structural consequences of site-specific glycosylation and to understand how these effects can be exploited in protein design with advantageous properties. In this study, the impacts of N-glycans on protein structure and dynamics are systematically investigated using an integrated computational approach of the Protein Data Bank structure analysis and atomistic molecular dynamics simulations of glycosylated and deglycosylated proteins. Our study reveals that N-glycosylation does not induce significant changes in protein structure, but decreases protein dynamics, likely leading to an increase in protein stability. Overall, these results suggest not only a common role of glycosylation in proteins, but also a need for certain proteins to be properly glycosylated to gain their intrinsic dynamic properties.

  4. The effect of alpha-ketoglutaric acid on tyrosinase activity and conformation: Kinetics and molecular dynamics simulation study.

    Science.gov (United States)

    Gou, Lin; Lee, Jinhyuk; Yang, Jun-Mo; Park, Yong-Doo; Zhou, Hai-Meng; Zhan, Yi; Lü, Zhi-Rong

    2017-12-01

    Alpha-ketoglutaric acid (AKG) is naturally found in organisms and is a well-known intermediate in the production of ATP or GTP in the Krebs cycle. We elucidated the effects of AKG on tyrosinase activity and conformation via methods of inhibition kinetics integrated with molecular dynamics (MD) simulations. AKG was found to be a reversible inhibitor of tyrosinase (IC 50 =15±0.5mM) and induced parabolic slope mixed-type inhibition. Based on our newly established equation, the dissociation constant (K islope ) was determined to be 7.93±0.31mM. The spectrofluorimetry studies showed that AKG mainly induced regional changes in the active site of tyrosinase, which reflects the flexibility of the active site. The computational docking and molecular dynamics (MD) simulations further demonstrated that AKG could interact with several residues near the substrate-binding site located in the tyrosinase active site pocket. Our study provides insight into the mechanism by which energy-producing intermediates such as AKG inhibit tyrosinase through its ketone groups. Also, AKG could be a potential natural antipigmentation agent due to its non-toxic property. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. Applications of hydrogen deuterium exchange (HDX for the characterization of conformational dynamics in light-activated photoreceptors

    Directory of Open Access Journals (Sweden)

    Robert eLindner

    2015-06-01

    Full Text Available Rational design of optogenetic tools is inherently linked to the understanding of photoreceptor function. Structural analysis of elements involved in signal integration in individual sensor domains provides an initial idea of their mode of operation, but understanding how local structural rearrangements eventually affect signal transmission to output domains requires inclusion of the effector regions in the characterization. However, the dynamic nature of these assemblies renders their structural analysis challenging and therefore a combination of high- and low-resolution techniques is required to appreciate functional aspects of photoreceptors.This review focuses on the potential of Hydrogen-Deuterium exchange coupled to mass spectrometry (HDX-MS for complementing the structural characterization of photoreceptors. In this respect, the ability of HDX-MS to provide information on the conformational dynamics and the possibility to address multiple functionally relevant states in solution render this methodology ideally suitable. We highlight recent examples demonstrating the potential of HDX-MS and discuss how these results can help to improve existing optogenetic systems or guide the design of novel optogenetic tools.

  6. The effects of mutating Tyr9 and Arg15 on the structure, stability, conformational dynamics and mechanism of GSTA3-3

    CSIR Research Space (South Africa)

    Robertson, GJ

    2017-03-01

    Full Text Available an interdomain salt-bridge at the active site. Hydrogen-deuterium exchange mass spectrometry also revealed that neither mutation had a significant effect on the conformational dynamics of GSTA3-3. The R15L and Y9F mutations are equally important to the specific...

  7. Molecular dynamics of 18-crown-6 complexes with alkali metal cations and urea-prediction of their conformations and comparison with data from the Cambridge Structural Database

    NARCIS (Netherlands)

    Leuwerink, F.T.H.; Harkema, Sybolt; Briels, Willem J.; Feil, D.; Feil, D.

    1993-01-01

    Complexes of 18-crown-6 with alkali-metal cations (Na+, K+, and Rb+), urea, and the uncomplexed crown ether were studied in vacuo with the molecular dynamics method. Conformational data from these calculations (simulation times in the range from 6-15 ns) was compared with information from the

  8. Anion induced conformational preference of Cα NN motif residues in functional proteins.

    Science.gov (United States)

    Patra, Piya; Ghosh, Mahua; Banerjee, Raja; Chakrabarti, Jaydeb

    2017-12-01

    Among different ligand binding motifs, anion binding C α NN motif consisting of peptide backbone atoms of three consecutive residues are observed to be important for recognition of free anions, like sulphate or biphosphate and participate in different key functions. Here we study the interaction of sulphate and biphosphate with C α NN motif present in different proteins. Instead of total protein, a peptide fragment has been studied keeping C α NN motif flanked in between other residues. We use classical force field based molecular dynamics simulations to understand the stability of this motif. Our data indicate fluctuations in conformational preferences of the motif residues in absence of the anion. The anion gives stability to one of these conformations. However, the anion induced conformational preferences are highly sequence dependent and specific to the type of anion. In particular, the polar residues are more favourable compared to the other residues for recognising the anion. © 2017 Wiley Periodicals, Inc.

  9. CATS (Coordinates of Atoms by Taylor Series): protein design with backbone flexibility in all locally feasible directions.

    Science.gov (United States)

    Hallen, Mark A; Donald, Bruce R

    2017-07-15

    When proteins mutate or bind to ligands, their backbones often move significantly, especially in loop regions. Computational protein design algorithms must model these motions in order to accurately optimize protein stability and binding affinity. However, methods for backbone conformational search in design have been much more limited than for sidechain conformational search. This is especially true for combinatorial protein design algorithms, which aim to search a large sequence space efficiently and thus cannot rely on temporal simulation of each candidate sequence. We alleviate this difficulty with a new parameterization of backbone conformational space, which represents all degrees of freedom of a specified segment of protein chain that maintain valid bonding geometry (by maintaining the original bond lengths and angles and ω dihedrals). In order to search this space, we present an efficient algorithm, CATS, for computing atomic coordinates as a function of our new continuous backbone internal coordinates. CATS generalizes the iMinDEE and EPIC protein design algorithms, which model continuous flexibility in sidechain dihedrals, to model continuous, appropriately localized flexibility in the backbone dihedrals ϕ and ψ as well. We show using 81 test cases based on 29 different protein structures that CATS finds sequences and conformations that are significantly lower in energy than methods with less or no backbone flexibility do. In particular, we show that CATS can model the viability of an antibody mutation known experimentally to increase affinity, but that appears sterically infeasible when modeled with less or no backbone flexibility. Our code is available as free software at https://github.com/donaldlab/OSPREY_refactor . mhallen@ttic.edu or brd+ismb17@cs.duke.edu. Supplementary data are available at Bioinformatics online. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

  10. Conformations of flanking bases in HIV-1 RNA DIS kissing complexes studied by molecular dynamics

    Czech Academy of Sciences Publication Activity Database

    Réblová, Kamila; Fadrná, E.; Sarzynska, J.; Kulinski, T.; Kulhánek, P.; Ennifar, E.; Koča, J.; Šponer, Jiří

    2007-01-01

    Roč. 93, č. 11 (2007), s. 3932-3949 ISSN 0006-3495 R&D Projects: GA MŠk(CZ) LC06030; GA ČR(CZ) GA203/05/0009; GA ČR(CZ) GA203/05/0388; GA AV ČR(CZ) 1QS500040581 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : molecular dynamics * RNA * virus Subject RIV: BO - Biophysics Impact factor: 4.627, year: 2007

  11. Dynamics of bio-membranes investigated by neutron spin echo: Effects of phospholipid conformations and presence of lidocaine

    Science.gov (United States)

    Yi, Zheng

    Bio-membranes of the natural living cells are made of bilayers of phospholipids molecules embedded with other constituents, such as cholesterol and membrane proteins, which help to accomplish a broad range of functions. Vesicles made of lipid bilayers can serve as good model systems for bio-membranes. Therefore these systems have been extensively characterized and much is known about their shape, size, porosity and functionality. In this dissertation we report the studies of the effects of the phosoholipid conformation, such as hydrocarbon number and presence of double bond in hydrophobic tails on dynamics of phospholipids bilayers studied by neutron spin echo (NSE) technique. We have investigated how lidocaine, the most medically used local anesthetics (LA), influence the structural and dynamical properties of model bio-membranes by small angle neutron scattering (SANS), NSE and differential scanning calorimetry (DSC). To investigate the influence of phospholipid conformation on bio-membranes, the bending elasticities kappac of seven saturated and monounsaturated phospholipid bilayers were investigated by NSE spectroscopy. kappa c of phosphatidylcholines (PCS) in liquid crystalline (L alpha) phase ranges from 0.38x10-19 J for 1,2-Dimyristoyl- sn-Glycero-3-Phosphocholine (14:0 PC) to 0.64x10-19 J for 1,2-Dieicosenoyl-sn-Glycero-3-Phosphocholine (20:1 PC). It was confirmed that when the area modulus KA varies little with chain unsaturation or length, the elastic ratios (kappac/ KA)1/2 of bilayers varies linearly with lipid hydrophobic thickness d. For the study of the influence of LA on bio-membranes, SANS measurements have been performed on 14:0 PC bilayers with different concentrations of lidocaine to determine the bilayer thickness dL as a function of the lidocaine concentration. NSE has been used to study the influence of lidocaine on the bending elasticity of 14:0 PC bilayers in Lalpha and ripple gel (Pbeta') phases. Our results confirmed that the molecules of

  12. Conformational sampling enhancement of replica exchange molecular dynamics simulations using swarm particle intelligence

    International Nuclear Information System (INIS)

    Kamberaj, Hiqmet

    2015-01-01

    In this paper, we present a new method based on swarm particle social intelligence for use in replica exchange molecular dynamics simulations. In this method, the replicas (representing the different system configurations) are allowed communicating with each other through the individual and social knowledge, in additional to considering them as a collection of real particles interacting through the Newtonian forces. The new method is based on the modification of the equations of motion in such way that the replicas are driven towards the global energy minimum. The method was tested for the Lennard-Jones clusters of N = 4,  5, and 6 atoms. Our results showed that the new method is more efficient than the conventional replica exchange method under the same practical conditions. In particular, the new method performed better on optimizing the distribution of the replicas among the thermostats with time and, in addition, ergodic convergence is observed to be faster. We also introduce a weighted histogram analysis method allowing analyzing the data from simulations by combining data from all of the replicas and rigorously removing the inserted bias

  13. Conformational dynamics of Rouse chains during creep/recovery processes: a review

    International Nuclear Information System (INIS)

    Watanabe, Hiroshi; Inoue, Tadashi

    2005-01-01

    The Rouse model is a well-established model for non-entangled polymer chains and also serves as a fundamental model for entangled chains. The dynamic behaviour of this model under strain-controlled conditions has been fully analysed in the literature. However, despite the importance of the Rouse model, no analysis has been made so far of the orientational anisotropy of the Rouse eigenmodes during the stress-controlled, creep and recovery processes. For completeness of the analysis of the model, the Rouse equation of motion is solved to calculate this anisotropy for monodisperse chains and their binary blends during the creep/recovery processes. The calculation is simple and straightforward, but the result is intriguing in the sense that each Rouse eigenmode during these processes has a distribution in the retardation times. This behaviour, reflecting the interplay/correlation among the Rouse eigenmodes of different orders (and for different chains in the blends) under the constant stress condition, is quite different from the behaviour under rate-controlled flow (where each eigenmode exhibits retardation/relaxation associated with a single characteristic time). Furthermore, the calculation indicates that the Rouse chains exhibit affine deformation on sudden imposition/removal of the stress and the magnitude of this deformation is inversely proportional to the number of bond vectors per chain. In relation to these results, a difference between the creep and relaxation properties is also discussed for chains obeying multiple relaxation mechanisms (Rouse and reptation mechanisms). (topical review)

  14. Subdiffusion in hair bundle dynamics: The role of protein conformational fluctuations

    Science.gov (United States)

    Sharma, Rati; Cherayil, Binny J.

    2012-12-01

    The detection of sound signals in vertebrates involves a complex network of different mechano-sensory elements in the inner ear. An especially important element in this network is the hair bundle, an antenna-like array of stereocilia containing gated ion channels that operate under the control of one or more adaptation motors. Deflections of the hair bundle by sound vibrations or thermal fluctuations transiently open the ion channels, allowing the flow of ions through them, and producing an electrical signal in the process, eventually causing the sensation of hearing. Recent high frequency (0.1-10 kHz) measurements by Kozlov et al. [Proc. Natl. Acad. Sci. U.S.A. 109, 2896 (2012)], 10.1073/pnas.1121389109 of the power spectrum and the mean square displacement of the thermal fluctuations of the hair bundle suggest that in this regime the dynamics of the hair bundle are subdiffusive. This finding has been explained in terms of the simple Brownian motion of a filament connecting neighboring stereocilia (the tip link), which is modeled as a viscoelastic spring. In the present paper, the diffusive anomalies of the hair bundle are ascribed to tip link fluctuations that evolve by fractional Brownian motion, which originates in fractional Gaussian noise and is characterized by a power law memory. The predictions of this model for the power spectrum of the hair bundle and its mean square displacement are consistent with the experimental data and the known properties of the tip link.

  15. Conformational sampling enhancement of replica exchange molecular dynamics simulations using swarm particle intelligence

    Energy Technology Data Exchange (ETDEWEB)

    Kamberaj, Hiqmet, E-mail: hkamberaj@ibu.edu.mk [Department of Computer Engineering, International Balkan University, Tashko Karadza 11A, Skopje (Macedonia, The Former Yugoslav Republic of)

    2015-09-28

    In this paper, we present a new method based on swarm particle social intelligence for use in replica exchange molecular dynamics simulations. In this method, the replicas (representing the different system configurations) are allowed communicating with each other through the individual and social knowledge, in additional to considering them as a collection of real particles interacting through the Newtonian forces. The new method is based on the modification of the equations of motion in such way that the replicas are driven towards the global energy minimum. The method was tested for the Lennard-Jones clusters of N = 4,  5, and 6 atoms. Our results showed that the new method is more efficient than the conventional replica exchange method under the same practical conditions. In particular, the new method performed better on optimizing the distribution of the replicas among the thermostats with time and, in addition, ergodic convergence is observed to be faster. We also introduce a weighted histogram analysis method allowing analyzing the data from simulations by combining data from all of the replicas and rigorously removing the inserted bias.

  16. Conformational sampling enhancement of replica exchange molecular dynamics simulations using swarm particle intelligence.

    Science.gov (United States)

    Kamberaj, Hiqmet

    2015-09-28

    In this paper, we present a new method based on swarm particle social intelligence for use in replica exchange molecular dynamics simulations. In this method, the replicas (representing the different system configurations) are allowed communicating with each other through the individual and social knowledge, in additional to considering them as a collection of real particles interacting through the Newtonian forces. The new method is based on the modification of the equations of motion in such way that the replicas are driven towards the global energy minimum. The method was tested for the Lennard-Jones clusters of N = 4, 5, and 6 atoms. Our results showed that the new method is more efficient than the conventional replica exchange method under the same practical conditions. In particular, the new method performed better on optimizing the distribution of the replicas among the thermostats with time and, in addition, ergodic convergence is observed to be faster. We also introduce a weighted histogram analysis method allowing analyzing the data from simulations by combining data from all of the replicas and rigorously removing the inserted bias.

  17. Effects of sucrose and benzyl alcohol on GCSF conformational dynamics revealed by hydrogen deuterium exchange mass spectrometry.

    Science.gov (United States)

    Zhang, Jun; Banks, Douglas D; He, Feng; Treuheit, Michael J; Becker, Gerald W

    2015-05-01

    Protein stability, one of the major concerns for therapeutic protein development, can be optimized during process development by evaluating multiple formulation conditions. This can be a costly and lengthy procedure where different excipients and storage conditions are tested for their impact on protein stability. A better understanding of the effects of different formulation conditions at the molecular level will provide information on the local interactions within the protein leading to a more rational design of stable and efficacious formulations. In this study, we examined the roles of the excipients, sucrose and benzyl alcohol, on the conformational dynamics of recombinant human granulocyte colony stimulating factor using hydrogen/deuterium exchange coupled with mass spectrometry (HDX-MS). Under physiological pH and temperature, sucrose globally protects the whole molecule from deuterium uptake, whereas benzyl alcohol induces increased deuterium uptake of the regions within the α-helical bundle, with even larger extent. The HDX experiments described were incorporated a set of internal peptides (Zhang et al., 2012. Anal Chem 84:4942-4949) to monitor the differences in intrinsic exchange rates in different formulations. In addition, we discussed the feasibility of implementing HDX-MS with these peptide probes in protein formulation development. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

  18. Path lumping: An efficient algorithm to identify metastable path channels for conformational dynamics of multi-body systems

    Science.gov (United States)

    Meng, Luming; Sheong, Fu Kit; Zeng, Xiangze; Zhu, Lizhe; Huang, Xuhui

    2017-07-01

    Constructing Markov state models from large-scale molecular dynamics simulation trajectories is a promising approach to dissect the kinetic mechanisms of complex chemical and biological processes. Combined with transition path theory, Markov state models can be applied to identify all pathways connecting any conformational states of interest. However, the identified pathways can be too complex to comprehend, especially for multi-body processes where numerous parallel pathways with comparable flux probability often coexist. Here, we have developed a path lumping method to group these parallel pathways into metastable path channels for analysis. We define the similarity between two pathways as the intercrossing flux between them and then apply the spectral clustering algorithm to lump these pathways into groups. We demonstrate the power of our method by applying it to two systems: a 2D-potential consisting of four metastable energy channels and the hydrophobic collapse process of two hydrophobic molecules. In both cases, our algorithm successfully reveals the metastable path channels. We expect this path lumping algorithm to be a promising tool for revealing unprecedented insights into the kinetic mechanisms of complex multi-body processes.

  19. Conformational Dynamics of the Focal Adhesion Targeting Domain Control Specific Functions of Focal Adhesion Kinase in Cells

    KAUST Repository

    Kadaré, Gress

    2015-01-02

    Focal adhesion (FA) kinase (FAK) regulates cell survival and motility by transducing signals from membrane receptors. The C-terminal FA targeting (FAT) domain of FAK fulfils multiple functions, including recruitment to FAs through paxillin binding. Phosphorylation of FAT on Tyr925 facilitates FA disassembly and connects to the MAPK pathway through Grb2 association, but requires dissociation of the first helix (H1) of the four-helix bundle of FAT. We investigated the importance of H1 opening in cells by comparing the properties of FAK molecules containing wild-type or mutated FAT with impaired or facilitated H1 openings. These mutations did not alter the activation of FAK, but selectively affected its cellular functions, including self-association, Tyr925 phosphorylation, paxillin binding, and FA targeting and turnover. Phosphorylation of Tyr861, located between the kinase and FAT domains, was also enhanced by the mutation that opened the FAT bundle. Similarly phosphorylation of Ser910 by ERK in response to bombesin was increased by FAT opening. Although FAK molecules with the mutation favoring FAT opening were poorly recruited at FAs, they efficiently restored FA turnover and cell shape in FAK-deficient cells. In contrast, the mutation preventing H1 opening markedly impaired FAK function. Our data support the biological importance of conformational dynamics of the FAT domain and its functional interactions with other parts of the molecule.

  20. Conformational changes and slow dynamics through microsecond polarized atomistic molecular simulation of an integral Kv1.2 ion channel.

    Directory of Open Access Journals (Sweden)

    Pär Bjelkmar

    2009-02-01

    Full Text Available Structure and dynamics of voltage-gated ion channels, in particular the motion of the S4 helix, is a highly interesting and hotly debated topic in current membrane protein research. It has critical implications for insertion and stabilization of membrane proteins as well as for finding how transitions occur in membrane proteins-not to mention numerous applications in drug design. Here, we present a full 1 micros atomic-detail molecular dynamics simulation of an integral Kv1.2 ion channel, comprising 120,000 atoms. By applying 0.052 V/nm of hyperpolarization, we observe structural rearrangements, including up to 120 degrees rotation of the S4 segment, changes in hydrogen-bonding patterns, but only low amounts of translation. A smaller rotation ( approximately 35 degrees of the extracellular end of all S4 segments is present also in a reference 0.5 micros simulation without applied field, which indicates that the crystal structure might be slightly different from the natural state of the voltage sensor. The conformation change upon hyperpolarization is closely coupled to an increase in 3(10 helix contents in S4, starting from the intracellular side. This could support a model for transition from the crystal structure where the hyperpolarization destabilizes S4-lipid hydrogen bonds, which leads to the helix rotating to keep the arginine side chains away from the hydrophobic phase, and the driving force for final relaxation by downward translation is partly entropic, which would explain the slow process. The coordinates of the transmembrane part of the simulated channel actually stay closer to the recently determined higher-resolution Kv1.2 chimera channel than the starting structure for the entire second half of the simulation (0.5-1 micros. Together with lipids binding in matching positions and significant thinning of the membrane also observed in experiments, this provides additional support for the predictive power of microsecond-scale membrane

  1. Dynamic conformations compared for IgE and IgG1 in solution and bound to receptors.

    Science.gov (United States)

    Zheng, Y; Shopes, B; Holowka, D; Baird, B

    1992-08-25

    Dynamic conformations of two distinct immunoglobulin (Ig) isotypes, murine IgE and human IgG1, were examined with fluorescence resonance energy transfer measurements. The IgE mutant epsilon/C gamma 3* and the IgG1 mutant gamma/C gamma 3* each bind [5-(dimethylamino)naphthalen-1-yl]sulfonyl (DNS) in two identical antigen binding sites at the amino (N)-terminal ends of the Ig in the Fab segments. Eosin-DNS bound in these Fab sites served as the acceptor probe in these studies. Both Ig have a carboxy (C)-terminal domain (C gamma 3*) which contains genetically introduced cysteine residues. Modification of these cysteine sulfhydryls with fluorescein maleimide provided donor probes near the C-terminal ends of the Ig in the Fc segment. Energy transfer between the C-terminal and N-terminal ends was compared for these two Ig in solution and when they were found to their respective high-affinity receptors on plasma membranes: IgE-Fc epsilon RI on RBL cell membranes and IgG1-Fc gamma RI on U937 cell membranes. Previous energy-transfer measurements with these probes yielded an average end-to-end distance of 71 A for IgE in solution and 69 A for IgE bound to Fc epsilon RI, indicating that in both situations IgE is bent such that the axes of the Fab segments and the axis of the Fc segment do not form a planar Y-shape [Zheng, Shopes, Holowka, & Baird (1991) Biochemistry 30, 9125]. In the current study we found the average end-to-end distance for IgG1 in solution is 75 A and greater than or equal to 85 A for IgG1 bound to Fc gamma RI, suggesting an average bend conformation for IgG1 as well. The contributions of segmental flexibility to the average distances were assessed directly by measuring the efficiency of energy transfer as a function of variations in donor quantum yield caused by a collisional quencher and using these data to extract a Gaussian distribution of end-to-end distances. The distribution average (rho) and half-width (hw) were determined to be as follows: rho = 75

  2. Versatile phosphite ligands based on silsesquioxane backbones

    NARCIS (Netherlands)

    van der Vlugt, JI; Ackerstaff, J; Dijkstra, TW; Mills, AM; Kooijman, H; Spek, AL; Meetsma, A; Abbenhuis, HCL; Vogt, D

    Silsesquioxanes are employed as ligand backbones for the synthesis of novel phosphite compounds with 3,3'-5,5'-tetrakis(tert-butyl)-2,2'-di-oxa-1,1'-biphenyl substituents. Both mono- and bidentate phosphites are prepared in good yields. Two types of silsesquioxanes are employed as starting

  3. Conformational landscape of an amyloid intra-cellular domain and Landau-Ginzburg-Wilson paradigm in protein dynamics

    International Nuclear Information System (INIS)

    Dai, Jin; He, Jianfeng; Niemi, Antti J.

    2016-01-01

    The Landau-Ginzburg-Wilson paradigm is proposed as a framework, to investigate the conformational landscape of intrinsically unstructured proteins. A universal Cα-trace Landau free energy is deduced from general symmetry considerations, with the ensuing all-atom structure modeled using publicly available reconstruction programs Pulchra and Scwrl. As an example, the conformational stability of an amyloid precursor protein intra-cellular domain (AICD) is inspected; the reference conformation is the crystallographic structure with code 3DXC in Protein Data Bank (PDB) that describes a heterodimer of AICD and a nuclear multi-domain adaptor protein Fe65. Those conformations of AICD that correspond to local or near-local minima of the Landau free energy are identified. For this, the response of the original 3DXC conformation to variations in the ambient temperature is investigated, using the Glauber algorithm. The conclusion is that in isolation the AICD conformation in 3DXC must be unstable. A family of degenerate conformations that minimise the Landau free energy is identified, and it is proposed that the native state of an isolated AICD is a superposition of these conformations. The results are fully in line with the presumed intrinsically unstructured character of isolated AICD and should provide a basis for a systematic analysis of AICD structure in future NMR experiments.

  4. Conformational landscape of an amyloid intra-cellular domain and Landau-Ginzburg-Wilson paradigm in protein dynamics

    Energy Technology Data Exchange (ETDEWEB)

    Dai, Jin; He, Jianfeng, E-mail: Antti.Niemi@physics.uu.se, E-mail: hjf@bit.edu.cn [School of Physics, Beijing Institute of Technology, Beijing 100081 (China); Niemi, Antti J., E-mail: Antti.Niemi@physics.uu.se, E-mail: hjf@bit.edu.cn [School of Physics, Beijing Institute of Technology, Beijing 100081 (China); Department of Physics and Astronomy, Uppsala University, P.O. Box 803, S-75108 Uppsala (Sweden); Laboratoire de Mathematiques et Physique Theorique CNRS UMR 6083, Fédération Denis Poisson, Université de Tours, Parc de Grandmont, F37200 Tours (France)

    2016-07-28

    The Landau-Ginzburg-Wilson paradigm is proposed as a framework, to investigate the conformational landscape of intrinsically unstructured proteins. A universal Cα-trace Landau free energy is deduced from general symmetry considerations, with the ensuing all-atom structure modeled using publicly available reconstruction programs Pulchra and Scwrl. As an example, the conformational stability of an amyloid precursor protein intra-cellular domain (AICD) is inspected; the reference conformation is the crystallographic structure with code 3DXC in Protein Data Bank (PDB) that describes a heterodimer of AICD and a nuclear multi-domain adaptor protein Fe65. Those conformations of AICD that correspond to local or near-local minima of the Landau free energy are identified. For this, the response of the original 3DXC conformation to variations in the ambient temperature is investigated, using the Glauber algorithm. The conclusion is that in isolation the AICD conformation in 3DXC must be unstable. A family of degenerate conformations that minimise the Landau free energy is identified, and it is proposed that the native state of an isolated AICD is a superposition of these conformations. The results are fully in line with the presumed intrinsically unstructured character of isolated AICD and should provide a basis for a systematic analysis of AICD structure in future NMR experiments.

  5. Quantitative conformational analysis of the core region of N-glycans using residual dipolar couplings, aqueous molecular dynamics, and steric alignment

    International Nuclear Information System (INIS)

    Almond, Andrew; Duus, Jens O.

    2001-01-01

    A method is described for quantitatively investigating the dynamic conformation of small oligosaccharides containing an α(1 → 6) linkage. It was applied to the oligosaccharide Man-α(1 → 3) {Man-α (1 → 6)}Man-α-O-Me, which is a core region frequently observed in N-linked glycans. The approach tests an aqueous molecular dynamics simulation, capable of predicting microscopic dynamics, against experimental residual dipolar couplings, by assuming that alignment is caused purely by steric hindrance. The experimental constraints were heteronuclear and homonuclear residual dipolar couplings, and in particular those within the α(1 → 6) linkage itself. Powerful spin-state-selective pulse sequences and editing schemes were used to obtain the most relevant couplings for testing the model. Molecular dynamics simulations in water over a period of 50 ns were not able to predict the correct rotamer population at the α(1 → 6) linkage to agree with the experimental data. However, this sampling problem could be corrected using a simple maximum likelihood optimisation, indicating that the simulation was modelling local dynamics correctly. The maximum likelihood prediction of the residual dipolar couplings was found to be an almost equal population of the gg and gt rotamer conformations at the α(1 → 6) linkage, and the tg conformation was predicted to be unstable and unpopulated in aqueous solution. In this case all twelve measured residual dipolar couplings could be satisfied. This conformer population could also be used to make predictions of scalar couplings with the use of a previously derived empirical equation, and is qualitatively in agreement with previous predictions based on NMR, X-ray crystallography and optical data

  6. Isolation of Pristine Electronics Grade Semiconducting Carbon Nanotubes by Switching the Rigidity of the Wrapping Polymer Backbone on Demand.

    Science.gov (United States)

    Joo, Yongho; Brady, Gerald J; Shea, Matthew J; Oviedo, M Belén; Kanimozhi, Catherine; Schmitt, Samantha K; Wong, Bryan M; Arnold, Michael S; Gopalan, Padma

    2015-10-27

    Conjugated polymers are among the most selective carbon nanotube sorting agents discovered and enable the isolation of ultrahigh purity semiconducting singled-walled carbon nanotubes (s-SWCNTs) from heterogeneous mixtures that contain problematic metallic nanotubes. The strong selectivity though highly desirable for sorting, also leads to irreversible adsorption of the polymer on the s-SWCNTs, limiting their electronic and optoelectronic properties. We demonstrate how changes in polymer backbone rigidity can trigger its release from the nanotube surface. To do so, we choose a model polymer, namely poly[(9,9-dioctylfluorenyl-2,7-diyl)-alt-co-(6,60-(2,20-bipyridine))] (PFO-BPy), which provides ultrahigh selectivity for s-SWCNTs, which are useful specifically for FETs, and has the chemical functionality (BPy) to alter the rigidity using mild chemistry. Upon addition of Re(CO)5Cl to the solution of PFO-BPy wrapped s-SWCNTs, selective chelation with the BPy unit in the copolymer leads to the unwrapping of PFO-BPy. UV-vis, XPS, and Raman spectroscopy studies show that binding of the metal ligand complex to BPy triggers up to 85% removal of the PFO-BPy from arc-discharge s-SWCNTs (diameter = 1.3-1.7 nm) and up to 72% from CoMoCAT s-SWCNTs (diameter = 0.7-0.8 nm). Importantly, Raman studies show that the electronic structure of the s-SWCNTs is preserved through this process. The generalizability of this method is demonstrated with two other transition metal salts. Molecular dynamics simulations support our experimental findings that the complexation of BPy with Re(CO)5Cl in the PFO-BPy backbone induces a dramatic conformational change that leads to a dynamic unwrapping of the polymer off the nanotube yielding pristine s-SWCNTs.

  7. Cardiac Exposure in the Dynamic Conformal Arc Therapy, Intensity-Modulated Radiotherapy and Volumetric Modulated Arc Therapy of Lung Cancer.

    Directory of Open Access Journals (Sweden)

    Xin Ming

    Full Text Available To retrospectively evaluate the cardiac exposure in three cohorts of lung cancer patients treated with dynamic conformal arc therapy (DCAT, intensity-modulated radiotherapy (IMRT, or volumetric modulated arc therapy (VMAT at our institution in the past seven years.A total of 140 lung cancer patients were included in this institutional review board approved study: 25 treated with DCAT, 70 with IMRT and 45 with VMAT. All plans were generated in a same commercial treatment planning system and have been clinically accepted and delivered. The dose distribution to the heart and the effects of tumor laterality, the irradiated heart volume and the beam-to-heart distance on the cardiac exposure were investigated.The mean dose to the heart among all 140 plans was 4.5 Gy. Specifically, the heart received on average 2.3, 5.2 and 4.6 Gy in the DCAT, IMRT and VMAT plans, respectively. The mean heart doses for the left and right lung tumors were 4.1 and 4.8 Gy, respectively. No patients died with evidence of cardiac disease. Three patients (2% with preexisting cardiac condition developed cardiac disease after treatment. Furthermore, the cardiac exposure was found to increase linearly with the irradiated heart volume while decreasing exponentially with the beam-to-heart distance.Compared to old technologies for lung cancer treatment, modern radiotherapy treatment modalities demonstrated better heart sparing. But the heart dose in lung cancer radiotherapy is still higher than that in the radiotherapy of breast cancer and Hodgkin's disease where cardiac complications have been extensively studied. With strong correlations of mean heart dose with beam-to-heart distance and irradiated heart volume, cautions should be exercised to avoid long-term cardiac toxicity in the lung cancer patients undergoing radiotherapy.

  8. Nuclear magnetic resonance provides a quantitative description of protein conformational flexibility on physiologically important time scales.

    Science.gov (United States)

    Salmon, Loïc; Bouvignies, Guillaume; Markwick, Phineus; Blackledge, Martin

    2011-04-12

    A complete description of biomolecular activity requires an understanding of the nature and the role of protein conformational dynamics. In recent years, novel nuclear magnetic resonance-based techniques that provide hitherto inaccessible detail concerning biomolecular motions occurring on physiologically important time scales have emerged. Residual dipolar couplings (RDCs) provide precise information about time- and ensemble-averaged structural and dynamic processes with correlation times up to the millisecond and thereby encode key information for understanding biological activity. In this review, we present the application of two very different approaches to the quantitative description of protein motion using RDCs. The first is purely analytical, describing backbone dynamics in terms of diffusive motions of each peptide plane, using extensive statistical analysis to validate the proposed dynamic modes. The second is based on restraint-free accelerated molecular dynamics simulation, providing statistically sampled free energy-weighted ensembles that describe conformational fluctuations occurring on time scales from pico- to milliseconds, at atomic resolution. Remarkably, the results from these two approaches converge closely in terms of distribution and absolute amplitude of motions, suggesting that this kind of combination of analytical and numerical models is now capable of providing a unified description of protein conformational dynamics in solution.

  9. Structural Insights into Conformation Differences between DNA/TNA and RNA/TNA Chimeric Duplexes.

    Science.gov (United States)

    Anosova, Irina; Kowal, Ewa A; Sisco, Nicholas J; Sau, Sujay; Liao, Jen-Yu; Bala, Saikat; Rozners, Eriks; Egli, Martin; Chaput, John C; Van Horn, Wade D

    2016-09-15

    Threose nucleic acid (TNA) is an artificial genetic polymer capable of heredity and evolution, and is studied in the context of RNA chemical etiology. It has a four-carbon threose backbone in place of the five-carbon ribose of natural nucleic acids, yet forms stable antiparallel complementary Watson-Crick homoduplexes and heteroduplexes with DNA and RNA. TNA base-pairs more favorably with RNA than with DNA but the reason is unknown. Here, we employed NMR, ITC, UV, and CD to probe the structural and dynamic properties of heteroduplexes of RNA/TNA and DNA/TNA. The results indicate that TNA templates the structure of heteroduplexes, thereby forcing an A-like helical geometry. NMR measurement of kinetic and thermodynamic parameters for individual base pair opening events reveal unexpected asymmetric "breathing" fluctuations of the DNA/TNA helix. The results suggest that DNA is unable to fully adapt to the conformational constraints of the rigid TNA backbone and that nucleic acid breathing dynamics are determined from both backbone and base contributions. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  10. Recombinant expression of backbone-cyclized polypeptides.

    Science.gov (United States)

    Borra, Radhika; Camarero, Julio A

    2013-09-01

    Here we review the different biochemical approaches available for the expression of backbone-cyclized polypeptides, including peptides and proteins. These methods allow for the production of circular polypeptides either in vitro or in vivo using standard recombinant DNA expression techniques. Polypeptide circularization provides a valuable tool to study the effects of topology on protein stability and folding kinetics. Furthermore, having biosynthetic access to backbone-cyclized polypeptides makes the production of genetically encoded libraries of cyclic polypeptides possible. The production of such libraries, which was previously restricted to the domain of synthetic chemistry, now offers biologists access to highly diverse and stable molecular libraries that can be screened using high-throughput methods for the rapid selection of novel cyclic polypeptide sequences with new biological activities. Copyright © 2013 Wiley Periodicals, Inc.

  11. Histidine side-chain dynamics and protonation monitored by C-13 CPMG NMR relaxation dispersion

    DEFF Research Database (Denmark)

    Hass, M. A. S.; Yilmaz, A.; Christensen, Hans Erik Mølager

    2009-01-01

    the chemical shift titration experiments, and the CPMG derived exchange rates agree with those obtained previously from N-15 backbone relaxation measurements. Compared to measurements of backbone nuclei, C-13(epsilon 1) dispersion provides a more direct method to monitor interchanging protonation states...... or other kinds of conformational changes of histidine side chains or their environment. Advantages and shortcomings of using the C-13(epsilon 1) dispersion experiments in combination with chemical shift titration experiments to obtain information on exchange dynamics of the histidine side chains...

  12. Conformational Changes in Two Inter-Helical Loops of Mhp1 Membrane Transporter.

    Directory of Open Access Journals (Sweden)

    Hyun Deok Song

    Full Text Available Mhp1 is a bacterial secondary transporter with high-resolution crystal structures available for both the outward- and inward-facing conformations. Through molecular dynamics simulations of the ligand-free Mhp1 as well as analysis of its crystal structures, here we show that two inter-helical loops, respectively located at the extra- and intracellular ends of the "hash motif" in the protein, play important roles in the conformational transition. In the outward- and inward-facing states of the protein, the loops adopt different secondary structures, either wrapped to the end of an alpha-helix, or unwrapped to extended conformations. In equilibrium simulations of 100 ns with Mhp1 in explicit lipids and water, the loop conformations remain largely stable. In targeted molecular dynamics simulations with the protein structure driven from one state to the other, the loops exhibit resistance and only undergo abrupt changes when other parts of the protein already approach the target conformation. Free energy calculations on the isolated loops further confirm that the wrapping/unwrapping transitions are associated with substantial energetic barriers, and consist of multiple sequential steps involving the rotation of certain backbone torsion angles. Furthermore, in simulations with the loops driven from one state to the other, a large part of the protein follows the loops to the target conformation. Taken together, our simulations suggest that changes of the loop secondary structures would be among the slow degrees of freedom in the conformational transition of the entire protein. Incorporation of detailed loop structures into the reaction coordinate, therefore, should improve the convergence and relevance of the resulting conformational free energy.

  13. Quantification of protein backbone hydrogen-deuterium exchange rates by solid state NMR spectroscopy.

    Science.gov (United States)

    del Amo, Juan-Miguel Lopez; Fink, Uwe; Reif, Bernd

    2010-12-01

    We present the quantification of backbone amide hydrogen-deuterium exchange rates (HDX) for immobilized proteins. The experiments make use of the deuterium isotope effect on the amide nitrogen chemical shift, as well as on proton dilution by deuteration. We find that backbone amides in the microcrystalline α-spectrin SH3 domain exchange rather slowly with the solvent (with exchange rates negligible within the individual (15)N-T (1) timescales). We observed chemical exchange for 6 residues with HDX exchange rates in the range from 0.2 to 5 s(-1). Backbone amide (15)N longitudinal relaxation times that we determined previously are not significantly affected for most residues, yielding no systematic artifacts upon quantification of backbone dynamics (Chevelkov et al. 2008b). Significant exchange was observed for the backbone amides of R21, S36 and K60, as well as for the sidechain amides of N38, N35 and for W41ε. These residues could not be fit in our previous motional analysis, demonstrating that amide proton chemical exchange needs to be considered in the analysis of protein dynamics in the solid-state, in case D(2)O is employed as a solvent for sample preparation. Due to the intrinsically long (15)N relaxation times in the solid-state, the approach proposed here can expand the range of accessible HDX rates in the intermediate regime that is not accessible so far with exchange quench and MEXICO type experiments.

  14. Quantification of protein backbone hydrogen-deuterium exchange rates by solid state NMR spectroscopy

    International Nuclear Information System (INIS)

    Lopez del Amo, Juan-Miguel; Fink, Uwe; Reif, Bernd

    2010-01-01

    We present the quantification of backbone amide hydrogen-deuterium exchange rates (HDX) for immobilized proteins. The experiments make use of the deuterium isotope effect on the amide nitrogen chemical shift, as well as on proton dilution by deuteration. We find that backbone amides in the microcrystalline α-spectrin SH3 domain exchange rather slowly with the solvent (with exchange rates negligible within the individual 15 N-T 1 timescales). We observed chemical exchange for 6 residues with HDX exchange rates in the range from 0.2 to 5 s -1 . Backbone amide 15 N longitudinal relaxation times that we determined previously are not significantly affected for most residues, yielding no systematic artifacts upon quantification of backbone dynamics (Chevelkov et al. 2008b). Significant exchange was observed for the backbone amides of R21, S36 and K60, as well as for the sidechain amides of N38, N35 and for W41ε. These residues could not be fit in our previous motional analysis, demonstrating that amide proton chemical exchange needs to be considered in the analysis of protein dynamics in the solid-state, in case D 2 O is employed as a solvent for sample preparation. Due to the intrinsically long 15 N relaxation times in the solid-state, the approach proposed here can expand the range of accessible HDX rates in the intermediate regime that is not accessible so far with exchange quench and MEXICO type experiments.

  15. Insight into microtubule destabilization mechanism of 3,4,5-trimethoxyphenyl indanone derivatives using molecular dynamics simulation and conformational modes analysis

    Science.gov (United States)

    Tripathi, Shubhandra; Srivastava, Gaurava; Singh, Aastha; Prakasham, A. P.; Negi, Arvind S.; Sharma, Ashok

    2018-03-01

    Colchicine site inhibitors are microtubule destabilizers having promising role in cancer therapeutics. In the current study, four such indanone derivatives (t1, t9, t14 and t17) with 3,4,5-trimethoxyphenyl fragment (ring A) and showing significant microtubule destabilization property have been explored. The interaction mechanism and conformational modes triggered by binding of these indanone derivatives and combretastatin at colchicine binding site (CBS) of αβ-tubulin dimer were studied using molecular dynamics (MD) simulation, principle component analysis and free energy landscape analysis. In the MD results, t1 showed binding similar to colchicine interacting in the deep hydrophobic core at the CBS. While t9, t14 and t17 showed binding conformation similar to combretastatin, with ring A superficially binding at the CBS. Results demonstrated that ring A played a vital role in binding via hydrophobic interactions and got anchored between the S8 and S9 sheets, H8 helix and T7 loop at the CBS. Conformational modes study revealed that twisting and bending conformational motions (as found in the apo system) were nearly absent in the ligand bound systems. Absence of twisting motion might causes loss of lateral contacts in microtubule, thus promoting microtubule destabilization. This study provides detailed account of microtubule destabilization mechanism by indanone ligands and combretastatin, and would be helpful for designing microtubule destabilizers with higher activity.

  16. Molecular Dynamics Simulations and Classical Multidimensional Scaling Unveil New Metastable States in the Conformational Landscape of CDK2.

    Directory of Open Access Journals (Sweden)

    Pasquale Pisani

    Full Text Available Protein kinases are key regulatory nodes in cellular networks and their function has been shown to be intimately coupled with their structural flexibility. However, understanding the key structural mechanisms of large conformational transitions remains a difficult task. CDK2 is a crucial regulator of cell cycle. Its activity is finely tuned by Cyclin E/A and the catalytic segment phosphorylation, whereas its deregulation occurs in many types of cancer. ATP competitive inhibitors have failed to be approved for clinical use due to toxicity issues raised by a lack of selectivity. However, in the last few years type III allosteric inhibitors have emerged as an alternative strategy to selectively modulate CDK2 activity. In this study we have investigated the conformational variability of CDK2. A low dimensional conformational landscape of CDK2 was modeled using classical multidimensional scaling on a set of 255 crystal structures. Microsecond-scale plain and accelerated MD simulations were used to populate this landscape by using an out-of-sample extension of multidimensional scaling. CDK2 was simulated in the apo-form and in complex with the allosteric inhibitor 8-anilino-1-napthalenesulfonic acid (ANS. The apo-CDK2 landscape analysis showed a conformational equilibrium between an Src-like inactive conformation and an active-like form. These two states are separated by different metastable states that share hybrid structural features with both forms of the kinase. In contrast, the CDK2/ANS complex landscape is compatible with a conformational selection picture where the binding of ANS in proximity of the αC helix causes a population shift toward the inactive conformation. Interestingly, the new metastable states could enlarge the pool of candidate structures for the development of selective allosteric CDK2 inhibitors. The method here presented should not be limited to the CDK2 case but could be used to systematically unmask similar mechanisms

  17. Internet Backbone in the Democratic Republic of Congo : Feasibility ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    The participants noted the following priorities for the DRC: a national Internet backbone, urban networks and computing equipment. The national Internet backbone was given highest priority. This project aims to study the feasibility of establishing an Internet backbone en RDC. Researchers will identify suitable technological ...

  18. Transportation Conformity

    Science.gov (United States)

    This section provides information on: current laws, regulations and guidance, policy and technical guidance, project-level conformity, general information, contacts and training, adequacy review of SIP submissions

  19. Exploiting Oligo(amido amine) Backbones for the Multivalent Presentation of Coiled-Coil Peptides.

    Science.gov (United States)

    Gerling-Driessen, Ulla I M; Mujkic-Ninnemann, Nina; Ponader, Daniela; Schöne, Daniel; Hartmann, Laura; Koksch, Beate; Gerling-Driessen, U I M; Schöne, D; Koksch, B; Ponader, D; Mujkic-Ninnemann, N; Hartmann, L

    2015-08-10

    The investigation of coiled coil formation for one mono- and two divalent peptide-polymer conjugates is presented. Through the assembly of the full conjugates on solid support, monodisperse sequence-defined conjugates are obtained with defined positions and distances between the peptide side chains along the polymeric backbone. A heteromeric peptide design was chosen, where peptide K is attached to the polymer backbone, and coiled-coil formation is only expected through complexation with the complementary peptide E. Indeed, the monovalent peptide K-polymer conjugate displays rapid coiled-coil formation when mixed with the complementary peptide E sequence. The divalent systems show intramolecular homomeric coiled-coil formation on the polymer backbone despite the peptide design. Interestingly, this intramolecular assembly undergoes a conformational rearrangement by the addition of the complementary peptide E leading to the formation of heteromeric coiled coil-polymer aggregates. The polymer backbone acts as a template bringing the covalently bound peptide strands in close proximity to each other, increasing the local concentration and inducing the otherwise nonfavorable formation of intramolecular helical assemblies.

  20. Quantum Chemical Benchmark Study on 46 RNA Backbone Families Using a Dinucleotide Unit

    Czech Academy of Sciences Publication Activity Database

    Kruse, H.; Mládek, Arnošt; Gkionis, Konstantinos; Hansen, A.; Grimme, S.; Šponer, Jiří

    2015-01-01

    Roč. 11, č. 10 (2015), s. 4972-4991 ISSN 1549-9618 R&D Projects: GA ČR(CZ) GBP305/12/G034 Institutional support: RVO:68081707 Keywords : MOLECULAR-DYNAMICS SIMULATIONS * DENSITY-FUNCTIONAL THEORY * SUGAR -PHOSPHATE BACKBONE Subject RIV: BO - Biophysics Impact factor: 5.301, year: 2015

  1. Conformational Flexibility Differentiates Naturally Occurring Bet v 1 Isoforms

    Directory of Open Access Journals (Sweden)

    Sarina Grutsch

    2017-06-01

    Full Text Available The protein Bet v 1 represents the main cause for allergic reactions to birch pollen in Europe and North America. Structurally homologous isoforms of Bet v 1 can have different properties regarding allergic sensitization and Th2 polarization, most likely due to differential susceptibility to proteolytic cleavage. Using NMR relaxation experiments and molecular dynamics simulations, we demonstrate that the initial proteolytic cleavage sites in two naturally occurring Bet v 1 isoforms, Bet v 1.0101 (Bet v 1a and Bet v 1.0102 (Bet v 1d, are conformationally flexible. Inaccessible cleavage sites in helices and strands are highly flexible on the microsecond-millisecond time scale, whereas those located in loops display faster nanosecond-microsecond flexibility. The data consistently show that Bet v 1.0102 is more flexible and conformationally heterogeneous than Bet v 1.0101. Moreover, NMR hydrogen-deuterium exchange measurements reveal that the backbone amides in Bet v 1.0102 are significantly more solvent exposed, in agreement with this isoform’s higher susceptibility to proteolytic cleavage. The differential conformational flexibility of Bet v 1 isoforms, along with the transient exposure of inaccessible sites to the protein surface, may be linked to proteolytic susceptibility, representing a potential structure-based rationale for the observed differences in Th2 polarization and allergic sensitization.

  2. Ligand binding and conformational dynamics in a flavin-based electron-bifurcating enzyme complex revealed by Hydrogen-Deuterium Exchange Mass Spectrometry.

    Science.gov (United States)

    Demmer, Julius K; Rupprecht, Fiona A; Eisinger, Martin L; Ermler, Ulrich; Langer, Julian D

    2016-12-01

    Flavin-based electron bifurcation (FBEB) is a novel mechanism of energy coupling used by anaerobic microorganisms to optimize their energy metabolism efficiency. The first high-resolution structure of a complete FBEB enzyme complex, the NADH-dependent reduced ferredoxin: NADP + -oxidoreductase (NfnAB) of Thermotoga maritima, was recently solved. However, no experimental evidence for the NADPH-binding site and conformational changes during the FBEB reaction are available. Here we analyzed ligand binding and the conformational dynamics of oxygen-sensitive NfnAB using Hydrogen-Deuterium Exchange Mass-Spectrometry, including a customized anaerobic workflow. We confirmed the NADH and the previously postulated NADPH-binding site. Furthermore, we observed an NfnA-NfnB rearrangement upon NADPH binding which supports the proposed FBEB mechanism. © 2016 Federation of European Biochemical Societies.

  3. Porous solid backbone impregnation for electrochemical energy conversion systems

    KAUST Repository

    Boulfrad, Samir

    2013-09-19

    An apparatus and method for impregnating a porous solid backbone. The apparatus may include a platform for holding a porous solid backbone, an ink jet nozzle configured to dispense a liquid solution onto the porous solid backbone, a positioning mechanism configured to position the ink jet nozzle proximate to a plurality of locations of the porous solid backbone, and a control unit configured to control the positioning mechanism to position the ink jet nozzle proximate to the plurality of locations and cause the ink jet nozzle to dispense the liquid solution onto the porous solid backbone.

  4. Effects of glycosylation on the conformation and dynamics of O-linked glycoproteins: Carbon-13 NMR studies of ovine submaxillary mucin

    International Nuclear Information System (INIS)

    Gerken, T.A.; Butenhof, K.J.; Shogren, R.

    1989-01-01

    Carbon-13 NMR spectroscopic studies of native and sequentially deglycosylated ovine submaxillary mucin (OSM) have been performed to examine the effects of glycosylation on the conformation and dynamics of the peptide core of O-linked glycoproteins. OSM is a large nonglobular glycoprotein in which nearly one-third of the amino acid residues are Ser and Thr which are glycosylated by the α-Neu-NAc(2-6)α-Ga1NAc- disaccharide. The β-carbon resonances of glycosylated Ser and Thr residues in intact and asialo mucin display considerable chemical shift heterogeneity which, upon the complete removal of carbohydrate, coalesces to single sharp resonances. This chemical shift heterogeneity is due to peptide sequence variability and is proposed to reflect the presence of sequence-dependent conformations of the peptide core. These different conformations are thought to be determined by steric interactions of the Ga1NAc residue with adjacent peptide residues. The absence of chemical shift heterogeneity in apo mucin is taken to indicate a loss in the peptide-carbohydrate steric interactions, consistent with a more relaxed random coiled structure. On the basis of the 13 C relaxation behavior the dynamics of the α-carbons appear to be unique to each amino acid type and glycosylation state. These results are consistent with the changes in molecular dimensions determined by light-scattering techniques for the same series of modified mucins. Taken together, these results further demonstrate that mucins possess a highly expanded conformation that is dominated by steric interactions between the peptide core and the O-linked Ga1NAc residue

  5. Workers’ Conformism

    Directory of Open Access Journals (Sweden)

    Nikolay Ivantchev

    2013-10-01

    Full Text Available Conformism was studied among 46 workers with different kinds of occupations by means of two modified scales measuring conformity by Santor, Messervey, and Kusumakar (2000 – scale for perceived peer pressure and scale for conformism in antisocial situations. The hypothesis of the study that workers’ conformism is expressed in a medium degree was confirmed partly. More than a half of the workers conform in a medium degree for taking risk, and for the use of alcohol and drugs, and for sexual relationships. More than a half of the respondents conform in a small degree for anti-social activities (like a theft. The workers were more inclined to conform for risk taking (10.9%, then – for the use of alcohol, drugs and for sexual relationships (8.7%, and in the lowest degree – for anti-social activities (6.5%. The workers who were inclined for the use of alcohol and drugs tended also to conform for anti-social activities.

  6. Peptoid-Peptide hybrid backbone architectures

    DEFF Research Database (Denmark)

    Olsen, Christian Adam

    2010-01-01

    Peptidomimetic oligomers and foldamers have received considerable attention for over a decade, with beta-peptides and the so-called peptoids (N-alkylglycine oligomers) representing prominent examples of such architectures. Lately, hybrid or mixed backbones consisting of both alpha- and beta......-amino acids (alpha/beta-peptides) have been investigated in some detail as well. The present Minireview is a survey of the literature concerning hybrid structures of alpha-amino acids and peptoids, including beta-peptoids (N-alkyl-beta-alanine oligomers), and is intended to give an overview of this area...

  7. Self-assembly, Dynamics and Chirality of Conformational Switches on Metal Surfaces Studied by UHV-STM

    DEFF Research Database (Denmark)

    Nuermaimaiti, Ajiguli

    2013-01-01

    such as molecular electronics, and surface functionalization. In this thesis, implications of the extra-degrees of freedom introduced by molecular conformational flexibility are explicitly explored using high-resolution, fast-scanning STM under ultra-high vacuum conditions. Accompanying investigations of adsorption...

  8. Self-reciprocal M. Born's model and the dynamic picture in the conformal-flat gaussian-type metric

    International Nuclear Information System (INIS)

    Tomil'chik, L.M.

    2010-01-01

    It is shown that Born's self-reciprocal equation coincides in form with the D'Alembert general covariant equation in the conformal-flat Gaussian-type metric and the geodesic equations reproduce the hyperbolic motion of the probe particle. The relation between the energy-momentum tensor generating such a metric and the corresponding Minkowski force. (authors)

  9. Different conformational dynamics of β-arrestin1 and β-arrestin2 analyzed by hydrogen/deuterium exchange mass spectrometry

    Energy Technology Data Exchange (ETDEWEB)

    Yun, Youngjoo; Kim, Dong Kyun [School of Pharmacy, Sungkyunkwan University, Suwon (Korea, Republic of); Seo, Min-Duk [College of Pharmacy & Department of Molecular Science and Technology, Ajou University, Suwon (Korea, Republic of); Kim, Kyeong-Man [College of Pharmacy, Chonnam National University, Gwang-Ju (Korea, Republic of); Chung, Ka Young, E-mail: kychung2@skku.edu [School of Pharmacy, Sungkyunkwan University, Suwon (Korea, Republic of)

    2015-01-30

    Highlights: • The conformational dynamics of β-arrestin1 or β-arrestin2 were analyzed by HDX-MS. • β-Strands II through IV were more dynamic in β-arrestin2 than in β-arrestin1. • The middle loop was less dynamic in β-arrestin2 than in β-arrestin1. • Upon pre-activation by the R169E mutation, β-arrestins became more dynamic. • Pre-activation affected a wider region of β-arrestin1 compared to β-arrestin2. - Abstract: Arrestins have important roles in G protein-coupled receptor (GPCR) signaling including desensitization of GPCRs and G protein-independent signaling. There have been four arrestins identified: arrestin1, arrestin2 (e.g. β-arrestin1), arrestin3 (e.g. β-arrestin2), and arrestin4. β-Arrestin1 and β-arrestin2 are ubiquitously expressed and regulate a broad range of GPCRs, while arrestin1 and arrestin4 are expressed in the visual system. Although the functions of β-arrestin1 and β-arrestin2 widely overlap, β-arrestin2 has broader receptor selectivity, and a few studies have suggested that β-arrestin1 and β-arrestin2 have distinct cellular functions. Here, we compared the conformational dynamics of β-arrestin1 and β-arrestin2 by hydrogen/deuterium exchange mass spectrometry (HDX-MS). We also used the R169E mutant as a pre-activation model system. HDX-MS data revealed that β-strands II through IV were more dynamic in β-arrestin2 in the basal state, while the middle loop was more dynamic in β-arrestin1. With pre-activation, both β-arrestin1 and β-arrestin2 became more flexible, but broader regions of β-arrestin1 became flexible compared to β-arrestin2. The conformational differences between β-arrestin1 and β-arrestin2 in both the basal and pre-activated states might determine their different receptor selectivities and different cellular functions.

  10. Coupling Protein Side-Chain and Backbone Flexibility Improves the Re-design of Protein-Ligand Specificity.

    Directory of Open Access Journals (Sweden)

    Noah Ollikainen

    Full Text Available Interactions between small molecules and proteins play critical roles in regulating and facilitating diverse biological functions, yet our ability to accurately re-engineer the specificity of these interactions using computational approaches has been limited. One main difficulty, in addition to inaccuracies in energy functions, is the exquisite sensitivity of protein-ligand interactions to subtle conformational changes, coupled with the computational problem of sampling the large conformational search space of degrees of freedom of ligands, amino acid side chains, and the protein backbone. Here, we describe two benchmarks for evaluating the accuracy of computational approaches for re-engineering protein-ligand interactions: (i prediction of enzyme specificity altering mutations and (ii prediction of sequence tolerance in ligand binding sites. After finding that current state-of-the-art "fixed backbone" design methods perform poorly on these tests, we develop a new "coupled moves" design method in the program Rosetta that couples changes to protein sequence with alterations in both protein side-chain and protein backbone conformations, and allows for changes in ligand rigid-body and torsion degrees of freedom. We show significantly increased accuracy in both predicting ligand specificity altering mutations and binding site sequences. These methodological improvements should be useful for many applications of protein-ligand design. The approach also provides insights into the role of subtle conformational adjustments that enable functional changes not only in engineering applications but also in natural protein evolution.

  11. The determinants of bond angle variability in protein/peptide backbones: A comprehensive statistical/quantum mechanics analysis.

    Science.gov (United States)

    Improta, Roberto; Vitagliano, Luigi; Esposito, Luciana

    2015-11-01

    The elucidation of the mutual influence between peptide bond geometry and local conformation has important implications for protein structure refinement, validation, and prediction. To gain insights into the structural determinants and the energetic contributions associated with protein/peptide backbone plasticity, we here report an extensive analysis of the variability of the peptide bond angles by combining statistical analyses of protein structures and quantum mechanics calculations on small model peptide systems. Our analyses demonstrate that all the backbone bond angles strongly depend on the peptide conformation and unveil the existence of regular trends as function of ψ and/or φ. The excellent agreement of the quantum mechanics calculations with the statistical surveys of protein structures validates the computational scheme here employed and demonstrates that the valence geometry of protein/peptide backbone is primarily dictated by local interactions. Notably, for the first time we show that the position of the H(α) hydrogen atom, which is an important parameter in NMR structural studies, is also dependent on the local conformation. Most of the trends observed may be satisfactorily explained by invoking steric repulsive interactions; in some specific cases the valence bond variability is also influenced by hydrogen-bond like interactions. Moreover, we can provide a reliable estimate of the energies involved in the interplay between geometry and conformations. © 2015 Wiley Periodicals, Inc.

  12. Nonribosomal biosynthesis of backbone-modified peptides

    Science.gov (United States)

    Niquille, David L.; Hansen, Douglas A.; Mori, Takahiro; Fercher, David; Kries, Hajo; Hilvert, Donald

    2018-03-01

    Biosynthetic modification of nonribosomal peptide backbones represents a potentially powerful strategy to modulate the structure and properties of an important class of therapeutics. Using a high-throughput assay for catalytic activity, we show here that an L-Phe-specific module of an archetypal nonribosomal peptide synthetase can be reprogrammed to accept and process the backbone-modified amino acid (S)-β-Phe with near-native specificity and efficiency. A co-crystal structure with a non-hydrolysable aminoacyl-AMP analogue reveals the origins of the 40,000-fold α/β-specificity switch, illuminating subtle but precise remodelling of the active site. When the engineered catalyst was paired with downstream module(s), (S)-β-Phe-containing peptides were produced at preparative scale in vitro (~1 mmol) and high titres in vivo (~100 mg l-1), highlighting the potential of biosynthetic pathway engineering for the construction of novel nonribosomal β-frameworks.

  13. Conformal Infinity

    Directory of Open Access Journals (Sweden)

    Frauendiener Jörg

    2004-01-01

    Full Text Available The notion of conformal infinity has a long history within the research in Einstein's theory of gravity. Today, 'conformal infinity' is related to almost all other branches of research in general relativity, from quantisation procedures to abstract mathematical issues to numerical applications. This review article attempts to show how this concept gradually and inevitably evolved from physical issues, namely the need to understand gravitational radiation and isolated systems within the theory of gravitation, and how it lends itself very naturally to the solution of radiation problems in numerical relativity. The fundamental concept of null-infinity is introduced. Friedrich's regular conformal field equations are presented and various initial value problems for them are discussed. Finally, it is shown that the conformal field equations provide a very powerful method within numerical relativity to study global problems such as gravitational wave propagation and detection.

  14. Conformal Infinity

    Directory of Open Access Journals (Sweden)

    Frauendiener Jörg

    2000-08-01

    Full Text Available The notion of conformal infinity has a long history within the research in Einstein's theory of gravity. Today, ``conformal infinity'' is related with almost all other branches of research in general relativity, from quantisation procedures to abstract mathematical issues to numerical applications. This review article attempts to show how this concept gradually and inevitably evolved out of physical issues, namely the need to understand gravitational radiation and isolated systems within the theory of gravitation and how it lends itself very naturally to solve radiation problems in numerical relativity. The fundamental concept of null-infinity is introduced. Friedrich's regular conformal field equations are presented and various initial value problems for them are discussed. Finally, it is shown that the conformal field equations provide a very powerful method within numerical relativity to study global problems such as gravitational wave propagation and detection.

  15. General Conformity

    Science.gov (United States)

    The General Conformity requirements ensure that the actions taken by federal agencies in nonattainment and maintenance areas do not interfere with a state’s plans to meet national standards for air quality.

  16. Conformity evaluation

    International Nuclear Information System (INIS)

    2010-01-01

    The conformity assessment activities involve the IRD's actions related to the CNEN regulatory processing for licensing and control of nuclear and radioactive facilities in the country. They include regulatory inspections of radiation protection

  17. A dosimetric comparison of three-dimensional conformal radiotherapy, volumetric-modulated arc therapy, and dynamic conformal arc therapy in the treatment of non-small cell lung cancer using stereotactic body radiotherapy.

    Science.gov (United States)

    Rauschenbach, Bradley M; Mackowiak, Luke; Malhotra, Harish K

    2014-09-08

    This study evaluates three-dimensional conformal radiotherapy (3D CRT), volumetric-modulated arc therapy (VMAT), and dynamic conformal arc therapy (DCAT) planning techniques using dosimetric indices from Radiation Therapy Oncology Group (RTOG) protocols 0236, 0813, and 0915 for the treatment of early-stage non-small cell lung cancer (NSCLC) using stereotactic body radiotherapy (SBRT). Twenty-five clinical patients, five per lung lobe, previously treated for NSCLC using 3D CRT SBRT under respective RTOG protocols were replanned with VMAT and DCAT techniques. All plans were compared using respective RTOG dosimetric indices. High- and low-dose spillage improved for VMAT and DCAT plans, though only VMAT was able to improve dose to all organs at risk (OARs). DCAT was only able to provide a minimal improvement in dose to the heart and ipsilateral brachial plexus. Mean bilateral, contralateral, and V20 (percentage of bilateral lung receiving at least 20 Gy dose) doses were reduced with VMAT in comparison with respective 3D CRT clinical plans. Though some of the DCAT plans had values for the above indices slightly higher than their respective 3D CRT plans, they still were able to meet the RTOG constraints. VMAT and DCAT were able to offer improved skin dose by 1.1% and 11%, respectively. Monitor units required for treatment delivery increased with VMAT by 41%, but decreased with DCAT by 26%. VMAT and DCAT provided improved dose distributions to the PTV, but only VMAT was consistently superior in sparing dose to OARs in all the five lobes. DCAT should still remain an alternative to 3D CRT in facilities that do not have VMAT or intensity-modulated radiotherapy (IMRT) capabilities.

  18. A switch I mutant of Cdc42 exhibits decreased conformational freedom

    Science.gov (United States)

    Chandrashekar, Reena; Salem, Omar; Krizova, Hana; McFeeters, Robert; Adams, Paul D.

    2011-01-01

    Cdc42 is a Ras-related small G-protein, and functions as a molecular switch in signal transduction pathways linked with cell growth and differentiation. It is controlled by cycling between GTP-bound (active) and GDP-bound (inactive) forms. Nucleotide binding and hydrolysis are modulated by interactions with effectors and/or regulatory proteins. These interactions are centralized in two relatively flexible “Switch” regions as characterized by internal dynamics on multiple timescales (Loh et al., (2001) Biochemistry 40, 4590–4600), and this flexibility may be essential for protein interactions. In the Switch I region, Thr35 seems critical for function, as it is completely invariant in Ras-related proteins. To investigate the importance of conformational flexibility in Switch I of Cdc42, we mutated threonine to alanine, determined the solution structure and characterized the backbone dynamics of the single-point mutant protein, Cdc42(T35A). Backbone dynamics data suggests that the mutation changes the timescale of the internal motions of several residues, with several resonances appearing not discernable in Cdc42 wild type (Adams and Oswald (2007) Biomolecular NMR Assignments 1, 225–227). The mutation does not appear to affect the thermal stability of Cdc42, and chymotrypsin digestion data further suggests that changes in conformational flexibility in Switch I slow proteolytic cleavage relative to wild type. In-vitro binding assays show reduced binding of Cdc42(T35A), relative to wild type, to a GTPase binding protein that inhibits GTP hydrolysis in Cdc42. These results suggest that the mutation of T35 leads to the loss of conformational freedom in Switch I that could affect effector/regulatory protein interactions. PMID:21667996

  19. Extracting the information backbone in online system.

    Science.gov (United States)

    Zhang, Qian-Ming; Zeng, An; Shang, Ming-Sheng

    2013-01-01

    Information overload is a serious problem in modern society and many solutions such as recommender system have been proposed to filter out irrelevant information. In the literature, researchers have been mainly dedicated to improving the recommendation performance (accuracy and diversity) of the algorithms while they have overlooked the influence of topology of the online user-object bipartite networks. In this paper, we find that some information provided by the bipartite networks is not only redundant but also misleading. With such "less can be more" feature, we design some algorithms to improve the recommendation performance by eliminating some links from the original networks. Moreover, we propose a hybrid method combining the time-aware and topology-aware link removal algorithms to extract the backbone which contains the essential information for the recommender systems. From the practical point of view, our method can improve the performance and reduce the computational time of the recommendation system, thus improving both of their effectiveness and efficiency.

  20. Structural Analysis of Streptococcus pyogenes NADH Oxidase: Conformational Dynamics Involved in Formation of the C(4a)-Peroxyflavin Intermediate.

    Science.gov (United States)

    Wallen, Jamie R; Mallett, T Conn; Okuno, Takashi; Parsonage, Derek; Sakai, Hiroaki; Tsukihara, Tomitake; Claiborne, Al

    2015-11-17

    In probing the oxygen reactivity of an Enterococcus faecalis NADH oxidase (Nox; O2 → 2H2O) C42S mutant lacking the Cys42-sulfenic acid (Cys42-SOH) redox center, we provided direct evidence of a C(4a)-peroxyflavin intermediate in the oxidative half-reaction and also described a conformational or chemical change that is rate-limiting for full reoxidation of the homodimer. In this work, the Nox from Streptococcus pyogenes (SpyNox) has been expressed and crystallized, and the overoxidized wild-type [Cys44-SOH → Cys44-sulfinic acid (Cys44-SO2H)] and C44S mutant enzyme structures have been refined at 2.0 and 2.15 Å, respectively. We show that azide binds to the two-electron reduced wild-type (EH2) enzyme and to the mutant enzyme in solution, but with a significantly higher affinity for the mutant protein. The spectral course of the titration with the SpyNox EH2 form clearly indicates progressive displacement of the Cys44-S(-) → FAD charge-transfer interaction. An azide soak with C44S Nox crystals led to the structure of the complex, as refined at 2.10 Å. The active-site N3(-) ligand is proximal to the Ser44 and His11 side chains, and a significant shift in the Ser44 side chain also appears. This provides an attractive explanation for the azide-induced loss of charge-transfer absorbance seen with the wild-type EH2 form and also permits accommodation of a C(4a)-peroxyflavin structural model. The conformation of Ser44 and the associated helical element, and the resulting steric accommodation, appear to be linked to the conformational change described in the E. faecalis C42S Nox oxidative half-reaction.

  1. Practical considerations for investigation of protein conformational dynamics by {sup 15}N R{sub 1ρ} relaxation dispersion

    Energy Technology Data Exchange (ETDEWEB)

    Walinda, Erik [Kyoto University, Department of Molecular and Cellular Physiology, Graduate School of Medicine (Japan); Morimoto, Daichi; Shirakawa, Masahiro; Sugase, Kenji, E-mail: sugase@moleng.kyoto-u.ac.jp [Kyoto University, Department of Molecular Engineering, Graduate School of Engineering (Japan)

    2017-03-15

    It is becoming increasingly apparent that proteins are not static entities and that their function often critically depends on accurate sampling of multiple conformational states in aqueous solution. Accordingly, the development of methods to study conformational states in proteins beyond their ground-state structure (“excited states”) has crucial biophysical importance. Here we investigate experimental schemes for optimally probing chemical exchange processes in proteins on the micro- to millisecond timescale by {sup 15}N R{sub 1ρ} relaxation dispersion. The schemes use selective Hartmann–Hahn cross-polarization (CP) transfer for excitation, and derive peak integrals from 1D NMR spectra (Korzhnev et al. in J Am Chem Soc 127:713–721, 2005; Hansen et al. in J Am Chem Soc 131:3818–3819, 2009). Simulation and experiment collectively show that in such CP-based schemes care has to be taken to achieve accurate suppression of undesired off-resonance coherences, when using weak spin-lock fields. This then (i) ensures that relaxation dispersion profiles in the absence of chemical exchange are flat, and (ii) facilitates extraction of relaxation dispersion profiles in crowded regions of the spectrum. Further improvement in the quality of the experimental data is achieved by recording the free-induction decays in an interleaved manner and including a heating-compensation element. The reported considerations will particularly benefit the use of CP-based R{sub 1ρ} relaxation dispersion to analyze conformational exchange processes in larger proteins, where resonance line overlap becomes the main limiting factor.

  2. Steady states in conformal theories

    CERN Multimedia

    CERN. Geneva

    2015-01-01

    A novel conjecture regarding the steady state behavior of conformal field theories placed between two heat baths will be presented. Some verification of the conjecture will be provided in the context of fluid dynamics and holography.

  3. Exploring the conformational and reactive dynamics of biomolecules in solution using an extended version of the glycine reactive force field

    DEFF Research Database (Denmark)

    Monti, Susanna; Corozzi, Alessandro; Fristrup, Peter

    2013-01-01

    In order to describe possible reaction mechanisms involving amino acids, and the evolution of the protonation state of amino acid side chains in solution, a reactive force field (ReaxFF-based description) for peptide and protein simulations has been developed as an expansion of the previously...... force field on a relatively short time scale (500 ps) is validated by comparison with classical non-reactive simulations and experimental data of well characterized test cases, comprising capped amino acids, peptides, and small proteins, and reaction mechanisms connected to the pharmaceutical sector....... A good agreement of ReaxFF predicted conformations and kinetics with reference data is obtained....

  4. Use of the neutron diffraction - H/D exchange technique to determine the conformational dynamics of trypsin

    International Nuclear Information System (INIS)

    Kossiakoff, A.A.

    1982-01-01

    Reported here are studies analyzing the extent and nature of the inherent conformational fluctuations in trypsin by neutron diffraction - hydrogen exchange techniques. The pattern of exchange investigates systematic relationships between exchangeable sites and the structural and chemical properties of the molecule. Our findings that pH 7, 20 0 and 1 year of soaking all sites of trypsin are fully exchanged except those which are especially well protected by the structure. Essentially all the sites in which the peptide hydrogens are bonded directly to water molecules - either in the bulk solvent regions or in interior clusters - are fully exchanged. 41 references, 10 figures

  5. Conformal and non conformal dilaton gravity

    Science.gov (United States)

    Alvarez, Enrique; Herrero-Valea, Mario; Martín, C. P.

    2014-10-01

    The quantum dynamics of the gravitational field non-minimally coupled to an (also dynamical) scalar field is studied in the broken phase. For a particular value of the coupling the system is classically conformal, and can actually be understood as the group averaging of Einstein-Hilbert's action under conformal transformations. Conformal invariance implies a simple Ward identity asserting that the trace of the equation of motion for the graviton is the equation of motion of the scalar field. We perform an explicit one-loop computation to show that the DeWitt effective action is not UV divergent on shell and to find that the Weyl symmetry Ward identity is preserved on shell at that level. We also discuss the fate of this Ward identity at the two-loop level — under the assumption that the two-loop UV divergent part of the effective action can be retrieved from the Goroff-Sagnotti counterterm — and show that its preservation in the renormalized theory requires the introduction of counterterms which exhibit a logarithmic dependence on the dilaton field.

  6. Molecular mechanism of melting of a helical polymer crystal: Role of conformational order, packing and mobility of polymers

    Science.gov (United States)

    Cheerla, Ramesh; Krishnan, Marimuthu

    2018-03-01

    The molecular mechanism of melting of a superheated helical polymer crystal has been investigated using isothermal-isobaric molecular dynamics simulation that allows anisotropic deformation of the crystal lattice. A detailed microscopic analysis of the onset and progression of melting and accompanying changes in the polymer conformational order, translational, and orientation order of the solid along the melting pathway is presented. Upon gradual heating from room temperature to beyond the melting point at ambient pressure, the crystal exhibits signatures of premelting well below the solid-to-liquid melting transition at the melting point. The melting transition is manifested by abrupt changes in the crystal volume, lattice energy, polymer conformation, and dynamical properties. In the premelting stage, the crystal lattice structure and backbone orientation of the polymer chains are retained but with the onset of weakening of long-range helical order and interchain packing of polymers perpendicular to the fibre axis of the crystal. The premelting also marks the onset of conformational defects and anisotropic solid-state diffusion of polymers along the fibre axis. The present study underscores the importance of the interplay between intermolecular packing, interactions, and conformational dynamics at the atomic level in determining the macroscopic melting behavior of polymer crystals.

  7. Single-Molecule Protein Folding: A Study of the Surface-Mediated Conformational Dynamics of a Model Amphipathic Peptide

    Science.gov (United States)

    Cunningham, Joy; English, Douglas

    2004-03-01

    Most surface-active polypeptides, composed of 10-50 amino acids, are devoid of well-defined tertiary structure. The conformation of these proteins is greatly dependent upon their environment and may assume totally different characteristics in an aqueous environment, in a detergent micelle, or in an organic solvent. Most antimicrobial peptides are helix-forming and are activated upon interaction with a membrane-mimicking environment. We are seeking to physically characterize the mechanism of membrane-peptide interaction through studying a simple model peptide, MT-1. MT-1 was designed as a nonhomologous analogue of melittin, the principle component in bee venom. We are using single molecule spectroscopy to examine the induction of secondary structure upon interaction of MT-1 with various membrane-mimicking interfaces. Specifically, we monitor coil-to-helix transition through single molecule fluorescence resonance energy transfer (sm-FRET) to determine conformational distributions of folded and unfolded peptides at an interface. Studies with MT-1 will focus upon the biologically relevant issues of orientation, aggregation, and folding at surfaces using both ensemble and single molecule experiments.

  8. NHC Backbone Configuration in Ruthenium-Catalyzed Olefin Metathesis.

    Science.gov (United States)

    Paradiso, Veronica; Costabile, Chiara; Grisi, Fabia

    2016-01-20

    The catalytic properties of olefin metathesis ruthenium complexes bearing N-heterocyclic carbene ligands with stereogenic centers on the backbone are described. Differences in catalytic behavior depending on the backbone configurations of symmetrical and unsymmetrical NHCs are discussed. In addition, an overview on asymmetric olefin metathesis promoted by chiral catalysts bearing C₂-symmetric and C₁-symmetric NHCs is provided.

  9. NHC Backbone Configuration in Ruthenium-Catalyzed Olefin Metathesis

    Directory of Open Access Journals (Sweden)

    Veronica Paradiso

    2016-01-01

    Full Text Available The catalytic properties of olefin metathesis ruthenium complexes bearing N-heterocyclic carbene ligands with stereogenic centers on the backbone are described. Differences in catalytic behavior depending on the backbone configurations of symmetrical and unsymmetrical NHCs are discussed. In addition, an overview on asymmetric olefin metathesis promoted by chiral catalysts bearing C2-symmetric and C1-symmetric NHCs is provided.

  10. Use of simulation models to study the dynamic of recall of non-conform perishable produce through the supply chain

    DEFF Research Database (Denmark)

    Busato, P.; Sopegno, A.; Berruto, R.

    2013-01-01

    with investigating the traceability within the firm, little work has been carried out on the investigation of the traceability system over the whole supply chain. The supply-chain of fresh produce is constituted of many links: producer/grower, warehouse, packing centre, distribution centre, retailers and finally...... the consumer. Each of these is a system itself that interacts with the other components of the supply-chain. The nonconformity could occur in each of these links. Because of processing plant requirement, storage requirements, and because of savings in the traceability process, often small size lots are merged...... together to form a large size lot at some points in the supply-chain. Larger lot size could imply higher risk for the consumers in case of recall of the produce and much higher recall time and cost for the supply-chain. When a non-conformity occurs, the time to recall the produce depends on many factors...

  11. Different conformational dynamics of PDZ1 and PDZ2 in full-length EBP50 analyzed by hydrogen/deuterium exchange mass spectrometry.

    Science.gov (United States)

    Park, Ji Young; Duc, Nguyen Minh; Kim, Dong Kyun; Lee, Su Youn; Li, Sheng; Seo, Min-Duk; Woods, Virgil L; Chung, Ka Young

    2015-08-01

    Ezrin-radixin-moesin-binding protein 50 (EBP50) is a scaffolding protein expressed in polarized epithelial cells in various organs, including the liver, kidney, and small intestine, in which it regulates the trafficking and targeting cellular proteins. EBP50 contains two postsynaptic density-95/disk-large/ZO-1 homology (PDZ) domains (e.g., PDZ1 and PDZ2) and an ezrin/radixin/moesin-binding (EB) domain. PDZ domains are one of the major scaffolding domains regulating protein-protein interactions with critical biological roles in cell polarity, migration, proliferation, recognition, and cell-cell interaction. PDZ1 and PDZ2 in EBP50 have different ligand selectivity, although several high-resolution structural studies of isolated PDZ1 and PDZ2 showed similar structures. We studied the conformations of full-length EBP50 and isolated PDZ1 and PDZ2 using hydrogen/deuterium exchange mass spectrometry (HDX-MS). The deuterium uptake profiles of isolated PDZ1 and PDZ2 were similar to those of full-length EBP50. Interestingly, PDZ1 was more dynamic than PDZ2, and these PDZ domains underwent different conformational changes upon ligand binding. These results might explain the differences in ligand-selectivity between PDZ1 and PDZ2.

  12. Nucleotide-dependence of G-actin conformation from multiple molecular dynamics simulations and observation of a putatively polymerization-competent superclosed state.

    Science.gov (United States)

    Splettstoesser, Thomas; Noé, Frank; Oda, Toshiro; Smith, Jeremy C

    2009-08-01

    The assembly of monomeric G-actin into filamentous F-actin is nucleotide dependent: ATP-G-actin is favored for filament growth at the "barbed end" of F-actin, whereas ADP-G-actin tends to dissociate from the "pointed end." Structural differences between ATP- and ADP-G-actin are examined here using multiple molecular dynamics simulations. The "open" and "closed" conformational states of G-actin in aqueous solution are characterized, with either ATP or ADP in the nucleotide binding pocket. With both ATP and ADP bound, the open state closes in the absence of actin-bound profilin. The position of the nucleotide in the protein is found to be correlated with the degree of opening of the active site cleft. Further, the simulations reveal the existence of a structurally well-defined, compact, "superclosed" state of ATP-G-actin, as yet unseen crystallographically and absent in the ADP-G-actin simulations. The superclosed state resembles structurally the actin monomer in filament models derived from fiber diffraction and is putatively the polymerization competent conformation of ATP-G-actin. 2008 Wiley-Liss, Inc.

  13. High Performance Infiltrated Backbones for Cathode-Supported SOFC's

    DEFF Research Database (Denmark)

    Gil, Vanesa; Kammer Hansen, Kent

    2014-01-01

    The concept of using highly ionic conducting backbones with subsequent infiltration of electronically conducting particles has widely been used to develop alternative anode-supported SOFC's. In this work, the idea was to develop infiltrated backbones as an alternative design based on cathode......-supported SOFC. The cathodes are obtained by infiltrating LSM into a sintered either thick (300 μm) yttria stabilized zirconia (YSZ) backbone or a thin YSZ backbone (10-15 μm) integrated onto a thick (300 μm) porous strontium substituted lanthanum manganite (LSM) and YSZ composite. Fabrication challenges...... printed symmetrical cells. Samples with LSM/YSZ composite and YSZ backbones made with graphite+PMMA as pore formers exhibited comparable Rp values to the screen printed LSM/YSZ cathode. This route was chosen as the best to fabricate the cathode supported cells. SEM micrograph of a cathode supported cell...

  14. Extracting the information backbone in online system.

    Directory of Open Access Journals (Sweden)

    Qian-Ming Zhang

    Full Text Available Information overload is a serious problem in modern society and many solutions such as recommender system have been proposed to filter out irrelevant information. In the literature, researchers have been mainly dedicated to improving the recommendation performance (accuracy and diversity of the algorithms while they have overlooked the influence of topology of the online user-object bipartite networks. In this paper, we find that some information provided by the bipartite networks is not only redundant but also misleading. With such "less can be more" feature, we design some algorithms to improve the recommendation performance by eliminating some links from the original networks. Moreover, we propose a hybrid method combining the time-aware and topology-aware link removal algorithms to extract the backbone which contains the essential information for the recommender systems. From the practical point of view, our method can improve the performance and reduce the computational time of the recommendation system, thus improving both of their effectiveness and efficiency.

  15. High Speed Fibre Optic Backbone LAN

    Science.gov (United States)

    Tanimoto, Masaaki; Hara, Shingo; Kajita, Yuji; Kashu, Fumitoshi; Ikeuchi, Masaru; Hagihara, Satoshi; Tsuzuki, Shinji

    1987-09-01

    Our firm has developed the SUMINET-4100 series, a fibre optic local area network (LAN), to serve the communications system trunk line needs for facilities, such as steel refineries, automobile plants and university campuses, that require large transmission capacity, and for the backbone networks used in intelligent building systems. The SUMINET-4100 series is already in service in various fields of application. Of the networks available in this series, the SUMINET-4150 has a trunk line speed of 128 Mbps and the multiplexer used for time division multiplexing (TDM) was enabled by designing an ECL-TTL gate array (3000 gates) based custom LSI. The synchronous, full-duplex V.24 and V.3.5 interfaces (SUMINET-2100) are provided for use with general purpose lines. And the IBM token ring network, the SUMINET-3200, designed for heterogeneous PCs and the Ethernet can all be connected to sub loops. Further, the IBM 3270 TCA and 5080 CADAM can be connected in the local mode. Interfaces are also provided for the NTT high-speed digital service, the digital PBX systems, and the Video CODEC system. The built-in loop monitor (LM) and network supervisory processor (NSP) provide management of loop utilization and send loop status signals to the host CPU's network configuration and control facility (NCCF). These built-in functions allow both the computer system and LAN to be managed from a single source at the host. This paper outlines features of the SUMINET-4150 and provides an example of its installation.

  16. Extracting the Information Backbone in Online System

    Science.gov (United States)

    Zhang, Qian-Ming; Zeng, An; Shang, Ming-Sheng

    2013-01-01

    Information overload is a serious problem in modern society and many solutions such as recommender system have been proposed to filter out irrelevant information. In the literature, researchers have been mainly dedicated to improving the recommendation performance (accuracy and diversity) of the algorithms while they have overlooked the influence of topology of the online user-object bipartite networks. In this paper, we find that some information provided by the bipartite networks is not only redundant but also misleading. With such “less can be more” feature, we design some algorithms to improve the recommendation performance by eliminating some links from the original networks. Moreover, we propose a hybrid method combining the time-aware and topology-aware link removal algorithms to extract the backbone which contains the essential information for the recommender systems. From the practical point of view, our method can improve the performance and reduce the computational time of the recommendation system, thus improving both of their effectiveness and efficiency. PMID:23690946

  17. Steered molecular dynamics simulations of a bacterial type IV pilus reveal characteristics of an experimentally-observed, force-induced conformational transition

    Science.gov (United States)

    Baker, Joseph; Biais, Nicolas; Tama, Florence

    2011-10-01

    Type IV pili (T4P) are long, filamentous structures that emanate from the cellular surface of many infectious bacteria. They are built from a 158 amino acid long subunit called pilin. T4P can grow to many micrometers in length, and can withstand large tension forces. During the infection process, pili attach themselves to host cells, and therefore naturally find themselves under tension. We investigated the response of a T4 pilus to a pulling force using the method of steered molecular dynamics (SMD) simulation. Our simulations expose to the external environment an amino acid sequence initially hidden in the native filament, in agreement with experimental data. Therefore, our simulations might be probing the initial stage of the transition to a force-induced conformation of the T4 pilus. Additional exposed amino acid sequences that might be useful targets for drugs designed to mitigate bacterial infection were also predicted.

  18. Conformality lost

    International Nuclear Information System (INIS)

    Kaplan, David B.; Lee, Jong-Wan; Son, Dam T.; Stephanov, Mikhail A.

    2009-01-01

    We consider zero-temperature transitions from conformal to nonconformal phases in quantum theories. We argue that there are three generic mechanisms for the loss of conformality in any number of dimensions: (i) fixed point goes to zero coupling, (ii) fixed point runs off to infinite coupling, or (iii) an IR fixed point annihilates with a UV fixed point and they both disappear into the complex plane. We give both relativistic and nonrelativistic examples of the last case in various dimensions and show that the critical behavior of the mass gap behaves similarly to the correlation length in the finite temperature Berezinskii-Kosterlitz-Thouless (BKT) phase transition in two dimensions, ξ∼exp(c/|T-T c | 1/2 ). We speculate that the chiral phase transition in QCD at large number of fermion flavors belongs to this universality class, and attempt to identify the UV fixed point that annihilates with the Banks-Zaks fixed point at the lower end of the conformal window.

  19. Conformational determination of potent antagonist analogues of oxytocin by nuclear magnetic resonance spectroscopy and molecular dynamics simulations

    Czech Academy of Sciences Publication Activity Database

    Kritsi, E.; Potamitis, C.; Zoumpoulakis, P.; Borovičková, Lenka; Slaninová, Jiřina; Assimomytis, N. L.; Magafa, V.; Cordopatis, P.

    2014-01-01

    Roč. 20, Suppl S1 (2014), S200-S201 ISSN 1075-2617. [European Peptide Symposium /33./. 31.08.2014-05.09.2014, Sofia ] Institutional support: RVO:61388963 Keywords : oxytocin analogues * antagonistic activity * NMR * molecular dynamics Subject RIV: CC - Organic Chemistry

  20. Radiation Safety System (RSS) backbones: Design, engineering, fabrication, and installation

    Science.gov (United States)

    Wilmarth, J. E.; Sturrock, J. C.; Gallegos, F. R.

    1998-12-01

    The Radiation Safety System (RSS) backbones are part of an electrical/electronic/mechanical system ensuring safe access and exclusion of personnel to areas at the Los Alamos Neutron Science Center (LANSCE) accelerator. The RSS backbones control the safety-fusible beam plugs which terminate transmission of accelerated ion beams in response to predefined conditions. Any beam or access fault of the backbone inputs will cause insertion of the beam plugs in the low-energy beam transport. The backbones serve the function of tying the beam plugs to the access control systems, beam spill monitoring systems and current-level limiting systems. In some ways the backbones may be thought of as a spinal column with beam plugs at the head and nerve centers along the spinal column. The two linac backbone segments and the experimental area segments form a continuous cable plant over 3500 feet from the beam plugs to the tip on the longest tail. The backbones were installed in compliance with current safety standards, such as installation of the two segments in separate conduits or tray. Monitoring for ground-faults and input wiring verification was an added enhancement to the system. The system has the capability to be tested remotely.

  1. Radiation safety system (RSS) backbones: Design, engineering, fabrication and installation

    International Nuclear Information System (INIS)

    Wilmarth, J.E.; Sturrock, J.C.; Gallegos, F.R.

    1998-01-01

    The Radiation Safety System (RSS) Backbones are part of an electrical/electronic/mechanical system insuring safe access and exclusion of personnel to areas at the Los Alamos Neutron Science Center (LANSCE) accelerator. The RSS Backbones control the safety fusible beam plugs which terminate transmission of accelerated ion beams in response to predefined conditions. Any beam or access fault of the backbone inputs will cause insertion of the beam plugs in the low energy beam transport. The Backbones serve the function of tying the beam plugs to the access control systems, beam spill monitoring systems and current-level limiting systems. In some ways the Backbones may be thought of as a spinal column with beam plugs at the head and nerve centers along the spinal column. The two Linac Backbone segments and experimental area segments form a continuous cable plant over 3,500 feet from beam plugs to the tip on the longest tail. The Backbones were installed in compliance with current safety standards, such as installation of the two segments in separate conduits or tray. Monitoring for ground-faults and input wiring verification was an added enhancement to the system. The system has the capability to be tested remotely

  2. Data Acquisition Backbone Core DABC release v1.0

    International Nuclear Information System (INIS)

    Adamczewski-Musch, J; Kurz, N; Linev, S; Essel, H G

    2010-01-01

    The Data Acquisition Backbone Core (DABC) is a general purpose software framework designed for the implementation of a wide-range of data acquisition systems - from various small detector test beds to high performance systems. DABC consists of a compact data-flow kernel and a number of plug-ins for various functional components like data inputs, device drivers, user functional modules and applications. DABC provides configurable components for implementing event building over fast networks like InfiniBand or Gigabit Ethernet. A generic Java GUI provides the dynamic control and visualization of control parameters and commands, provided by DIM servers. A first set of application plug-ins has been implemented to use DABC as event builder for the front-end components of the GSI standard DAQ system MBS (Multi Branch System). Another application covers the connection to DAQ readout chains from detector front-end boards (N-XYTER) linked to read-out controller boards (ROC) over UDP into DABC for event building, archiving and data serving. This was applied for data taking in the September 2008 test beamtime for the CBM experiment at GSI. DABC version 1.0 is released and available from the website.

  3. Data Acquisition Backbone Core DABC release v1.0

    Science.gov (United States)

    Adamczewski-Musch, J.; Essel, H. G.; Kurz, N.; Linev, S.

    2010-04-01

    The Data Acquisition Backbone Core (DABC) is a general purpose software framework designed for the implementation of a wide-range of data acquisition systems - from various small detector test beds to high performance systems. DABC consists of a compact data-flow kernel and a number of plug-ins for various functional components like data inputs, device drivers, user functional modules and applications. DABC provides configurable components for implementing event building over fast networks like InfiniBand or Gigabit Ethernet. A generic Java GUI provides the dynamic control and visualization of control parameters and commands, provided by DIM servers. A first set of application plug-ins has been implemented to use DABC as event builder for the front-end components of the GSI standard DAQ system MBS (Multi Branch System). Another application covers the connection to DAQ readout chains from detector front-end boards (N-XYTER) linked to read-out controller boards (ROC) over UDP into DABC for event building, archiving and data serving. This was applied for data taking in the September 2008 test beamtime for the CBM experiment at GSI. DABC version 1.0 is released and available from the website.

  4. Structural elements involved in proton translocation by cytochrome c oxidase as revealed by backbone amide hydrogen-deuterium exchange of the E286H mutant.

    Science.gov (United States)

    Busenlehner, Laura S; Brändén, Gisela; Namslauer, Ida; Brzezinski, Peter; Armstrong, Richard N

    2008-01-08

    Cytochrome c oxidase is the terminal electron acceptor in the respiratory chains of aerobic organisms and energetically couples the reduction of oxygen to water to proton pumping across the membrane. The mechanisms of proton uptake, gating, and pumping have yet to be completely elucidated at the molecular level for these enzymes. For Rhodobacter sphaeroides CytcO (cytochrome aa3), it appears as though the E286 side chain of subunit I is a branching point from which protons are shuttled either to the catalytic site for O2 reduction or to the acceptor site for pumped protons. Amide hydrogen-deuterium exchange mass spectrometry was used to investigate how mutation of this key branching residue to histidine (E286H) affects the structures and dynamics of four redox intermediate states. A functional characterization of this mutant reveals that E286H CytcO retains approximately 1% steady-state activity that is uncoupled from proton pumping and that proton transfer from H286 is significantly slowed. Backbone amide H-D exchange kinetics indicates that specific regions of CytcO, perturbed by the E286H mutation, are likely to be involved in proton gating and in the exit pathway for pumped protons. The results indicate that redox-dependent conformational changes around E286 are essential for internal proton transfer. E286H CytcO, however, is incapable of these specific conformational changes and therefore is insensitive to the redox state of the enzyme. These data support a model where the side chain conformation of E286 controls proton translocation in CytcO through its interactions with the proton gate, which directs the flow of protons either to the active site or to the exit pathway. In the E286H mutant, the proton gate does not function properly and the exit channel is unresponsive. These results provide new insight into the structure and mechanism of proton translocation by CytcO.

  5. Conformational dynamics of DNA hairpins at millisecond resolution obtained from analysis of single-molecule FRET histograms.

    Science.gov (United States)

    Tsukanov, Roman; Tomov, Toma E; Berger, Yaron; Liber, Miran; Nir, Eyal

    2013-12-19

    Here we provide high resolution study of DNA hairpin dynamics achieved by probability distribution analysis (PDA) of diffusion-based single-molecule Förster resonance energy transfer (sm-FRET) histograms. The opening and closing rates of three hairpins both free and attached to DNA origami were determined. The agreement with rates previously obtained using the total internal reflection (TIRF) technique and between free hairpins and hairpins attached to origami validated the PDA and demonstrated that the origami had no influence on the hairpin dynamics. From comparison of rates of four DNA hairpins, differing only in stem sequence, and from comparison with rates calculated using nearest-neighbor method and standard transition state theory, we conclude that the unfolding reaction resembles that of melting of DNA duplex with a corresponding sequence and that the folding reaction depends on counterion concentration and not on stem sequence. Our validation and demonstration of the PDA method will encourage its implementation in future high-resolution dynamic studies of freely diffusing biomolecules.

  6. Hotspot mutations in KIT receptor differentially modulate its allosterically coupled conformational dynamics: impact on activation and drug sensitivity.

    Directory of Open Access Journals (Sweden)

    Isaure Chauvot de Beauchêne

    2014-07-01

    Full Text Available Receptor tyrosine kinase KIT controls many signal transduction pathways and represents a typical allosterically regulated protein. The mutation-induced deregulation of KIT activity impairs cellular physiological functions and causes serious human diseases. The impact of hotspots mutations (D816H/Y/N/V and V560G/D localized in crucial regulatory segments, the juxtamembrane region (JMR and the activation (A- loop, on KIT internal dynamics was systematically studied by molecular dynamics simulations. The mutational outcomes predicted in silico were correlated with in vitro and in vivo activation rates and drug sensitivities of KIT mutants. The allosteric regulation of KIT in the native and mutated forms is described in terms of communication between the two remote segments, JMR and A-loop. A strong correlation between the communication profile and the structural and dynamical features of KIT in the native and mutated forms was established. Our results provide new insight on the determinants of receptor KIT constitutive activation by mutations and resistance of KIT mutants to inhibitors. Depiction of an intra-molecular component of the communication network constitutes a first step towards an integrated description of vast communication pathways established by KIT in physiopathological contexts.

  7. Conformational fluctuation dynamics of domain I of human serum albumin in the course of chemically and thermally induced unfolding using fluorescence correlation spectroscopy.

    Science.gov (United States)

    Yadav, Rajeev; Sengupta, Bhaswati; Sen, Pratik

    2014-05-22

    The present study elucidates the involvement of conformational fluctuation dynamics during chemically and thermally induced unfolding of human serum albumin (HSA) by fluorescence correlation spectroscopic (FCS) study, time-resolved fluorescence measurements, and circular dichroism (CD) spectroscopic methods. Two fluorescent probes, tetramethylrhodamine-5-maleimide (TMR) and N-(7-dimethylamino-4-methylcoumarin-3-yl) iodoacetamide (DACIA) were used to selectively label the domain I of HSA through the reaction with cys-34 for these studies. The guanidine hydrochloride (GnHCl) induced global structural change of HSA is monitored through its hydrodynamic radius (r(H)) and CD response, which is found to be two step in nature. In FCS experiment, along with the diffusion time component we have observed an exponential relaxation time component (τ(R)) that has been ascribed to the concerted chain dynamics of HSA. Unlike in the global structural change, we found that the τ(R) value changes in a different manner in the course of the unfolding. The dependence of τ(R) on the concentration of GnHCl was best fitted with a four state model, indicating the involvement of two intermediate states during the unfolding process, which were not observed through the CD response and r(H) data. The fluorescence lifetime measurement also supports our observation of intermediate states during the unfolding of HSA. However, no such intermediate states were observed during thermally induced unfolding of HSA.

  8. Antibody side chain conformations are position-dependent.

    Science.gov (United States)

    Leem, Jinwoo; Georges, Guy; Shi, Jiye; Deane, Charlotte M

    2018-01-10

    Side chain prediction is an integral component of computational antibody design and structure prediction. Current antibody modelling tools use backbone-dependent rotamer libraries with conformations taken from general proteins. Here we present our antibody-specific rotamer library, where rotamers are binned according to their immunogenetics (IMGT) position, rather than their local backbone geometry. We find that for some amino acid types at certain positions, only a restricted number of side chain conformations are ever observed. Using this information, we are able to reduce the breadth of the rotamer sampling space. Based on our rotamer library, we built a side chain predictor, position-dependent antibody rotamer swapper (PEARS). On a blind test set of 95 antibody model structures, PEARS had the highest average χ 1 and χ1+2 accuracy (78.7% and 64.8%) compared to three leading backbone-dependent side chain predictors. Our use of IMGT position, rather than backbone ϕ/ψ, meant that PEARS was more robust to errors in the backbone of the model structure. PEARS also achieved the lowest number of side chain-side chain clashes. PEARS is freely available as a web application at http://opig.stats.ox.ac.uk/webapps/pears. © 2018 Wiley Periodicals, Inc.

  9. Dynamic conformations of nucleophosmin (NPM1 at a key monomer-monomer interface affect oligomer stability and interactions with granzyme B.

    Directory of Open Access Journals (Sweden)

    Wei D Duan-Porter

    Full Text Available Nucleophosmin (NPM1 is an abundant, nucleolar tumor antigen with important roles in cell proliferation and putative contributions to oncogenesis. Wild-type NPM1 forms pentameric oligomers through interactions at the amino-terminal core domain. A truncated form of NPM1 found in some hepatocellular carcinoma tissue formed an unusually stable oligomer and showed increased susceptibility to cleavage by granzyme B. Initiation of translation at the seventh methionine generated a protein (M7-NPM that shared all these properties. We used deuterium exchange mass spectrometry (DXMS to perform a detailed structural analysis of wild-type NPM1 and M7-NPM, and found dynamic conformational shifts or local "unfolding" at a specific monomer-monomer interface which included the β-hairpin "latch." We tested the importance of interactions at the β-hairpin "latch" by replacing a conserved tyrosine in the middle of the β-hairpin loop with glutamic acid, generating Y67E-NPM. Y67E-NPM did not form stable oligomers and further, prevented wild-type NPM1 oligomerization in a dominant-negative fashion, supporting the critical role of the β-hairpin "latch" in monomer-monomer interactions. Also, we show preferential cleavage by granzyme B at one of two available aspartates (either D161 or D122 in M7-NPM and Y67E-NPM, whereas wild-type NPM1 was cleaved at both sites. Thus, we observed a correlation between the propensity to form oligomers and granzyme B cleavage site selection in nucleophosmin proteins, suggesting that a small change at an important monomer-monomer interface can affect conformational shifts and impact protein-protein interactions.

  10. Influence of a charged graphene surface on the orientation and conformation of covalently attached oligonucleotides: a molecular dynamics study

    Czech Academy of Sciences Publication Activity Database

    Kabeláč, Martin; Kroutil, O.; Předota, M.; Lankaš, Filip; Šíp, M.

    2012-01-01

    Roč. 14, č. 12 (2012), s. 4217-4229 ISSN 1463-9076 R&D Projects: GA ČR GC204/09/J010; GA MŠk LC512; GA AV ČR IAA400550808 Grant - others:GA ČR(CZ) GA203/08/0094; GA MŠk(CZ) LM2010005 Program:GA Institutional research plan: CEZ:AV0Z40550506 Keywords : DNA * graphene * charge density * molecular dynamics * Amber Subject RIV: CF - Physical ; Theoretical Chemistry Impact factor: 3.829, year: 2012

  11. APPECT: An Approximate Backbone-Based Clustering Algorithm for Tags

    DEFF Research Database (Denmark)

    Zong, Yu; Xu, Guandong; Jin, Pin

    2011-01-01

    resulting from the severe difficulty of ambiguity, redundancy and less semantic nature of tags. Clustering method is a useful tool to address the aforementioned difficulties. Most of the researches on tag clustering are directly using traditional clustering algorithms such as K-means or Hierarchical...... algorithm for Tags (APPECT). The main steps of APPECT are: (1) we execute the K-means algorithm on a tag similarity matrix for M times and collect a set of tag clustering results Z={C1,C2,…,Cm}; (2) we form the approximate backbone of Z by executing a greedy search; (3) we fix the approximate backbone...... Agglomerative Clustering on tagging data, which possess the inherent drawbacks, such as the sensitivity of initialization. In this paper, we instead make use of the approximate backbone of tag clustering results to find out better tag clusters. In particular, we propose an APProximate backbonE-based Clustering...

  12. Towards a natural classification and backbone tree for Sordariomycete

    Digital Repository Service at National Institute of Oceanography (India)

    Maharachchikumbura, S.S.N.; Hyde, K.D.; Jones, E.B.G.; McKenzie, E.H.C.; Huang, S.-K.; Abdel-Wahab, M.A.; Daranagama, D.A.; Dayarathne, M.; D'souza, M.J.; Goonasekara, I.D.; Hongsanan, S.; Jayawardena, R.S.; Kirk, P.M.; Konta, S.; Liu, J.-K.; Liu, Z.-Y.; Norphanphoun, C.; Pang, K.-L.; Perera, R.H.; Senanayake, I.C.; Shang, Q.; Shenoy, B.D.; Xiao, Y.; Bahkali, A.H.; Kang, J.; Somrothipol, S.; Suetrong, S.; Wen, T.; Xu, J.

    , lichenized or lichenicolous taxa The class includes freshwater, marine and terrestrial taxa and has a worldwide distribution This paper provides an updated outline of the Sordariomycetes and a backbone tree incorporating asexual and sexual genera in the class...

  13. Solution conformation of purine-pyrimidine DNA octamers using nuclear magnetic resonance, restrained molecular dynamics and NOE-based refinement.

    Science.gov (United States)

    Baleja, J D; Germann, M W; van de Sande, J H; Sykes, B D

    1990-10-05

    The solution structures of two alternating purine-pyrimidine octamers, [d(G-T-A-C-G-T-A-C)]2 and the reverse sequence [d(C-A-T-G-C-A-T-G)]2, are investigated by using nuclear magnetic resonance spectroscopy and restrained molecular dynamics calculations. Chemical shift assignments are obtained for non-exchangeable protons by a combination of two-dimensional correlation and nuclear Overhauser enhancement (NOE) spectroscopy experiments. Distances between protons are estimated by extrapolating distances derived from time-dependent NOE measurements to zero mixing time. Approximate dihedral angles are determined within the deoxyribose ring from coupling constants observed in one and two-dimensional spectra. Sets of distance and dihedral determinations for each of the duplexes form the bases for structure determination. Molecular dynamics is then used to generate structures that satisfy the experimental restraints incorporated as effective potentials into the total energy. Separate runs start from classical A and B-form DNA and converge to essentially identical structures. To circumvent the problems of spin diffusion and differential motion associated with distance measurements within molecules, models are improved by NOE-based refinement in which observed NOE intensities are compared to those calculated using a full matrix analysis procedure. The refined structures generally have the global features of B-type DNA. Some, but not all, variations in dihedral angles and in the spatial relationships of adjacent base-pairs are observed to be in synchrony with the alternating purine-pyrimidine sequence.

  14. The dynamic Atg13-free conformation of the Atg1 EAT domain is required for phagophore expansion.

    Science.gov (United States)

    Lin, Mary G; Schöneberg, Johannes; Davies, Christopher W; Ren, Xuefeng; Hurley, James H

    2018-03-14

    Yeast macroautophagy begins with the de novo formation of a double membrane phagophore at the preautophagosomal structure (PAS), followed by its expansion into the autophagosome responsible for cargo engulfment. The kinase Atg1 is recruited to the PAS by Atg13 through interactions between the EAT domain of the former and the tMIM motif of the latter. Mass spectrometry data has shown that in the absence of Atg13, the EAT domain structure is strikingly dynamic, but the function of this Atg13-free dynamic state has been unclear. We used structure-based mutational analysis and quantitative and superresolution microscopy to show that Atg1 is present on autophagic puncta at on average twice the stoichiometry of Atg13. Moreover, Atg1 co-localizes with the expanding autophagosome in a manner dependent on Atg8 but not Atg13. We used isothermal titration calorimetry and crystal structure information to design an EAT domain mutant allele ATG1 DD that selectively perturbs the function of the Atg13-free state. Atg1 DD shows reduced PAS formation and does not support phagophore expansion, showing that the EAT domain has an essential function that is separate from its Atg13-dependent role in autophagy initiation. © 2018 by The American Society for Cell Biology.

  15. Ligand induced change of β2 adrenergic receptor from active to inactive conformation and its implication for the closed/open state of the water channel: insight from molecular dynamics simulation, free energy calculation and Markov state model analysis.

    Science.gov (United States)

    Bai, Qifeng; Pérez-Sánchez, Horacio; Zhang, Yang; Shao, Yonghua; Shi, Danfeng; Liu, Huanxiang; Yao, Xiaojun

    2014-08-14

    The reported crystal structures of β2 adrenergic receptor (β2AR) reveal that the open and closed states of the water channel are correlated with the inactive and active conformations of β2AR. However, more details about the process by which the water channel states are affected by the active to inactive conformational change of β2AR remain illusive. In this work, molecular dynamics simulations are performed to study the dynamical inactive and active conformational change of β2AR induced by inverse agonist ICI 118,551. Markov state model analysis and free energy calculation are employed to explore the open and close states of the water channel. The simulation results show that inverse agonist ICI 118,551 can induce water channel opening during the conformational transition of β2AR. Markov state model (MSM) analysis proves that the energy contour can be divided into seven states. States S1, S2 and S5, which represent the active conformation of β2AR, show that the water channel is in the closed state, while states S4 and S6, which correspond to the intermediate state conformation of β2AR, indicate the water channel opens gradually. State S7, which represents the inactive structure of β2AR, corresponds to the full open state of the water channel. The opening mechanism of the water channel is involved in the ligand-induced conformational change of β2AR. These results can provide useful information for understanding the opening mechanism of the water channel and will be useful for the rational design of potent inverse agonists of β2AR.

  16. Study of structural and conformational change in cytochrome, C through molecular dynamic simulation in presence of gold nanoparticles

    Science.gov (United States)

    Moudgil, Lovika; Singh, Baljinder; Kaura, Aman; Singh, Gurinder; Tripathi, S. K.; Saini, G. S. S.

    2017-05-01

    Proteins are the most abundant organic molecules in living system having diverse structures and various functions than the other classes of macromolecules. We have done Molecular Dynamics (MD) simulation of the Cytochrome,C (Cyt,c) protein found in plants, animals and many unicellular animals in the presence of gold nanoparticles (Au NPs). MD results helped to recognize the amino acids that play important role to make the interaction possible between protein and gold surface. In the present study we have examined the structural change of protein in the presence of gold surface and its adsorption on the surface through MD simulations with the help of Gold-Protein (GolP) force field. Results were further analyzed to understand the protein interaction up to molecular level.

  17. Conformational and nuclear dynamics effects in molecular Auger spectra: fluorine core-hole decay in CF4

    Science.gov (United States)

    Arion, T.; Takahashi, O.; Püttner, R.; Ulrich, V.; Barth, S.; Lischke, T.; Bradshaw, A. M.; Förstel, M.; Hergenhahn, U.

    2014-06-01

    In a molecular Auger spectrum information on the decaying state is implicitly ensemble-averaged. For a repulsive core-ionized state, for example, contributions from all parts of its potential curve are superimposed in the Auger spectrum. Using carbon tetrafluoride (CF4, tetrafluoromethane), we demonstrate for the first time that these contributions can be disentangled by recording photoelectron-Auger electron coincidence spectra with high energy resolution. For the F K-VV spectrum of CF4, there are significant differences in the Auger decay at different intermediate state (single core hole) geometries. With the help of calculations, we show that these differences result primarily from zero-point fluctuations in the neutral molecular ground state, but are amplified by the nuclear dynamics during Auger decay.

  18. Conformational and nuclear dynamics effects in molecular Auger spectra: fluorine core-hole decay in CF4

    International Nuclear Information System (INIS)

    Arion, T; Ulrich, V; Barth, S; Lischke, T; Bradshaw, A M; Takahashi, O; Püttner, R; Förstel, M; Hergenhahn, U

    2014-01-01

    In a molecular Auger spectrum information on the decaying state is implicitly ensemble-averaged. For a repulsive core-ionized state, for example, contributions from all parts of its potential curve are superimposed in the Auger spectrum. Using carbon tetrafluoride (CF 4 , tetrafluoromethane), we demonstrate for the first time that these contributions can be disentangled by recording photoelectron–Auger electron coincidence spectra with high energy resolution. For the F K-VV spectrum of CF 4 , there are significant differences in the Auger decay at different intermediate state (single core hole) geometries. With the help of calculations, we show that these differences result primarily from zero-point fluctuations in the neutral molecular ground state, but are amplified by the nuclear dynamics during Auger decay. (paper)

  19. A Molecular Dynamics Investigation of Mycobacterium tuberculosis Prenyl Synthases: Conformational Flexibility and Implications for Computer-aided Drug Discovery.

    Science.gov (United States)

    Kim, Meekyum Olivia; Feng, Xinxin; Feixas, Ferran; Zhu, Wei; Lindert, Steffen; Bogue, Shannon; Sinko, William; de Oliveira, César; Rao, Guodong; Oldfield, Eric; McCammon, James Andrew

    2015-06-01

    With the rise in antibiotic resistance, there is interest in discovering new drugs active against new targets. Here, we investigate the dynamic structures of three isoprenoid synthases from Mycobacterium tuberculosis using molecular dynamics (MD) methods with a view to discovering new drug leads. Two of the enzymes, cis-farnesyl diphosphate synthase (cis-FPPS) and cis-decaprenyl diphosphate synthase (cis-DPPS), are involved in bacterial cell wall biosynthesis, while the third, tuberculosinyl adenosine synthase (Rv3378c), is involved in virulence factor formation. The MD results for these three enzymes were then compared with previous results on undecaprenyl diphosphate synthase (UPPS) by means of active site volume fluctuation and principal component analyses. In addition, an analysis of the binding of prenyl diphosphates to cis-FPPS, cis-DPPS, and UPPS utilizing the new MD results is reported. We also screened libraries of inhibitors against cis-DPPS, finding ~1 μm inhibitors, and used the receiver operating characteristic-area under the curve (ROC-AUC) method to test the predictive power of X-ray and MD-derived cis-DPPS receptors. We found that one compound with potent M. tuberculosis cell growth inhibition activity was an IC(50) ~0.5- to 20-μm inhibitor (depending on substrate) of cis-DPPS, a ~660-nm inhibitor of Rv3378c as well as a 4.8-μm inhibitor of cis-FPPS, opening up the possibility of multitarget inhibition involving both cell wall biosynthesis and virulence factor formation. © 2014 John Wiley & Sons A/S.

  20. Escherichia coli SufE sulfur transfer protein modulates the SufS cysteine desulfurase through allosteric conformational dynamics.

    Science.gov (United States)

    Singh, Harsimran; Dai, Yuyuan; Outten, F Wayne; Busenlehner, Laura S

    2013-12-20

    Fe-S clusters are critical metallocofactors required for cell function. Fe-S cluster biogenesis is carried out by assembly machinery consisting of multiple proteins. Fe-S cluster biogenesis proteins work together to mobilize sulfide and iron, form the nascent cluster, traffic the cluster to target metalloproteins, and regulate the assembly machinery in response to cellular Fe-S cluster demand. A complex series of protein-protein interactions is required for the assembly machinery to function properly. Despite considerable progress in obtaining static three-dimensional structures of the assembly proteins, little is known about transient protein-protein interactions during cluster assembly or the role of protein dynamics in the cluster assembly process. The Escherichia coli cysteine desulfurase SufS (EC 2.8.1.7) and its accessory protein SufE work together to mobilize persulfide from L-cysteine, which is then donated to the SufB Fe-S cluster scaffold. Here we use amide hydrogen/deuterium exchange mass spectrometry (HDX-MS) to characterize SufS-SufE interactions and protein dynamics in solution. HDX-MS analysis shows that SufE binds near the SufS active site to accept persulfide from Cys-364. Furthermore, SufE binding initiates allosteric changes in other parts of the SufS structure that likely affect SufS catalysis and alter SufS monomer-monomer interactions. SufE enhances the initial l-cysteine substrate binding to SufS and formation of the external aldimine with pyridoxal phosphate required for early steps in SufS catalysis. Together, these results provide a new picture of the SufS-SufE sulfur transferase pathway and suggest a more active role for SufE in promoting the SufS cysteine desulfurase reaction for Fe-S cluster assembly.

  1. Topologia dos backbones de internet no Brasil / Internet backbone topology in Brazil

    Directory of Open Access Journals (Sweden)

    Marcelo Paiva da Motta

    2012-04-01

    Full Text Available Este artigo visa reafirmar o papel do espaço no estudo das Novas Tecnologias de Informação e Comunicação (NTICs. Examinamos a topologia dos backbones de internet no Brasil usando as ferramentas matemáticas da teoria dos grafos. Através do cálculo de índices de centralidade (proximidade e intermediação, bem como de outras técnicas quantitativas, as redes físicas que compõem a internet são relacionadas à rede urbana preexistente, mostrando que em suas características gerais o funcionamento não subverte a geografia econômica do país, a despeito do ideário antigeográfico suscitado por parte da literatura sobre os impactos da tecnologia.

  2. HIV-1 Capsid Function is Regulated by Dynamics: Quantitative Atomic-Resolution Insights by Integrating Magic-Angle-Spinning NMR, QM/MM, and MD.

    Science.gov (United States)

    Zhang, Huilan; Hou, Guangjin; Lu, Manman; Ahn, Jinwoo; Byeon, In-Ja L; Langmead, Christopher J; Perilla, Juan R; Hung, Ivan; Gor'kov, Peter L; Gan, Zhehong; Brey, William W; Case, David A; Schulten, Klaus; Gronenborn, Angela M; Polenova, Tatyana

    2016-10-05

    HIV-1 CA capsid protein possesses intrinsic conformational flexibility, which is essential for its assembly into conical capsids and interactions with host factors. CA is dynamic in the assembled capsid, and residues in functionally important regions of the protein undergo motions spanning many decades of timescales. Chemical shift anisotropy (CSA) tensors, recorded in magic-angle-spinning NMR experiments, provide direct residue-specific probes of motions on nano- to microsecond timescales. We combined NMR, MD, and Density-Functional-Theory calculations, to gain quantitative understanding of internal backbone dynamics in CA assemblies, and found that the dynamically averaged 15 N CSA tensors calculated by this joined protocol are in remarkable agreement with experiment. Thus, quantitative atomic-level understanding of the relationships between CSA tensors, local backbone structure and motions in CA assemblies is achieved, demonstrating the power of integrating NMR experimental data and theory for characterizing atomic-resolution dynamics in biological systems.

  3. Tyr66 acts as a conformational switch in the closed-to-open transition of the SHP-2 N-SH2-domain phosphotyrosine-peptide binding cleft

    Directory of Open Access Journals (Sweden)

    MacKerell Alexander D

    2007-03-01

    Full Text Available Abstract Background The N-terminal SH2 domain (N-SH2 of the non-receptor tyrosine phosphatase SHP-2 is involved both in localization of SHP-2 by recognition of phosphotyrosine (pY peptides and self-inhibition of SHP-2 phosphatase activity through the formation of a protein – protein interface with the phosphatase domain. Mutations that disrupt this interface break the coupling between pY-peptide binding cleft conformation and self-inhibition, thereby increasing both SHP-2 phosphatase activity and pY-peptide binding affinity, and are associated with the congenital condition Noonan syndrome and various pediatric leukemias. To better characterize the molecular process involved in N-SH2 pY-dependent binding, we have applied explicit-solvent molecular dynamics simulations to study the closed-to-open transition of the N-SH2 pY-peptide binding cleft. Results The existence of stable conformations in the left-handed helical and the extended regions of Tyr66 φ/ψ space prevent rapid interconversion of the backbone and create a conformational switch such that Tyr66 in a left-handed helical backbone conformation results in an open cleft and in an extended backbone conformation results in a closed cleft. The stable conformations arise from deep, well-localized free-energy minima in the left-handed helical and extended regions of the Tyr66 φ/ψ map. Changing the Tyr66 backbone conformation from extended to left-handed helical induces a closed-to-open transition in the cleft, and the reverse change in backbone conformation induces the reverse, open-to-closed transition. In the open-cleft state, weak solvent-exposed interactions involving the sidechains of Tyr66, Asp40, Lys55, and Gln57 serve to anchor the Tyr66 sidechain to the surface of the protein and away from the binding cleft entrance, thereby facilitating pY-peptide access to the binding cleft. Conclusion The simulations point to a regulatory role for Tyr66 and surrounding residues in SHP-2 function

  4. Alteration in the cavity size adjacent to the active site of RB69 DNA polymerase changes its conformational dynamics.

    Science.gov (United States)

    Xia, Shuangluo; Wood, Marcus; Bradley, Michael J; De La Cruz, Enrique M; Konigsberg, William H

    2013-10-01

    Internal cavities are a common feature of many proteins, often having profound effects on the dynamics of their interactions with substrate and binding partners. RB69 DNA polymerase (pol) has a hydrophobic cavity right below the nucleotide binding pocket at the tip of highly conserved L415 side chain. Replacement of this residue with Gly or Met in other B family pols resulted in higher mutation rates. When similar substitutions for L415 were introduced into RB69pol, only L415A and L415G had dramatic effects on pre-steady-state kinetic parameters, reducing base selectivity by several hundred fold. On the other hand, the L415M variant behaved like the wild-type. Using a novel tC(o)-tCnitro Förster Resonance Energy Transfer (FRET) assay, we were able to show that the partition of the primer terminus between pol and exonuclease (exo) domains was compromised with the L415A and L415G mutants, but not with the L415M variant. These results could be rationalized by changes in their structures as determined by high resolution X-ray crystallography.

  5. Solution conformation and dynamics of a tetrasaccharide related to the Lewis{sup X} antigen deduced by NMR relaxation measurements

    Energy Technology Data Exchange (ETDEWEB)

    Poveda, Ana [Universidad Autonoma de Madrid, Servicio Interdepartamental de Investigacion (Spain); Asensio, Juan Luis; Martin-Pastor, Manuel; Jimenez-Barbero, Jesus [Instituto de Quimica Organica, CSIC, Grupo de Carbohidratos (Spain)

    1997-07-15

    {sup 1}H-NMR cross-relaxation rates and nonselective longitudinal relaxation times have been obtained at two magnetic fields (7.0 and 11.8 T) and at a variety of temperatures for the branched tetrasaccharide methyl 3-O-{alpha}-N-acetyl-galactosaminyl-{beta}-galactopyranosyl-(1{sup {yields}}4)[3-O-{alpha}-fucosyl] -glucopyranoside (1), an inhibitor of astrocyte growth. In addition, {sup 13}C-NMR relaxation data have also been recorded at both fields. The {sup 1}H-NMR relaxation data have been interpreted using different motional models to obtain proton-proton correlation times. The results indicate that the GalNAc and Fuc rings display more extensive local motion than the two inner Glc and Gal moieties, since those present significantly shorter local correlation times. The{sup 13}C-NMR relaxation parameters have been interpreted in terms of the Lipari-Szabo model-free approach. Thus, order parameters and internal motion correlation times have been deduced. As obtained for the{sup 1}H-NMR relaxation data, the two outer residues possess smaller order parameters than the two inner rings. Internal correlation times are in the order of 100 ps. The hydroxymethyl groups have also different behaviour,with the exocyclic carbon on the glucopyranoside unit showing the highestS{sup 2}. Molecular dynamics simulations using a solvated system have also been performed and internal motion correlation functions have been deduced from these calculations. Order parameters and interproton distances have been compared to those inferred from the NMR measurements. The obtained results are in fair agreement with the experimental data.

  6. Resolution of Two Sub-Populations of Conformers and Their Individual Dynamics by Time Resolved Ensemble Level FRET Measurements.

    Directory of Open Access Journals (Sweden)

    Gil Rahamim

    Full Text Available Most active biopolymers are dynamic structures; thus, ensembles of such molecules should be characterized by distributions of intra- or intermolecular distances and their fast fluctuations. A method of choice to determine intramolecular distances is based on Förster resonance energy transfer (FRET measurements. Major advances in such measurements were achieved by single molecule FRET measurements. Here, we show that by global analysis of the decay of the emission of both the donor and the acceptor it is also possible to resolve two sub-populations in a mixture of two ensembles of biopolymers by time resolved FRET (trFRET measurements at the ensemble level. We show that two individual intramolecular distance distributions can be determined and characterized in terms of their individual means, full width at half maximum (FWHM, and two corresponding diffusion coefficients which reflect the rates of fast ns fluctuations within each sub-population. An important advantage of the ensemble level trFRET measurements is the ability to use low molecular weight small-sized probes and to determine nanosecond fluctuations of the distance between the probes. The limits of the possible resolution were first tested by simulation and then by preparation of mixtures of two model peptides. The first labeled polypeptide was a relatively rigid Pro7 and the second polypeptide was a flexible molecule consisting of (Gly-Ser7 repeats. The end to end distance distributions and the diffusion coefficients of each peptide were determined. Global analysis of trFRET measurements of a series of mixtures of polypeptides recovered two end-to-end distance distributions and associated intramolecular diffusion coefficients, which were very close to those determined from each of the pure samples. This study is a proof of concept study demonstrating the power of ensemble level trFRET based methods in resolution of subpopulations in ensembles of flexible macromolecules.

  7. Biologically relevant conformational features of linear and cyclic proteolipid protein (PLP) peptide analogues obtained by high-resolution nuclear magnetic resonance and molecular dynamics

    Science.gov (United States)

    Kordopati, Golfo G.; Tzoupis, Haralambos; Troganis, Anastassios N.; Tsivgoulis, Gerasimos M.; Golic Grdadolnik, Simona; Simal, Carmen; Tselios, Theodore V.

    2017-09-01

    Proteolipid protein (PLP) is one of the main proteins of myelin sheath that are destroyed during the progress of multiple sclerosis (MS). The immunodominant PLP139-151 epitope is known to induce experimental autoimmune encephalomyelitis (EAE, animal model of MS), wherein residues 144 and 147 are recognized by T cell receptor (TCR) during the formation of trimolecular complex with peptide-antigen and major histocompability complex. The conformational behavior of linear and cyclic peptide analogues of PLP, namely PLP139-151 and cyclic (139-151) (L144, R147) PLP139-151, have been studied in solution by means of nuclear magnetic resonance (NMR) methods in combination with unrestrained molecular dynamics simulations. The results indicate that the side chains of mutated amino acids in the cyclic analogue have different spatial orientation compared with the corresponding side chains of the linear analogue, which can lead to reduced affinity to TCR. NMR experiments combined with theoretical calculations pave the way for the design and synthesis of potent restricted peptides of immunodominant PLP139-151 epitope as well as non peptide mimetics that rises as an ultimate goal.

  8. Thermoresponsive Poly(2-oxazoline) Molecular Brushes by Living Ionic Polymerization: Kinetic Investigations of Pendant Chain Grafting and Cloud Point Modulation by Backbone and Side Chain Length Variation

    KAUST Repository

    Zhang, Ning

    2012-04-17

    Molecular brushes of poly(2-oxazoline)s were prepared by living anionic polymerization of 2-iso-propenyl-2-oxazoline to form the backbone and subsequent living cationic ring-opening polymerization of 2-n- or 2-iso-propyl-2-oxazoline for pendant chain grafting. In situ kinetic studies indicate that the initiation efficiency and polymerization rates are independent from the number of initiator functions per initiator molecule. This was attributed to the high efficiency of oxazolinium salt and the stretched conformation of the backbone, which is caused by the electrostatic repulsion of the oxazolinium moieties along the macroinitiator. The resulting molecular brushes showed thermoresponsive properties, that is, having a defined cloud point (CP). The dependence of the CP as a function of backbone and side chain length as well as concentration was studied. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. Non-conformable, partial and conformable transposition

    DEFF Research Database (Denmark)

    König, Thomas; Mäder, Lars Kai

    2013-01-01

    Although member states are obliged to transpose directives into domestic law in a conformable manner and receive considerable time for their transposition activities, we identify three levels of transposition outcomes for EU directives: conformable, partially conformable and non-conformable...... and the Commission regarding a directive’s outcome, play a much more strategic role than has to date acknowledged in the transposition literature. Whereas disagreement of a member state delays conformable transposition, it speeds up non-conformable transposition. Disagreement of the Commission only prolongs...

  10. NMR backbone resonance assignments of the prodomain variants of BDNF in the urea denatured state.

    Science.gov (United States)

    Wang, Jing; Bains, Henrietta; Anastasia, Agustin; Bracken, Clay

    2018-04-01

    Brain derived neurotrophic factor (BDNF) is a member of the neurotrophin family of proteins which plays a central role in neuronal survival, growth, plasticity and memory. A single Val66Met variant has been identified in the prodomain of human BDNF that is associated with anxiety, depression and memory disorders. The structural differences within the full-length prodomain Val66 and Met66 isoforms could shed light on the mechanism of action of the Met66 and its impact on the development of neuropsychiatric-associated disorders. In the present study, we report the backbone 1 H, 13 C, and 15 N NMR assignments of both full-length Val66 and Met66 prodomains in the presence of 2 M urea. These conditions were utilized to suppress residual structure and aid subsequent native state structural investigations aimed at mapping and identifying variant-dependent conformational differences under native-state conditions.

  11. Comparing two strategies of dynamic intensity modulated radiation therapy (dIMRT with 3-dimensional conformal radiation therapy (3DCRT in the hypofractionated treatment of high-risk prostate cancer

    Directory of Open Access Journals (Sweden)

    Yartsev Slav

    2008-01-01

    Full Text Available Abstract Background To compare two strategies of dynamic intensity modulated radiation therapy (dIMRT with 3-dimensional conformal radiation therapy (3DCRT in the setting of hypofractionated high-risk prostate cancer treatment. Methods 3DCRT and dIMRT/Helical Tomotherapy(HT planning with 10 CT datasets was undertaken to deliver 68 Gy in 25 fractions (prostate and simultaneously delivering 45 Gy in 25 fractions (pelvic lymph node targets in a single phase. The paradigms of pelvic vessel targeting (iliac vessels with margin are used to target pelvic nodes and conformal normal tissue avoidance (treated soft tissues of the pelvis while limiting dose to identified pelvic critical structures were assessed compared to 3DCRT controls. Both dIMRT/HT and 3DCRT solutions were compared to each other using repeated measures ANOVA and post-hoc paired t-tests. Results When compared to conformal pelvic vessel targeting, conformal normal tissue avoidance delivered more homogenous PTV delivery (2/2 t-test comparisons; p dose, 1–3 Gy over 5/10 dose points; p Conclusion dIMRT/HT nodal and pelvic targeting is superior to 3DCRT in dose delivery and critical structure sparing in the setting of hypofractionation for high-risk prostate cancer. The pelvic targeting paradigm is a potential solution to deliver highly conformal pelvic radiation treatment in the setting of nodal location uncertainty in prostate cancer and other pelvic malignancies.

  12. Basic residues R260 and K357 affect the conformational dynamics of the major facilitator superfamily multidrug transporter LmrP.

    Directory of Open Access Journals (Sweden)

    Wei Wang

    Full Text Available Secondary-active multidrug transporters can confer resistance on cells to pharmaceuticals by mediating their extrusion away from intracellular targets via substrate/H(+(Na(+ antiport. While the interactions of catalytic carboxylates in these transporters with coupling ions and substrates (drugs have been studied in some detail, the functional importance of basic residues has received much less attention. The only two basic residues R260 and K357 in transmembrane helices in the Major Facilitator Superfamily transporter LmrP from Lactococcus lactis are present on the outer surface of the protein, where they are exposed to the phospholipid head group region of the outer leaflet (R260 and inner leaflet (K357 of the cytoplasmic membrane. Although our observations on the proton-motive force dependence and kinetics of substrate transport, and substrate-dependent proton transport demonstrate that K357A and R260A mutants are affected in ethidium-proton and benzalkonium-proton antiport compared to wildtype LmrP, our findings suggest that R260 and K357 are not directly involved in the binding of substrates or the translocation of protons. Secondary-active multidrug transporters are thought to operate by a mechanism in which binding sites for substrates are alternately exposed to each face of the membrane. Disulfide crosslinking experiments were performed with a double cysteine mutant of LmrP that reports the substrate-stimulated transition from the outward-facing state to the inward-facing state with high substrate-binding affinity. In the experiments, the R260A and K357A mutations were found to influence the dynamics of these major protein conformations in the transport cycle, potentially by removing the interactions of R260 and K357 with phospholipids and/or other residues in LmrP. The R260A and K357A mutations therefore modify the maximum rate at which the transport cycle can operate and, as the transitions between conformational states are differently

  13. Probing the flexibility of large conformational changes in protein structures through local perturbations.

    Directory of Open Access Journals (Sweden)

    Bosco K Ho

    2009-04-01

    Full Text Available Protein conformational changes and dynamic behavior are fundamental for such processes as catalysis, regulation, and substrate recognition. Although protein dynamics have been successfully explored in computer simulation, there is an intermediate-scale of motions that has proven difficult to simulate - the motion of individual segments or domains that move independently of the body the protein. Here, we introduce a molecular-dynamics perturbation method, the Rotamerically Induced Perturbation (RIP, which can generate large, coherent motions of structural elements in picoseconds by applying large torsional perturbations to individual sidechains. Despite the large-scale motions, secondary structure elements remain intact without the need for applying backbone positional restraints. Owing to its computational efficiency, RIP can be applied to every residue in a protein, producing a global map of deformability. This map is remarkably sparse, with the dominant sites of deformation generally found on the protein surface. The global map can be used to identify loops and helices that are less tightly bound to the protein and thus are likely sites of dynamic modulation that may have important functional consequences. Additionally, they identify individual residues that have the potential to drive large-scale coherent conformational change. Applying RIP to two well-studied proteins, Dihdydrofolate Reductase and Triosephosphate Isomerase, which possess functionally-relevant mobile loops that fluctuate on the microsecond/millisecond timescale, the RIP deformation map identifies and recapitulates the flexibility of these elements. In contrast, the RIP deformation map of alpha-lytic protease, a kinetically stable protein, results in a map with no significant deformations. In the N-terminal domain of HSP90, the RIP deformation map clearly identifies the ligand-binding lid as a highly flexible region capable of large conformational changes. In the Estrogen

  14. Conformations and Conformational Processes of Hexahydrobenzazocines by NMR and DFT Studies.

    Science.gov (United States)

    Musielak, Bogdan; Holak, Tad A; Rys, Barbara

    2015-09-18

    Conformational processes that occur in hexahydrobenzazocines have been studied with the (1)H and (13)C dynamic nuclear magnetic resonance (DNMR) spectroscopy. The coalescence effects are assigned to two different conformational processes: the ring-inversion of the ground-state conformations and the interconversion between two different conformers. The barriers for these processes are in the range of 42-52 and 42-43 kJ mol(-1), respectively. Molecular modeling on the density functional theory (DFT) level and the gauge invariant atomic orbitals (GIAO)-DFT calculations of isotropic shieldings and coupling constants for the set of low-energy conformations were compared with the experimental NMR data. The ground-state of all compounds in solution is the boat-chair (BC) conformation. The BC form adopts two different conformations because the nitrogen atom can be in the boat or chair parts of the BC structure. These two conformers are engaged in the interconversion process.

  15. Conformational Change in the Mechanism of Inclusion of Ketoprofen in β-Cyclodextrin: NMR Spectroscopy, Ab Initio Calculations, Molecular Dynamics Simulations, and Photoreactivity.

    Science.gov (United States)

    Guzzo, T; Mandaliti, W; Nepravishta, R; Aramini, A; Bodo, E; Daidone, I; Allegretti, M; Topai, A; Paci, M

    2016-10-11

    Inclusion of drugs in cyclodextrins (CDs) is a recognized tool for modifying several properties such as solubility, stability, bioavailability, and so on. The photoreactive behavior of the β-CD/ketoprofen (KP) complex upon UV exposure showed a significant increase in photodecarboxylation, whereas the secondary degradation products by hydroxylation of the benzophenone moiety were inhibited. The results may account for an improvement of KP photophysical properties upon inclusion, thus better fostering its topical use. To correlate the structural details of the inclusion with these results, an NMR spectroscopic study of KP upon inclusion in β-CD was performed. Effects of the magnetically anisotropic centers of KP, changing their orientations upon inclusion and giving chemical shift variations, were specifically correlated with the results of the molecular dynamic simulations and ab initio calculations. In the large variety of papers focusing on the structural analysis of β-CD complexes, this work represents one of the few examples in which a detailed analysis of these simultaneous upfield-downfield NMR shifts of the same aromatic molecule upon inclusion is reported. Interestingly, the results demonstrate that the observed upfield and downfield shifts upon inclusion are not related to any direct magnetic role of β-CD. The conformational change of KP upon the inclusion process consists of a slight reduction in the angle between the two phenyl rings and in a remarkable reduction in the mobility of the carboxyl group, the latter being one of the main contributions to the NMR resonance shifts. These structural details help in understanding the features of the inclusion complex and, eventually, the driving force for its formation.

  16. Conformation and energy transfer in single conjugated polymers.

    Science.gov (United States)

    Bolinger, Joshua C; Traub, Matthew C; Brazard, Johanna; Adachi, Takuji; Barbara, Paul F; Vanden Bout, David A

    2012-11-20

    In contrast to the detailed understanding of inorganic materials, researchers lack a comprehensive view of how the properties of bulk organic materials arise from their individual components. For conjugated polymers to eventually serve as low cost semiconductor layers in electronic devices, researchers need to better understand their functionality. For organics, traditional materials science measurements tend to destroy the species of interest, especially at low concentrations. However, fluorescence continues to be a remarkably flexible, relatively noninvasive tool for probing the properties of individual molecules and allows researchers to carry out a broad range of experiments based on a relatively simple concept. In addition, the sensitivity of single-molecule spectroscopy allows researchers to see the properties of an individual component that would be masked in the bulk phase. In this Account, we examine several photophysical properties of different conjugated polymers using single-molecule spectroscopy. In these experiments, we probed the relationship between the conformation of single conjugated polymer chains and the distance scale and efficiency of energy transfer within the polymer. Recent studies used polarization anisotropy measurements on single polymer chains to study chain folding following spin-casting from solution. This Account summarizes the effects of monomer regioregularity and backbone rigidity, by comparing a regiorandom phenylene vinylene (MEH-PPV) with both a regiorandom and regioregular thiophene (P3HT). Synthesis of novel polymers allowed us to explore the role of different conformation-directing inclusions in a PPV backbone. We showed that these inclusions control the conformation of individual chains and that molecular dynamics can predict these structural effects. In situ solvent vapor annealing studies explored the dynamics of polymer chains as well as the effect of solvent evaporation on the structural equilibrium of the polymer. We

  17. Sortase-mediated backbone cyclization of proteins and peptides

    NARCIS (Netherlands)

    van 't Hof, W.; Hansenová Maňásková, S.; Veerman, E.C.I.; Bolscher, J.G.M.

    2015-01-01

    Backbone cyclization has a profound impact on the biological activity and thermal and proteolytic stability of proteins and peptides. Chemical methods for cyclization are not always feasible, especially for large peptides or proteins. Recombinant Staphylococcus aureus sortase A shows potential as a

  18. Stabilizing cations in the backbones of conjugated polymers

    NARCIS (Netherlands)

    Voortman, Thomas P.; de Gier, Hilde D.; Havenith, Remco W. A.; Chiechi, Ryan C.

    2014-01-01

    We synthesized a cross-conjugated polymer containing ketones in the backbone and converted it to a linearly conjugated, cationic polyarylmethine via a process we call "spinless doping" to create a new class of materials, conjugated polyions. This process involves activating the ketones with a Lewis

  19. The Graphical Representation of the Digital Astronaut Physiology Backbone

    Science.gov (United States)

    Briers, Demarcus

    2010-01-01

    This report summarizes my internship project with the NASA Digital Astronaut Project to analyze the Digital Astronaut (DA) physiology backbone model. The Digital Astronaut Project (DAP) applies integrated physiology models to support space biomedical operations, and to assist NASA researchers in closing knowledge gaps related to human physiologic responses to space flight. The DA physiology backbone is a set of integrated physiological equations and functions that model the interacting systems of the human body. The current release of the model is HumMod (Human Model) version 1.5 and was developed over forty years at the University of Mississippi Medical Center (UMMC). The physiology equations and functions are scripted in an XML schema specifically designed for physiology modeling by Dr. Thomas G. Coleman at UMMC. Currently it is difficult to examine the physiology backbone without being knowledgeable of the XML schema. While investigating and documenting the tags and algorithms used in the XML schema, I proposed a standard methodology for a graphical representation. This standard methodology may be used to transcribe graphical representations from the DA physiology backbone. In turn, the graphical representations can allow examination of the physiological functions and equations without the need to be familiar with the computer programming languages or markup languages used by DA modeling software.

  20. Performance of Flow-Aware Networking in LTE backbone

    DEFF Research Database (Denmark)

    Sniady, Aleksander; Soler, José

    2012-01-01

    technologies, such as Long Term Evolution (LTE). This paper proposes usage of a modified Flow Aware Networking (FAN) technique for enhancing Quality of Service (QoS) in the all-IP transport networks underlying LTE backbone. The results obtained with OPNET Modeler show that FAN, in spite of being relatively...

  1. Internet Backbone in the Democratic Republic of Congo : Feasibility ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Internet Backbone in the Democratic Republic of Congo : Feasibility Study and Advocacy. During 7-10 February 2005, representatives of five francophone African countries (Cameroon, Morocco, Niger, Sénégal, and the Democratic Republic of Congo - DRC) met to consider ways and means of galvanizing the appropriation ...

  2. Frequency response of a protein to local conformational perturbations.

    Directory of Open Access Journals (Sweden)

    Dilek Eren

    Full Text Available Signals created by local perturbations are known to propagate long distances through proteins via backbone connectivity and nonbonded interactions. In the current study, signal propagation from the flexible ligand binding loop to the rest of Protein Tyrosine Phosphatase 1B (PTP1B was investigated using frequency response techniques. Using restrained Targeted Molecular Dynamics (TMD potential on WPD and R loops, PTP1B was driven between its crystal structure conformations at different frequencies. Propagation of the local perturbation signal was manifested via peaks at the fundamental frequency and upper harmonics of 1/f distributed spectral density of atomic variables, such as Cα atoms, dihedral angles, or polar interaction distances. Frequency of perturbation was adjusted high enough (simulation length >∼10×period of a perturbation cycle not to be clouded by random diffusional fluctuations, and low enough (<∼0.8 ns(-1 not to attenuate the propagating signal and enhance the contribution of the side-chains to the dissipation of the signals. Employing Discrete Fourier Transform (DFT to TMD simulation trajectories of 16 cycles of conformational transitions at periods of 1.2 to 5 ns yielded Cα displacements consistent with those obtained from crystal structures. Identification of the perturbed atomic variables by statistical t-tests on log-log scale spectral densities revealed the extent of signal propagation in PTP1B, while phase angles of the filtered trajectories at the fundamental frequency were used to cluster collectively fluctuating elements. Hydrophobic interactions were found to have a higher contribution to signal transduction between side-chains compared to the role of polar interactions. Most of in-phase fluctuating residues on the signaling pathway were found to have high identity among PTP domains, and located over a wide region of PTP1B including the allosteric site. Due to its simplicity and efficiency, the suggested technique

  3. Deglycosylation induces extensive dynamics changes in α-amylase revealed by hydrogen/deuterium exchange mass spectrometry.

    Science.gov (United States)

    Ji, Chengjie; Wei, Gary

    2013-12-15

    N-Linked glycosylation plays important roles in modulating protein structure and function. The direct impact of the modification on protein conformation is not yet well understood. Here we probed the dynamic changes following Endo H trimming of high mannose glycans in α-amylase by means of amide hydrogen/deuterium exchange mass spectrometry. The results revealed that deglycosylation elicited extensive alterations in backbone dynamics, affecting regions both adjacent to and distal from the glycosylation site. The overall exchange rate is reduced in the glycosylated state, which indicates rigidity enhancement due to the attached carbohydrates. Copyright © 2013 John Wiley & Sons, Ltd.

  4. Study of the influence of neighboring amino acids on proline conformation

    Directory of Open Access Journals (Sweden)

    Jose Elias Cancino Herrera

    2016-07-01

    Full Text Available DFT calculations made at the B3LYP/6-31+G(d level were used to investigate how the incorporation of a second amino acid into the backbone affects the conformational preferences of proline. Specifically, the this research studied the second amino acids L-proline and L-alanine and the trans isomerism of the peptide bonds. The lowest energy minimum has been found to have a different conformation for the two systems investigated; while the third presents a different conformation. The results obtained offer evidence of the influence of these systems on the conformational preference of proline.

  5. Tracking the dynamic seroma cavity using fiducial markers in patients treated with accelerated partial breast irradiation using 3D conformal radiotherapy

    International Nuclear Information System (INIS)

    Yue, Ning J.; Haffty, Bruce G.; Goyal, Sharad; Kearney, Thomas; Kirstein, Laurie; Chen Sining

    2013-01-01

    Purpose: The purpose of the present study was to perform an analysis of the changes in the dynamic seroma cavity based on fiducial markers in early stage breast cancer patients treated with accelerated partial breast irradiation (APBI) using three-dimensional conformal external beam radiotherapy (3D-CRT). Methods: A prospective, single arm trial was designed to investigate the utility of gold fiducial markers in image guided APBI using 3D-CRT. At the time of lumpectomy, four to six suture-type gold fiducial markers were sutured to the walls of the cavity. Patients were treated with a fractionation scheme consisting of 15 fractions with a fractional dose of 333 cGy. Treatment design and planning followed NSABP/RTOG B-39 guidelines. During radiation treatment, daily kV imaging was performed and the markers were localized and tracked. The change in distance between fiducial markers was analyzed based on the planning CT and daily kV images. Results: Thirty-four patients were simulated at an average of 28 days after surgery, and started the treatment on an average of 39 days after surgery. The average intermarker distance (AiMD) between fiducial markers was strongly correlated to seroma volume. The average reduction in AiMD was 19.1% (range 0.0%–41.4%) and 10.8% (range 0.0%–35.6%) for all the patients between simulation and completion of radiotherapy, and between simulation and beginning of radiotherapy, respectively. The change of AiMD fits an exponential function with a half-life of seroma shrinkage. The average half-life for seroma shrinkage was 15 days. After accounting for the reduction which started to occur after surgery through CT simulation and treatment, radiation was found to have minimal impact on the distance change over the treatment course. Conclusions: Using the marker distance change as a surrogate for seroma volume, it appears that the seroma cavity experiences an exponential reduction in size. The change in seroma size has implications in the size

  6. The Role of Conformational Entropy in the Determination of Structural-Kinetic Relationships for Helix-Coil Transitions

    Directory of Open Access Journals (Sweden)

    Joseph F. Rudzinski

    2018-02-01

    Full Text Available Coarse-grained molecular simulation models can provide significant insight into the complex behavior of protein systems, but suffer from an inherently distorted description of dynamical properties. We recently demonstrated that, for a heptapeptide of alanine residues, the structural and kinetic properties of a simulation model are linked in a rather simple way, given a certain level of physics present in the model. In this work, we extend these findings to a longer peptide, for which the representation of configuration space in terms of a full enumeration of sequences of helical/coil states along the peptide backbone is impractical. We verify the structural-kinetic relationships by scanning the parameter space of a simple native-biased model and then employ a distinct transferable model to validate and generalize the conclusions. Our results further demonstrate the validity of the previous findings, while clarifying the role of conformational entropy in the determination of the structural-kinetic relationships. More specifically, while the global, long timescale kinetic properties of a particular class of models with varying energetic parameters but approximately fixed conformational entropy are determined by the overarching structural features of the ensemble, a shift in these kinetic observables occurs for models with a distinct representation of steric interactions. At the same time, the relationship between structure and more local, faster kinetic properties is not affected by varying the conformational entropy of the model.

  7. Chain conformation-dependent thermal conductivity of amorphous polymer blends: the impact of inter- and intra-chain interactions.

    Science.gov (United States)

    Wei, Xingfei; Zhang, Teng; Luo, Tengfei

    2016-11-30

    Polymers with high thermal conductivities are of great interest for both scientific research and industrial applications. In this study, model amorphous polymer blends are studied using molecular dynamics simulations. We have examined the effects of inter- and intra-chain interactions on the molecular-level conformations of the blends, which in turn impact their thermal conductivity. It is found that the thermal conductivity of polymer blends is strongly related to the molecular conformation, especially the spatial extent of the molecular chains indicated by their radius of gyration. Tuning the intra-chain van der Waals (vdW) interaction leads to different molecular structures of the minor component in the binary blend, but the thermal conductivity is not changed. However, increasing the inter-chain vdW interactions between the major and the minor components will increase the thermal conductivity of the blend, which is due to the conformation change in the major component that leads to enhanced thermal transport along the chain backbone through the intra-chain bonding interactions. The fundamental structure-property relationship from this study may provide useful guidance for designing and synthesizing polymer blends with desirable thermal conductivity.

  8. Cross-correlated relaxation rates between protein backbone H–X dipolar interactions

    Energy Technology Data Exchange (ETDEWEB)

    Vögeli, Beat, E-mail: beat.vogeli@ucdenver.edu [University of Colorado Denver, Department of Biochemistry and Molecular Genetics (United States)

    2017-03-15

    The relaxation interference between dipole–dipole interactions of two separate spin pairs carries structural and dynamics information. In particular, when compared to individual dynamic behavior of those spin pairs, such cross-correlated relaxation (CCR) rates report on the correlation between the spin pairs. We have recently mapped out correlated motion along the backbone of the protein GB3, using CCR rates among and between consecutive H{sup N}–N and H{sup α}–C{sup α} dipole–dipole interactions. Here, we provide a detailed account of the measurement of the four types of CCR rates. All rates were obtained from at least two different pulse sequences, of which the yet unpublished ones are presented. Detailed comparisons between the different methods and corrections for unwanted pathways demonstrate that the averaged CCR rates are highly accurate and precise with errors of 1.5–3% of the entire value ranges.

  9. Cross-correlated relaxation rates between protein backbone H–X dipolar interactions

    International Nuclear Information System (INIS)

    Vögeli, Beat

    2017-01-01

    The relaxation interference between dipole–dipole interactions of two separate spin pairs carries structural and dynamics information. In particular, when compared to individual dynamic behavior of those spin pairs, such cross-correlated relaxation (CCR) rates report on the correlation between the spin pairs. We have recently mapped out correlated motion along the backbone of the protein GB3, using CCR rates among and between consecutive H N –N and H α –C α dipole–dipole interactions. Here, we provide a detailed account of the measurement of the four types of CCR rates. All rates were obtained from at least two different pulse sequences, of which the yet unpublished ones are presented. Detailed comparisons between the different methods and corrections for unwanted pathways demonstrate that the averaged CCR rates are highly accurate and precise with errors of 1.5–3% of the entire value ranges.

  10. Direct observation of hierarchical protein dynamics

    Science.gov (United States)

    Lewandowski, Józef R.; Halse, Meghan E.; Blackledge, Martin; Emsley, Lyndon

    2015-05-01

    One of the fundamental challenges of physical biology is to understand the relationship between protein dynamics and function. At physiological temperatures, functional motions arise from the complex interplay of thermal motions of proteins and their environments. Here, we determine the hierarchy in the protein conformational energy landscape that underlies these motions, based on a series of temperature-dependent magic-angle spinning multinuclear nuclear-magnetic-resonance relaxation measurements in a hydrated nanocrystalline protein. The results support strong coupling between protein and solvent dynamics above 160 kelvin, with fast solvent motions, slow protein side-chain motions, and fast protein backbone motions being activated consecutively. Low activation energy, small-amplitude local motions dominate at low temperatures, with larger-amplitude, anisotropic, and functionally relevant motions involving entire peptide units becoming dominant at temperatures above 220 kelvin.

  11. Distance-Based Configurational Entropy of Proteins from Molecular Dynamics Simulations.

    Science.gov (United States)

    Fogolari, Federico; Corazza, Alessandra; Fortuna, Sara; Soler, Miguel Angel; VanSchouwen, Bryan; Brancolini, Giorgia; Corni, Stefano; Melacini, Giuseppe; Esposito, Gennaro

    2015-01-01

    Estimation of configurational entropy from molecular dynamics trajectories is a difficult task which is often performed using quasi-harmonic or histogram analysis. An entirely different approach, proposed recently, estimates local density distribution around each conformational sample by measuring the distance from its nearest neighbors. In this work we show this theoretically well grounded the method can be easily applied to estimate the entropy from conformational sampling. We consider a set of systems that are representative of important biomolecular processes. In particular: reference entropies for amino acids in unfolded proteins are obtained from a database of residues not participating in secondary structure elements;the conformational entropy of folding of β2-microglobulin is computed from molecular dynamics simulations using reference entropies for the unfolded state;backbone conformational entropy is computed from molecular dynamics simulations of four different states of the EPAC protein and compared with order parameters (often used as a measure of entropy);the conformational and rototranslational entropy of binding is computed from simulations of 20 tripeptides bound to the peptide binding protein OppA and of β2-microglobulin bound to a citrate coated gold surface. This work shows the potential of the method in the most representative biological processes involving proteins, and provides a valuable alternative, principally in the shown cases, where other approaches are problematic.

  12. Jumping Dynamics

    DEFF Research Database (Denmark)

    Sannino, Francesco

    2013-01-01

    We propose an alternative paradigm to the conjectured Miransky scaling potentially underlying the physics describing the transition from the conformally broken to the conformally restored phase when tuning certain parameters such as the number of flavors in gauge theories. According to the new pa...... without particle interpretation. The jumping scenario, therefore, does not support a near-conformal dynamics of walking type. We will also discuss the impact of jumping dynamics on the construction of models of dynamical electroweak symmetry breaking....

  13. First-line HIV treatment: evaluation of backbone choice and its budget impact

    Directory of Open Access Journals (Sweden)

    Orietta Zaniolo

    2013-06-01

    Full Text Available OBJECTIVE: The gradual increase of persons living with HIV, mainly due to the reduced mortality achieved with effective antiretroviral therapies, calls for increased rationality and awareness in health resources consumption also during the early illness phases. Aim of this work is the estimation of the budget impact related to the variation in backbone prescribing trends in naïve patients.METHODS: Target population is the number of patients starting antiretroviral therapy each year, according to the Italian HIV surveillance registry, excluding patients receiving non-authorized or non-recommended regimens. We modeled 3-year mortality and durability rates on a dynamic cohort, basing on international literature. A prevalent patients analysis has also been conducted, for which the model is fed by a closed cohort consisting of all the patients without experience of virologic failure. The aim of this collateral analysis is to estimate the difference in current annual expenditures if the past prescription trends for patients starting therapy would have led to the evaluated hypothetical scenarios. Current Italian market shares of triple regimens containing first-choice or alternative backbones (tenofovir/emtricitabine, abacavir/lamivudine, tenofovir/lamivudine and zidovudine/lamivudine are compared to three hypothetical scenarios (base-case, minimum and maximum in which increasing shares of patients eligible to abacavir/lamivudine start first line treatment with this backbone. Annual cost for each regimen comprises drugs acquisition under hospital pricing rules, monitoring exams and preventive tests, valued basing on regional reimbursement tariffs.RESULTS: According to current prescribing trends, in the next three years about 13,000 patients starting HIV therapy will receive tenofovir/emtricitabine (83% of the target population, and minor portions other regimens (9% abacavir/lamivudine, 8% zidovudine/lamivudine. Patients that would be eligible to

  14. Conformation Change, Tension Propagation and Drift-Diffusion Properties of Polyelectrolyte in Nanopore Translocation

    Directory of Open Access Journals (Sweden)

    Pai-Yi Hsiao

    2016-10-01

    Full Text Available Using Langevin dynamics simulations, conformational, mechanical and dynamical properties of charged polymers threading through a nanopore are investigated. The shape descriptors display different variation behaviors for the cis- and trans-side sub-chains, which reflects a strong cis-trans dynamical asymmetry, especially when the driving field is strong. The calculation of bond stretching shows how the bond tension propagates on the chain backbone, and the chain section straightened by the tension force is determined by the ratio of the direct to the contour distances of the monomer to the pore. With the study of the waiting time function, the threading process is divided into the tension-propagation stage and the tail-retraction stage. At the end, the drift velocity, diffusive property and probability density distribution are explored. Owing to the non-equilibrium nature, translocation is not a simple drift-diffusion process, but exhibits several intermediate behaviors, such as ballistic motion, normal diffusion and super diffusion, before ending with the last, negative-diffusion behavior.

  15. Conformal Einstein spaces

    International Nuclear Information System (INIS)

    Kozameh, C.N.; Newman, E.T.; Tod, K.P.

    1985-01-01

    Conformal transformations in four-dimensional. In particular, a new set of two necessary and sufficient conditions for a space to be conformal to an Einstein space is presented. The first condition defines the class of spaces conformal to C spaces, whereas the last one (the vanishing of the Bach tensor) gives the particular subclass of C spaces which are conformally related to Einstein spaces. (author)

  16. Viscous conformal gauge theories

    DEFF Research Database (Denmark)

    Toniato, Arianna; Sannino, Francesco; Rischke, Dirk H.

    2017-01-01

    We present the conformal behavior of the shear viscosity-to-entropy density ratio and the fermion-number diffusion coefficient within the perturbative regime of the conformal window for gauge-fermion theories.......We present the conformal behavior of the shear viscosity-to-entropy density ratio and the fermion-number diffusion coefficient within the perturbative regime of the conformal window for gauge-fermion theories....

  17. On contribution of known atomic partial charges of protein backbone in electrostatic potential density maps.

    Science.gov (United States)

    Wang, Jimin

    2017-06-01

    Partial charges of atoms in a molecule and electrostatic potential (ESP) density for that molecule are known to bear a strong correlation. In order to generate a set of point-field force field parameters for molecular dynamics, Kollman and coworkers have extracted atomic partial charges for each of all 20 amino acids using restrained partial charge-fitting procedures from theoretical ESP density obtained from condensed-state quantum mechanics. The magnitude of atomic partial charges for neutral peptide backbone they have obtained is similar to that of partial atomic charges for ionized carboxylate side chain atoms. In this study, the effect of these known atomic partial charges on ESP is examined using computer simulations and compared with the experimental ESP density recently obtained for proteins using electron microscopy. It is found that the observed ESP density maps are most consistent with the simulations that include atomic partial charges of protein backbone. Therefore, atomic partial charges are integral part of atomic properties in protein molecules and should be included in model refinement. © 2017 The Protein Society.

  18. A computational study of radical initiated protein backbone homolytic dissociation on all natural amino acids.

    Science.gov (United States)

    Uranga, Jon; Lakuntza, Oier; Ramos-Cordoba, Eloy; Matxain, Jon M; Mujika, Jon I

    2016-11-16

    Hydroxyl radical (˙OH) is known to be one of the most reactive species. In this work, the hydrogen abstraction by ˙OH from C α and C β atoms of all amino acids is studied in the framework of density functional theory as this is the most favorable reaction mechanism when this kind of radical attacks a protein. From the myriad routes that the oxidation of a protein by a ˙OH radical may follow, fragmentation of the protein is one of the most damaging ones as it hampers the normal function of the protein. Therefore, cleavages of the C α -C and C α -N backbone bonds have been investigated as the second step of the mechanism. To the best of our knowledge, this is the first time that this reaction pathway has been systematically studied for all natural amino acids. The study includes the effects that the solvent dielectrics or the conformation of the peptide model employed has on the reaction. Interestingly, the results indicate that the nature of the side chain has little effect on the H abstraction reaction, and that for most of amino acids the attack at the C α atom is favored over the attack at the C β atom. The origin of this preference relies on the larger capability of the formed radical intermediate to delocalize the unpaired electron, thus maximizing the captodative effect. Moreover, the reaction is more favorable when the reactant presents a β-sheet conformation, with a completely planar peptide backbone. With respect to the homolytic splitting of the C α -C and C α -N bonds, the former is favorable for almost all amino acids, whereas Ser and Thr are the only amino acids favoring the latter. These results agree with previous investigations but an accurate description of the electronic density analysis performed indicates that the origin of the different reaction pathway preferences relies on a large stabilization of the product rather than bond weakening at the radical intermediate.

  19. Superspace conformal field theory

    International Nuclear Information System (INIS)

    Quella, Thomas

    2013-07-01

    Conformal sigma models and WZW models on coset superspaces provide important examples of logarithmic conformal field theories. They possess many applications to problems in string and condensed matter theory. We review recent results and developments, including the general construction of WZW models on type I supergroups, the classification of conformal sigma models and their embedding into string theory.

  20. Superspace conformal field theory

    Energy Technology Data Exchange (ETDEWEB)

    Quella, Thomas [Koeln Univ. (Germany). Inst. fuer Theoretische Physik; Schomerus, Volker [Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany)

    2013-07-15

    Conformal sigma models and WZW models on coset superspaces provide important examples of logarithmic conformal field theories. They possess many applications to problems in string and condensed matter theory. We review recent results and developments, including the general construction of WZW models on type I supergroups, the classification of conformal sigma models and their embedding into string theory.

  1. The introduction of hydrogen bond and hydrophobicity effects into the rotational isomeric states model for conformational analysis of unfolded peptides

    International Nuclear Information System (INIS)

    Engin, Ozge; Sayar, Mehmet; Erman, Burak

    2009-01-01

    Relative contributions of local and non-local interactions to the unfolded conformations of peptides are examined by using the rotational isomeric states model which is a Markov model based on pairwise interactions of torsion angles. The isomeric states of a residue are well described by the Ramachandran map of backbone torsion angles. The statistical weight matrices for the states are determined by molecular dynamics simulations applied to monopeptides and dipeptides. Conformational properties of tripeptides formed from combinations of alanine, valine, tyrosine and tryptophan are investigated based on the Markov model. Comparison with molecular dynamics simulation results on these tripeptides identifies the sequence-distant long-range interactions that are missing in the Markov model. These are essentially the hydrogen bond and hydrophobic interactions that are obtained between the first and the third residue of a tripeptide. A systematic correction is proposed for incorporating these long-range interactions into the rotational isomeric states model. Preliminary results suggest that the Markov assumption can be improved significantly by renormalizing the statistical weight matrices to include the effects of the long-range correlations

  2. Ligand-induced conformational dynamics of the Escherichia coli Na+/H+ antiporter NhaA revealed by hydrogen/deuterium exchange mass spectrometry.

    Science.gov (United States)

    Eisinger, Martin Lorenz; Dörrbaum, Aline Ricarda; Michel, Hartmut; Padan, Etana; Langer, Julian David

    2017-10-31

    Na + /H + antiporters comprise a family of membrane proteins evolutionarily conserved in all kingdoms of life and play an essential role in cellular ion homeostasis. The NhaA crystal structure of Escherichia coli has become the paradigm for this class of secondary active transporters. However, structural data are only available at low pH, where NhaA is inactive. Here, we adapted hydrogen/deuterium-exchange mass spectrometry (HDX-MS) to analyze conformational changes in NhaA upon Li + binding at physiological pH. Our analysis revealed a global conformational change in NhaA with two sets of movements around an immobile binding site. Based on these results, we propose a model for the ion translocation mechanism that explains previously controversial data for this antiporter. Furthermore, these findings contribute to our understanding of related human transporters that have been linked to various diseases. Published under the PNAS license.

  3. Structure of the antimicrobial beta-hairpin peptide protegrin-1 in a DLPC lipid bilayer investigated by molecular dynamics simulation

    DEFF Research Database (Denmark)

    Khandelia, Himanshu; Kaznessis, Yiannis N

    2007-01-01

    -18 to extend perpendicular to the beta-hairpin plane. This bend was driven by a highly persistent hydrogen-bond between the polar peptide side-chain of TYR7 and the unshielded backbone carbonyl oxygen atom of GLY17. The H-bond formation relieves the unfavorable free energy of insertion of polar groups......All atom molecular dynamics simulations of the 18-residue beta-hairpin antimicrobial peptide protegrin-1 (PG-1, RGGRLCYCRRRFCVCVGR-NH(2)) in a fully hydrated dilauroylphosphatidylcholine (DLPC) lipid bilayer have been implemented. The goal of the reported work is to investigate the structure......-550]), and to delineate specific peptide-membrane interactions which are responsible for the peptide's membrane binding properties. A novel, previously unknown, "kick" shaped conformation of the peptide was detected, where a bend at the C-terminal beta-strand of the peptide caused the peptide backbone at residues 16...

  4. High precision NOEs as a probe for low level conformers--a second conformation of strychnine.

    Science.gov (United States)

    Butts, Craig P; Jones, Catharine R; Harvey, Jeremy N

    2011-01-28

    A second conformer of strychnine, with a very low population (2.5%), has been identified experimentally, and confirmed by computation, demonstrating the ability of NOE measurements to discriminate minute contributions to dynamic structure ensembles in solution.

  5. Magic angle spinning NMR reveals sequence-dependent structural plasticity, dynamics, and the spacer peptide 1 conformation in HIV-1 capsid protein assemblies.

    Science.gov (United States)

    Han, Yun; Hou, Guangjin; Suiter, Christopher L; Ahn, Jinwoo; Byeon, In-Ja L; Lipton, Andrew S; Burton, Sarah; Hung, Ivan; Gor'kov, Peter L; Gan, Zhehong; Brey, William; Rice, David; Gronenborn, Angela M; Polenova, Tatyana

    2013-11-27

    A key stage in HIV-1 maturation toward an infectious virion requires sequential proteolytic cleavage of the Gag polyprotein leading to the formation of a conical capsid core that encloses the viral RNA genome and a small complement of proteins. The final step of this process involves severing the SP1 peptide from the CA-SP1 maturation intermediate, which triggers the condensation of the CA protein into the capsid shell. The details of the overall mechanism, including the conformation of the SP1 peptide in CA-SP1, are still under intense debate. In this report, we examine tubular assemblies of CA and the CA-SP1 maturation intermediate using magic angle spinning (MAS) NMR spectroscopy. At magnetic fields of 19.9 T and above, outstanding quality 2D and 3D MAS NMR spectra were obtained for tubular CA and CA-SP1 assemblies, permitting resonance assignments for subsequent detailed structural characterization. Dipolar- and scalar-based correlation experiments unequivocally indicate that SP1 peptide is in a random coil conformation and mobile in the assembled CA-SP1. Analysis of two CA protein sequence variants reveals that, unexpectedly, the conformations of the SP1 tail, the functionally important CypA loop, and the loop preceding helix 8 are modulated by residue variations at distal sites. These findings provide support for the role of SP1 as a trigger of the disassembly of the immature CA capsid for its subsequent de novo reassembly into mature cores and establish the importance of sequence-dependent conformational plasticity in CA assembly.

  6. Conformational Analysis of Indole Alkaloids Corynantheine and Dihydrocorynantheine by Dynamic 1H NMR Spectroscopy and Computational Methods: Steric Effects of Ethyl vs Vinyl Group

    DEFF Research Database (Denmark)

    Stærk, Dan; Norrby, Per-Ola; Jaroszewski, Jerzy W.

    2001-01-01

    ) = 60 +/- 6 kJ/mol and DeltaS(double dagger) = 24 +/- 6 J/mol(.)K, with DeltaG degrees = 1.3 kJ/mol at -45 degreesC. The difference in the exchange rates of the rotamers of corynantheine and dihydrocorynantheine (respectively, 350 s(-1) and 9 s(-1) at 0 degreesC) reflects the difference in the steric......H-1 NMR (400 MHz) spectra of the indole alkaloid dihydrocorynantheine recorded at room temperature show the presence of two conformers near coalescence. Low temperature H-1 NMR allowed characterization of the conformational equilibrium, which involves rotation of the 3-methoxypropenoate side chain....... Line-shape analysis yielded enthalpy of activation DeltaH(double dagger) = 71 +/- 6 kJ/mol, and entropy of activation DeltaS(double dagger) = 33 +/- 6 J/mol(.)K. The major and minor conformation contains the methyl ether group above and below the plane of the ring, respectively, as determined by low...

  7. Conformal Aspects of QCD

    Energy Technology Data Exchange (ETDEWEB)

    Brodsky, S

    2003-11-19

    Theoretical and phenomenological evidence is now accumulating that the QCD coupling becomes constant at small virtuality; i.e., {alpha}{sub s}(Q{sup 2}) develops an infrared fixed point in contradiction to the usual assumption of singular growth in the infrared. For example, the hadronic decays of the {tau} lepton can be used to determine the effective charge {alpha}{sub {tau}}(m{sub {tau}{prime}}{sup 2}) for a hypothetical {tau}-lepton with mass in the range 0 < m{sub {tau}{prime}} < m{sub {tau}}. The {tau} decay data at low mass scales indicates that the effective charge freezes at a value of s = m{sub {tau}{prime}}{sup 2} of order 1 GeV{sup 2} with a magnitude {alpha}{sub {tau}} {approx} 0.9 {+-} 0.1. The near-constant behavior of effective couplings suggests that QCD can be approximated as a conformal theory even at relatively small momentum transfer and why there are no significant running coupling corrections to quark counting rules for exclusive processes. The AdS/CFT correspondence of large N{sub c} supergravity theory in higher-dimensional anti-de Sitter space with supersymmetric QCD in 4-dimensional space-time also has interesting implications for hadron phenomenology in the conformal limit, including an all-orders demonstration of counting rules for exclusive processes and light-front wavefunctions. The utility of light-front quantization and light-front Fock wavefunctions for analyzing nonperturbative QCD and representing the dynamics of QCD bound states is also discussed.

  8. Transition paths of Met-enkephalin from Markov state modeling of a molecular dynamics trajectory.

    Science.gov (United States)

    Banerjee, Rahul; Cukier, Robert I

    2014-03-20

    Conformational states and their interconversion pathways of the zwitterionic form of the pentapeptide Met-enkephalin (MetEnk) are identified. An explicit solvent molecular dynamics (MD) trajectory is used to construct a Markov state model (MSM) based on dihedral space clustering of the trajectory, and transition path theory (TPT) is applied to identify pathways between open and closed conformers. In the MD trajectory, only four of the eight backbone dihedrals exhibit bistable behavior. Defining a conformer as the string XXXX with X = "+" or "-" denoting, respectively, positive or negative values of a given dihedral angle and obtaining the populations of these conformers shows that only four conformers are highly populated, implying a strong correlation among these dihedrals. Clustering in dihedral space to construct the MSM finds the same four bistable dihedral angles. These state populations are very similar to those found directly from the MD trajectory. TPT is used to obtain pathways, parametrized by committor values, in dihedral state space that are followed in transitioning from closed to open states. Pathway costs are estimated by introducing a kinetics-based procedure that orders pathways from least (shortest) to greater cost paths. The least costly pathways in dihedral space are found to only involve the same XXXX set of dihedral angles, and the conformers accessed in the closed to open transition pathways are identified. For these major pathways, a correlation between reaction path progress (committors) and the end-to-end distance is identified. A dihedral space principal component analysis of the MD trajectory shows that the first three modes capture most of the overall fluctuation, and pick out the same four dihedrals having essentially all the weight in those modes. A MSM based on root-mean-square backbone clustering was also carried out, with good agreement found with dihedral clustering for the static information, but with results that differ

  9. Backbone resonance assignments of the PRYSPRY domain of TRIM25.

    Science.gov (United States)

    Kong, Chen; Penumutchu, Srinivasa R; Hung, Kuo-Wei; Huang, Huiying; Lin, Tianwei; Yu, Chin

    2015-10-01

    TRIM25 is a member of the tripartite motif (TRIM) family and has been implicated in the regulation of innate immune signaling via the RIG-I (retinoic acid-inducible gene-I) pathway for antiviral defense. As the essential first step towards the structural and functional characterization of the TRIM25/RIG-I interaction, the backbone resonance of the PRYSPRY domain of TRIM25 is assigned here based on triple-resonance experiments using uniformly [(2)H, (13)C, (15)N]-labeled protein.

  10. DNA minor groove electrostatic potential: influence of sequence-specific transitions of the torsion angle gamma and deoxyribose conformations.

    Science.gov (United States)

    Zhitnikova, M Y; Shestopalova, A V

    2017-11-01

    The structural adjustments of the sugar-phosphate DNA backbone (switching of the γ angle (O5'-C5'-C4'-C3') from canonical to alternative conformations and/or C2'-endo → C3'-endo transition of deoxyribose) lead to the sequence-specific changes in accessible surface area of both polar and non-polar atoms of the grooves and the polar/hydrophobic profile of the latter ones. The distribution of the minor groove electrostatic potential is likely to be changing as a result of such conformational rearrangements in sugar-phosphate DNA backbone. Our analysis of the crystal structures of the short free DNA fragments and calculation of their electrostatic potentials allowed us to determine: (1) the number of classical and alternative γ angle conformations in the free B-DNA; (2) changes in the minor groove electrostatic potential, depending on the conformation of the sugar-phosphate DNA backbone; (3) the effect of the DNA sequence on the minor groove electrostatic potential. We have demonstrated that the structural adjustments of the DNA double helix (the conformations of the sugar-phosphate backbone and the minor groove dimensions) induce changes in the distribution of the minor groove electrostatic potential and are sequence-specific. Therefore, these features of the minor groove sizes and distribution of minor groove electrostatic potential can be used as a signal for recognition of the target DNA sequence by protein in the implementation of the indirect readout mechanism.

  11. Hydrogen/deuterium exchange studies of native rabbit MM-CK dynamics.

    Science.gov (United States)

    Mazon, Hortense; Marcillat, Olivier; Forest, Eric; Vial, Christian

    2004-02-01

    Creatine kinase (CK) isoenzymes catalyse the reversible transfer of a phosphoryl group from ATP onto creatine. This reaction plays a very important role in the regulation of intracellular ATP concentrations in excitable tissues. CK isoenzymes are highly resistant to proteases in native conditions. To appreciate localized backbone dynamics, kinetics of amide hydrogen exchange with deuterium was measured by pulse-labeling the dimeric cytosolic muscle CK isoenzyme. Upon exchange, the protein was digested with pepsin, and the deuterium content of the resulting peptides was determined by liquid chromatography coupled to mass spectrometry (MS). The deuteration kinetics of 47 peptides identified by MS/MS and covering 96% of the CK backbone were analyzed. Four deuteration patterns have been recognized: The less deuterated peptides are located in the saddle-shaped core of CK, whereas most of the highly deuterated peptides are close to the surface and located around the entrance to the active site. Their exchange kinetics are discussed by comparison with the known secondary and tertiary structures of CK with the goal to reveal the conformational dynamics of the protein. Some of the observed dynamic motions may be linked to the conformational changes associated with substrate binding and catalytic mechanism.

  12. Flexibility of backbone fibrils in α-chitin crystals with different degree of acetylation.

    Science.gov (United States)

    Yu, Zechuan; Lau, Denvid

    2017-10-15

    Acetyl groups are backbone outreaches that enhance inter-fibril connection in chitin and chitosan fibril bundle. Removal of acetyl groups affects flexibility of chitosan fibril bundle, thereby affecting mechanical strength of chitosan-based products. Understandings of relationship between degree of acetylation and flexibility of chitin fibril bundle conduce to optimization of synthetic chitin materials. Here, the relationship is examined by performing molecular dynamics simulations. Coiling of chitin and chitosan fibril bundle with different degree of acetylation is observed and flexibility of fibrils is measured. Number and alignment of acetyl groups are found to be important factors determining the flexibility of chitin and chitosan fibril bundle. Structural instability can be caused by incompatible alignment of acetyl groups. Our findings on synthetic chitin-based materials indicate that adding a small amount of acetyl groups to chitosan can significantly enhance the integrity of fibril bundle. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. APSY-NMR for protein backbone assignment in high-throughput structural biology

    Energy Technology Data Exchange (ETDEWEB)

    Dutta, Samit Kumar; Serrano, Pedro; Proudfoot, Andrew; Geralt, Michael [The Scripps Research Institute, Department of Integrative Structural and Computational Biology (United States); Pedrini, Bill [Paul Scherrer Institute (PSI), SwissFEL Project (Switzerland); Herrmann, Torsten [Université de Lyon, Institut des Sciences Analytiques, Centre de RMN à Très Hauts Champs, UMR 5280 CNRS, ENS Lyon, UCB Lyon 1 (France); Wüthrich, Kurt, E-mail: wuthrich@scripps.edu [The Scripps Research Institute, Department of Integrative Structural and Computational Biology (United States)

    2015-01-15

    A standard set of three APSY-NMR experiments has been used in daily practice to obtain polypeptide backbone NMR assignments in globular proteins with sizes up to about 150 residues, which had been identified as targets for structure determination by the Joint Center for Structural Genomics (JCSG) under the auspices of the Protein Structure Initiative (PSI). In a representative sample of 30 proteins, initial fully automated data analysis with the software UNIO-MATCH-2014 yielded complete or partial assignments for over 90 % of the residues. For most proteins the APSY data acquisition was completed in less than 30 h. The results of the automated procedure provided a basis for efficient interactive validation and extension to near-completion of the assignments by reference to the same 3D heteronuclear-resolved [{sup 1}H,{sup 1}H]-NOESY spectra that were subsequently used for the collection of conformational constraints. High-quality structures were obtained for all 30 proteins, using the J-UNIO protocol, which includes extensive automation of NMR structure determination.

  14. Constructing Battery-Aware Virtual Backbones in Wireless Sensor Networks

    Directory of Open Access Journals (Sweden)

    Chi Ma

    2007-05-01

    Full Text Available A critical issue in battery-powered sensor networks is to construct energy efficient virtual backbones for network routing. Recent study in battery technology reveals that batteries tend to discharge more power than needed and reimburse the over-discharged power if they are recovered. In this paper we first provide a mathematical battery model suitable for implementation in sensor networks. We then introduce the concept of battery-aware connected dominating set (BACDS and show that in general the minimum BACDS (MBACDS can achieve longer lifetime than the previous backbone structures. Then we show that finding a MBACDS is NP-hard and give a distributed approximation algorithm to construct the BACDS. The resulting BACDS constructed by our algorithm is at most (8+Δopt size, where Δ is the maximum node degree and opt is the size of an optimal BACDS. Simulation results show that the BACDS can save a significant amount of energy and achieve up to 30% longer network lifetime than previous schemes.

  15. Conformational dynamics of the bovine mitochondrial ADP/ATP carrier isoform 1 revealed by hydrogen/deuterium exchange coupled to mass spectrometry.

    Science.gov (United States)

    Rey, Martial; Man, Petr; Clémençon, Benjamin; Trézéguet, Véronique; Brandolin, Gérard; Forest, Eric; Pelosi, Ludovic

    2010-11-05

    The mitochondrial adenine nucleotide carrier (Ancp) catalyzes the transport of ADP and ATP across the mitochondrial inner membrane, thus playing an essential role in cellular energy metabolism. During the transport mechanism the carrier switches between two different conformations that can be blocked by two toxins: carboxyatractyloside (CATR) and bongkrekic acid. Therefore, our understanding of the nucleotide transport mechanism can be improved by analyzing structural differences of the individual inhibited states. We have solved the three-dimensional structure of bovine carrier isoform 1 (bAnc1p) in a complex with CATR, but the structure of the carrier-bongkrekic acid complex, and thus, the detailed mechanism of transport remains unknown. Improvements in sample processing in the hydrogen/deuterium exchange technique coupled to mass spectrometry (HDX-MS) have allowed us to gain novel insights into the conformational changes undergone by bAnc1p. This paper describes the first study of bAnc1p using HDX-MS. Results obtained with the CATR-bAnc1p complex were fully in agreement with published results, thus, validating our approach. On the other hand, the HDX kinetics of the two complexes displays marked differences. The bongkrekic acid-bAnc1p complex exhibits greater accessibility to the solvent on the matrix side, whereas the CATR-bAnc1p complex is more accessible on the intermembrane side. These results are discussed with respect to the structural and biochemical data available on Ancp.

  16. Backbone structure of Yersinia pestis Ail determined in micelles by NMR-restrained simulated annealing with implicit membrane solvation

    International Nuclear Information System (INIS)

    Marassi, Francesca M.; Ding, Yi; Schwieters, Charles D.; Tian, Ye; Yao, Yong

    2015-01-01

    The outer membrane protein Ail (attachment invasion locus) is a virulence factor of Yersinia pestis that mediates cell invasion, cell attachment and complement resistance. Here we describe its three-dimensional backbone structure determined in decyl-phosphocholine (DePC) micelles by NMR spectroscopy. The NMR structure was calculated using the membrane function of the implicit solvation potential, eefxPot, which we have developed to facilitate NMR structure calculations in a physically realistic environment. We show that the eefxPot force field guides the protein towards its native fold. The resulting structures provide information about the membrane-embedded global position of Ail, and have higher accuracy, higher precision and improved conformational properties, compared to the structures calculated with the standard repulsive potential

  17. Backbone structure of Yersinia pestis Ail determined in micelles by NMR-restrained simulated annealing with implicit membrane solvation.

    Science.gov (United States)

    Marassi, Francesca M; Ding, Yi; Schwieters, Charles D; Tian, Ye; Yao, Yong

    2015-09-01

    The outer membrane protein Ail (attachment invasion locus) is a virulence factor of Yersinia pestis that mediates cell invasion, cell attachment and complement resistance. Here we describe its three-dimensional backbone structure determined in decyl-phosphocholine (DePC) micelles by NMR spectroscopy. The NMR structure was calculated using the membrane function of the implicit solvation potential, eefxPot, which we have developed to facilitate NMR structure calculations in a physically realistic environment. We show that the eefxPot force field guides the protein towards its native fold. The resulting structures provide information about the membrane-embedded global position of Ail, and have higher accuracy, higher precision and improved conformational properties, compared to the structures calculated with the standard repulsive potential.

  18. Imaging of conformational changes

    Energy Technology Data Exchange (ETDEWEB)

    Michl, Josef [Univ. of Colorado, Boulder, CO (United States)

    2016-03-13

    Control of intramolecular conformational change in a small number of molecules or even a single one by an application of an outside electric field defined by potentials on nearby metal or dielectric surfaces has potential applications in both 3-D and 2-D nanotechnology. Specifically, the synthesis, characterization, and understanding of designed solids with controlled built-in internal rotational motion of a dipole promises a new class of materials with intrinsic dielectric, ferroelectric, optical and optoelectronic properties not found in nature. Controlled rotational motion is of great interest due to its expected utility in phenomena as diverse as transport, current flow in molecular junctions, diffusion in microfluidic channels, and rotary motion in molecular machines. A direct time-resolved observation of the dynamics of motion on ps or ns time scale in a single molecule would be highly interesting but is also very difficult and has yet to be accomplished. Much can be learned from an easier but still challenging comparison of directly observed initial and final orientational states of a single molecule, which is the basis of this project. The project also impacts the understanding of surface-enhanced Raman spectroscopy (SERS) and single-molecule spectroscopic detection, as well as the synthesis of solid-state materials with tailored properties from designed precursors.

  19. Evolution of robust network topologies: emergence of central backbones.

    Science.gov (United States)

    Peixoto, Tiago P; Bornholdt, Stefan

    2012-09-14

    We model the robustness against random failure or an intentional attack of networks with an arbitrary large-scale structure. We construct a block-based model which incorporates--in a general fashion--both connectivity and interdependence links, as well as arbitrary degree distributions and block correlations. By optimizing the percolation properties of this general class of networks, we identify a simple core-periphery structure as the topology most robust against random failure. In such networks, a distinct and small "core" of nodes with higher degree is responsible for most of the connectivity, functioning as a central "backbone" of the system. This centralized topology remains the optimal structure when other constraints are imposed, such as a given fraction of interdependence links and fixed degree distributions. This distinguishes simple centralized topologies as the most likely to emerge, when robustness against failure is the dominant evolutionary force.

  20. Transforming plastic surfaces with electrophilic backbones from hydrophobic to hydrophilic.

    Science.gov (United States)

    Kim, Samuel; Bowen, Raffick A R; Zare, Richard N

    2015-01-28

    We demonstrate a simple nonaqueous reaction scheme for transforming the surface of plastics from hydrophobic to hydrophilic. The chemical modification is achieved by base-catalyzed trans-esterification with polyols. It is permanent, does not release contaminants, and causes no optical or mechanical distortion of the plastic. We present contact angle measurements to show successful modification of several types of plastics including poly(ethylene terephthalate) (PET) and polycarbonate (PC). Its applicability to blood analysis is explored using chemically modified PET blood collection tubes and found to be quite satisfactory. We expect this approach will reduce the cost of manufacturing plastic devices with optimized wettability and can be generalized to other types of plastic materials having an electrophilic linkage as its backbone.

  1. Backbones of evolutionary history test biodiversity theory for microbes.

    Science.gov (United States)

    O'Dwyer, James P; Kembel, Steven W; Sharpton, Thomas J

    2015-07-07

    Identifying the ecological and evolutionary mechanisms that determine biological diversity is a central question in ecology. In microbial ecology, phylogenetic diversity is an increasingly common and relevant means of quantifying community diversity, particularly given the challenges in defining unambiguous species units from environmental sequence data. We explore patterns of phylogenetic diversity across multiple bacterial communities drawn from different habitats and compare these data to evolutionary trees generated using theoretical models of biodiversity. We have two central findings. First, although on finer scales the empirical trees are highly idiosyncratic, on coarse scales the backbone of these trees is simple and robust, consistent across habitats, and displays bursts of diversification dotted throughout. Second, we find that these data demonstrate a clear departure from the predictions of standard neutral theories of biodiversity and that an alternative family of generalized models provides a qualitatively better description. Together, these results lay the groundwork for a theoretical framework to connect ecological mechanisms to observed phylogenetic patterns in microbial communities.

  2. Intraresidue HNCA and COHNCA Experiments for Protein Backbone Resonance Assignment

    Science.gov (United States)

    Brutscher, Bernhard

    2002-05-01

    Two novel experiments, intra-HNCA and intra-COHNCA, are presented for sequential backbone resonance assignment of 13C, 15N labeled proteins. The advantage with respect to conventional pulse schemes is the suppression of the sequential 15N→13Cα coherence transfer pathway, which can be separately obtained from a HNCOCA correlation experiment. This results in a two-fold reduction of the number of detected correlation peaks. Spectral simplification is especially important for efficient automated assignment protocols as required in the context of high-throughput protein studies by NMR. The performance of the new experiments is demonstrated on an 18-kDa protein fragment of the E. coli sulfite reductase and compared to conventional techniques in terms of sensitivity and resolution.

  3. Conformational Dynamics in Penicillin-Binding Protein 2a of Methicillin-Resistant Staphylococcus aureus, Allosteric Communication Network and Enablement of Catalysis.

    Science.gov (United States)

    Mahasenan, Kiran V; Molina, Rafael; Bouley, Renee; Batuecas, María T; Fisher, Jed F; Hermoso, Juan A; Chang, Mayland; Mobashery, Shahriar

    2017-02-08

    The mechanism of the β-lactam antibacterials is the functionally irreversible acylation of the enzymes that catalyze the cross-linking steps in the biosynthesis of their peptidoglycan cell wall. The Gram-positive pathogen Staphylococcus aureus uses one primary resistance mechanism. An enzyme, called penicillin-binding protein 2a (PBP2a), is brought into this biosynthetic pathway to complete the cross-linking. PBP2a effectively discriminates against the β-lactam antibiotics as potential inhibitors, and in favor of the peptidoglycan substrate. The basis for this discrimination is an allosteric site, distal from the active site, that when properly occupied concomitantly opens the gatekeeper residues within the active site and realigns the conformation of key residues to permit catalysis. We address the molecular basis of this regulation using crystallographic studies augmented by computational analyses. The crystal structures of three β-lactams (oxacillin, cefepime, ceftazidime) complexes with PBP2a-each with the β-lactam in the allosteric site-defined (with preceding PBP2a structures) as the "open" or "partially open" PBP2a states. A particular loop motion adjacent to the active site is identified as the driving force for the active-site conformational change that accompanies active-site opening. Correlation of this loop motion to effector binding at the allosteric site, in order to identify the signaling pathway, was accomplished computationally in reference to the known "closed" apo-PBP2a X-ray crystal structure state. This correlation enabled the computational simulation of the structures coinciding with initial peptidoglycan substrate binding to PBP2a, acyl enzyme formation, and acyl transfer to a second peptidoglycan substrate to attain cross-linking. These studies offer important insights into the structural bases for allosteric site-to-active site communication and for β-lactam mimicry of the peptidoglycan substrates, as foundational to the mechanistic

  4. Design of an IPTV Multicast System for Internet Backbone Networks

    Directory of Open Access Journals (Sweden)

    T. H. Szymanski

    2010-01-01

    Full Text Available The design of an IPTV multicast system for the Internet backbone network is presented and explored through extensive simulations. In the proposed system, a resource reservation algorithm such as RSVP, IntServ, or DiffServ is used to reserve resources (i.e., bandwidth and buffer space in each router in an IP multicast tree. Each router uses an Input-Queued, Output-Queued, or Crosspoint-Queued switch architecture with unity speedup. A recently proposed Recursive Fair Stochastic Matrix Decomposition algorithm used to compute near-perfect transmission schedules for each IP router. The IPTV traffic is shaped at the sources using Application-Specific Token Bucker Traffic Shapers, to limit the burstiness of incoming network traffic. The IPTV traffic is shaped at the destinations using Application-Specific Playback Queues, to remove residual network jitter and reconstruct the original bursty IPTV video streams at each destination. All IPTV traffic flows are regenerated at the destinations with essentially zero delay jitter and essentially-perfect QoS. The destination nodes deliver the IPTV streams to the ultimate end users using the same IPTV multicast system over a regional Metropolitan Area Network. It is shown that all IPTV traffic is delivered with essentially-perfect end-to-end QoS, with deterministic bounds on the maximum delay and jitter on each video frame. Detailed simulations of an IPTV distribution system, multicasting several hundred high-definition IPTV video streams over several essentially saturated IP backbone networks are presented.

  5. Conformational stability of calreticulin

    DEFF Research Database (Denmark)

    Jørgensen, C.S.; Trandum, C.; Larsen, N.

    2005-01-01

    The conformational stability of calreticulin was investigated. Apparent unfolding temperatures (T-m) increased from 31 degrees C at pH 5 to 51 degrees C at pH 9, but electrophoretic analysis revealed that calreticulin oligomerized instead of unfolding. Structural analyses showed that the single C......-terminal a-helix was of major importance to the conformational stability of calreticulin....

  6. Conformational stability of calreticulin

    DEFF Research Database (Denmark)

    Jørgensen, Charlotte S; Trandum, Christa; Larsen, Nanna Brink

    2005-01-01

    The conformational stability of calreticulin was investigated. Apparent unfolding temperatures (Tm) increased from 31 degrees C at pH 5 to 51 degrees C at pH 9, but electrophoretic analysis revealed that calreticulin oligomerized instead of unfolding. Structural analyses showed that the single C......-terminal alpha-helix was of major importance to the conformational stability of calreticulin....

  7. Backbone-hydrazone-containing biodegradable copolymeric micelles for anticancer drug delivery

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Jing; Luan, Shujuan; Qin, Benkai; Wang, Yingying; Wang, Kai; Qi, Peilan; Song, Shiyong, E-mail: pharmsong@henu.edu.cn [Henan University, Institute of Pharmacy (China)

    2016-11-15

    Well-defined biodegradable, pH-sensitive amphiphilic block polymers, poly(ethylene glycol)-Hyd-poly(lactic acid) (mPEG-Hyd-PLA) which have acid-cleavable linkages in their backbones, were synthesized via ring-opening polymerization initiated from hydrazone-containing macroinitiators. Introducing a hydrazone bond onto the backbone of an amphiphilic copolymer will find a broad-spectrum encapsulation of hydrophobic drugs. Dynamic light scattering (DLS) and transmission electron microscopy showed that the diblock copolymers self-assembled into stable micelles with average diameters of 100 nm. The mean diameters and size distribution of the hydrazone-containing micelles changed obviously in mildly acidic pH (multiple peaks from 1 to 202 nm appeared under a pH 4.0 condition) than in neutral, while there were no changes in the case of non-sensitive ones. Doxorubicin (DOX) and paclitaxel (PTX) were loaded with drug loading content ranging from 2.4 to 3.5 %, respectively. Interestingly, the anticancer drugs released from mPEG-Hyd-PLA micelles could also be promoted by the increased acidity. An in vitro cytotoxicity study showed that the DOX-loaded mPEG-Hyd-PLA micelles have significantly enhanced cytotoxicity against HepG2 cells compared with the non-sensitive poly(ethylene glycol)-block-poly(lactic acid) (mPEG-PLA) micelles. Confocal microscopy observation indicated that more DOX were delivered into the nuclei of cells following 6 or 12 h incubation with DOX-loaded mPEG-Hyd-PLA micelles. In vivo studies on H22-bearing Swiss mice demonstrated the superior anticancer activity of DOX-loaded mPEG-Hyd-PLA micelles over free DOX and DOX-loaded mPEG-PLA micelles. These hydrazone-containing pH-responsive degradable micelles provide a useful strategy for antitumor drug delivery.

  8. Conformal invariance in supergravity

    International Nuclear Information System (INIS)

    Bergshoeff, E.A.

    1983-01-01

    In this thesis the author explains the role of conformal invariance in supergravity. He presents the complete structure of extended conformal supergravity for N <= 4. The outline of this work is as follows. In chapter 2 he briefly summarizes the essential properties of supersymmetry and supergravity and indicates the use of conformal invariance in supergravity. The idea that the introduction of additional symmetry transformations can make clear the structure of a field theory is not reserved to supergravity only. By means of some simple examples it is shown in chapter 3 how one can always introduce additional gauge transformations in a theory of massive vector fields. Moreover it is shown how the gauge invariant formulation sometimes explains the quantum mechanical properties of the theory. In chapter 4 the author defines the conformal transformations and summarizes their main properties. He explains how these conformal transformations can be used to analyse the structure of gravity. The supersymmetric extension of these results is discussed in chapter 5. Here he describes as an example how N=1 supergravity can be reformulated in a conformally-invariant way. He also shows that beyond N=1 the gauge fields of the superconformal symmetries do not constitute an off-shell field representation of extended conformal supergravity. Therefore, in chapter 6, a systematic method to construct the off-shell formulation of all extended conformal supergravity theories with N <= 4 is developed. As an example he uses this method to construct N=1 conformal supergravity. Finally, in chapter 7 N=4 conformal supergravity is discussed. (Auth.)

  9. A Multidomain Flexible Docking Approach to Deal with Large Conformational Changes in the Modeling of Biomolecular Complexes

    NARCIS (Netherlands)

    Karaca, E.|info:eu-repo/dai/nl/315554789; Bonvin, A.M.J.J.|info:eu-repo/dai/nl/113691238

    2011-01-01

    Binding-induced backbone and large-scale conformational changes represent one of the major challenges in the modeling of biomolecular complexes by docking. To address this challenge, we have developed a flexible multidomain docking protocol that follows a “divide-and-conquer” approach to model both

  10. Social conformity despite individual preferences for distinctiveness.

    Science.gov (United States)

    Smaldino, Paul E; Epstein, Joshua M

    2015-03-01

    We demonstrate that individual behaviours directed at the attainment of distinctiveness can in fact produce complete social conformity. We thus offer an unexpected generative mechanism for this central social phenomenon. Specifically, we establish that agents who have fixed needs to be distinct and adapt their positions to achieve distinctiveness goals, can nevertheless self-organize to a limiting state of absolute conformity. This seemingly paradoxical result is deduced formally from a small number of natural assumptions and is then explored at length computationally. Interesting departures from this conformity equilibrium are also possible, including divergence in positions. The effect of extremist minorities on these dynamics is discussed. A simple extension is then introduced, which allows the model to generate and maintain social diversity, including multimodal distinctiveness distributions. The paper contributes formal definitions, analytical deductions and counterintuitive findings to the literature on individual distinctiveness and social conformity.

  11. Conformal expansions and renormalons

    Energy Technology Data Exchange (ETDEWEB)

    Rathsman, J.

    2000-02-07

    The coefficients in perturbative expansions in gauge theories are factorially increasing, predominantly due to renormalons. This type of factorial increase is not expected in conformal theories. In QCD conformal relations between observables can be defined in the presence of a perturbative infrared fixed-point. Using the Banks-Zaks expansion the authors study the effect of the large-order behavior of the perturbative series on the conformal coefficients. The authors find that in general these coefficients become factorially increasing. However, when the factorial behavior genuinely originates in a renormalon integral, as implied by a postulated skeleton expansion, it does not affect the conformal coefficients. As a consequence, the conformal coefficients will indeed be free of renormalon divergence, in accordance with previous observations concerning the smallness of these coefficients for specific observables. The authors further show that the correspondence of the BLM method with the skeleton expansion implies a unique scale-setting procedure. The BLM coefficients can be interpreted as the conformal coefficients in the series relating the fixed-point value of the observable with that of the skeleton effective charge. Through the skeleton expansion the relevance of renormalon-free conformal coefficients extends to real-world QCD.

  12. Conformational transitions of a weak polyampholyte

    KAUST Repository

    Nair, Arun Kumar Narayanan

    2014-10-07

    Using grand canonical Monte Carlo simulations of a flexible polyelectrolyte where the charges are in contact with a reservoir of constant chemical potential given by the solution pH, we study the behavior of weak polyelectrolytes in poor and good solvent conditions for polymer backbone. We address the titration behavior and conformational properties of a flexible diblock polyampholyte chain formed of two oppositely charged weak polyelectrolyte blocks, each containing equal number of identical monomers. The change of solution pH induces charge asymmetry in a diblock polyampholyte. For diblock polyampholyte chains in poor solvents, we demonstrate that a discontinuous transition between extended (tadpole) and collapsed (globular) conformational states is attainable by varying the solution pH. The double-minima structure in the probability distribution of the free energy provides direct evidence for the first-order like nature of this transition. At the isoelectric point electrostatically driven coil-globule transition of diblock polyampholytes in good solvents is found to consist of different regimes identified with increasing electrostatic interaction strength. At pH values above or below the isoelectric point diblock chains are found to have polyelectrolyte-like behavior due to repulsion between uncompensated charges along the chain.

  13. A systematic molecular dynamics study of nearest-neighbor effects on base pair and base pair step conformations and fluctuations in B-DNA

    Czech Academy of Sciences Publication Activity Database

    Lavery, R.; Zakrzewska, K.; Beveridge, D.; Bishop, T. C.; Case, D. A.; Cheatham III, T. E.; Dixit, S.; Jayaram, B.; Lankaš, Filip; Laughton, Ch.; Maddocks, J. H.; Michon, A.; Osman, R.; Orozco, M.; Pérez, A.; Singh, T.; Špačková, Naďa; Šponer, Jiří

    2010-01-01

    Roč. 38, č. 1 (2010), s. 299-313 ISSN 0305-1048 R&D Projects: GA MŠk(CZ) LC06030; GA AV ČR(CZ) IAA400040802; GA ČR GA203/09/1476; GA MŠk LC512 Institutional research plan: CEZ:AV0Z40550506; CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : B-DNA * molecular dynamics * sequence dependet structure and dynamics Subject RIV: CF - Physical ; Theoretical Chemistry Impact factor: 7.836, year: 2010

  14. Conformal Lorentz geometry revisited

    Science.gov (United States)

    Teleman, Kostake

    1996-02-01

    . We also show that Mach's principle on inertial motions receives an explanation in our theory by considering the particular geodesic paths, for which one of the partners of an interacting pair is fixed and sent to infinity. In fact we study a dynamical system (W,L) which presents some formal and topological similarities with a system of two particles interacting gravitationally. (W,L) is the only conformally invariant relativistic two-point dynamical system. At the end we show that W can be naturally regarded as the base of a principal GL(2,C)-bundle which comes with a natural connection. We study this bundle from differential geometric point of view. Physical interpretations will be discussed in a future paper. This text is an improvement of a previous version, which was submitted under the title ``Hypertwistor Geometry.'' [See, K. Teleman, ``Hypertwistor Geometry (abstract),'' 14th International Conference on General Relativity and Gravitation, Florence, Italy, 1995.] The change of the title and many other improvements are due to the valuable comments of the referee, who also suggested the author to avoid hazardous interpretations.

  15. Electron Transfer Dissociation of Photolabeled Peptides. Backbone Cleavages Compete with Diazirine Ring Rearrangements

    Science.gov (United States)

    Marek, Aleš; Pepin, Robert; Peng, Bo; Laszlo, Kenneth J.; Bush, Matthew F.; Tureček, František

    2013-11-01

    Gas-phase conformations and electron transfer dissociations of pentapeptide ions containing the photo-Leu residue (L*) were studied. Exhaustive conformational search including molecular dynamics force-field, semi-empirical, ab initio, and density functional theory calculations established that the photo-Leu residue did not alter the gas-phase conformations of (GL*GGK + 2H)2+ and (GL*GGK-NH2 + H)+ ions, which showed the same conformer energy ranking as the unmodified Leu-containing ions. This finding is significant in that it simplifies conformational analysis of photo-labeled peptide ions. Electron transfer dissociation mass spectra of (GL*GGK + 2H)2+, (GL*GGK-NH2 + 2H)2+,(GL*GGKK + 2H)2+, (GL*GLK + 2H)2+, and (GL*LGK + 2H)2+ showed 16 %-21 % fragment ions originating by radical rearrangements and cleavages in the diazirine ring. These side-chain dissociations resulted in eliminations of N2H3, N2H4, [N2H5], and [NH4O] neutral fragments and were particularly abundant in long-lived charge-reduced cation-radicals. Deuterium labeling established that the neutral hydrazine molecules mainly contained two exchangeable and two nonexchangeable hydrogen atoms from the peptide and underwent further H/D exchange in an ion-molecule complex. Electron structure calculations on the charge-reduced ions indicated that the unpaired electron was delocalized between the diazirine and amide π* electronic systems in the low electronic states of the cation-radicals. The diazirine moiety in GL*GGK-NH2was calculated to have an intrinsic electron affinity of 1.5 eV, which was further increased by the Coulomb effect of the peptide positive charge. Mechanisms are proposed for the unusual elimination of hydrazine from the photo-labeled peptide ions.

  16. Analysis of a systematic search-based algorithm for determining protein backbone structure from a minimum number of residual dipolar couplings.

    Science.gov (United States)

    Wang, Lincong; Donald, Bruce Randall

    2004-01-01

    We have developed an ab initio algorithm for determining a protein backbone structure using global orientational restraints on internuclear vectors derived from residual dipolar couplings (RDCs) measured in one or two different aligning media by solution nuclear magnetic resonance (NMR) spectroscopy [14, 15]. Specifically, the conformation and global orientations of individual secondary structure elements are computed, independently, by an exact solution, systematic search-based minimization algorithm using only 2 RDCs per residue. The systematic search is built upon a quartic equation for computing, exactly and in constant time, the directions of an internuclear vector from RDCs, and linear or quadratic equations for computing the sines and cosines of backbone dihedral (phi, psi) angles from two vectors in consecutive peptide planes. In contrast to heuristic search such as simulated annealing (SA) or Monte-Carlo (MC) used by other NMR structure determination algorithms, our minimization algorithm can be analyzed rigorously in terms of expected algorithmic complexity and the coordinate precision of the protein structure as a function of error in the input data. The algorithm has been successfully applied to compute the backbone structures of three proteins using real NMR data.

  17. Bioactive focus in conformational ensembles: a pluralistic approach

    Science.gov (United States)

    Habgood, Matthew

    2017-12-01

    Computational generation of conformational ensembles is key to contemporary drug design. Selecting the members of the ensemble that will approximate the conformation most likely to bind to a desired target (the bioactive conformation) is difficult, given that the potential energy usually used to generate and rank the ensemble is a notoriously poor discriminator between bioactive and non-bioactive conformations. In this study an approach to generating a focused ensemble is proposed in which each conformation is assigned multiple rankings based not just on potential energy but also on solvation energy, hydrophobic or hydrophilic interaction energy, radius of gyration, and on a statistical potential derived from Cambridge Structural Database data. The best ranked structures derived from each system are then assembled into a new ensemble that is shown to be better focused on bioactive conformations. This pluralistic approach is tested on ensembles generated by the Molecular Operating Environment's Low Mode Molecular Dynamics module, and by the Cambridge Crystallographic Data Centre's conformation generator software.

  18. Effect of the aminoacid composition of model α-helical peptides on the physical properties of lipid bilayers and peptide conformation: a molecular dynamics simulation

    Czech Academy of Sciences Publication Activity Database

    Melicherčík, Milan; Holúbeková, A.; Hianik, T.; Urban, J.

    2013-01-01

    Roč. 19, č. 11 (2013), s. 4723-4730 ISSN 1610-2940 Institutional support: RVO:67179843 Keywords : Bilayer lipid membranes * Helical peptides * Molecular dynamics simulations * Phase transitions Subject RIV: BO - Biophysics Impact factor: 1.867, year: 2013

  19. Lid opening and conformational stability of T1 Lipase is mediated by increasing chain length polar solvents

    Directory of Open Access Journals (Sweden)

    Jonathan Maiangwa

    2017-05-01

    Full Text Available The dynamics and conformational landscape of proteins in organic solvents are events of potential interest in nonaqueous process catalysis. Conformational changes, folding transitions, and stability often correspond to structural rearrangements that alter contacts between solvent molecules and amino acid residues. However, in nonaqueous enzymology, organic solvents limit stability and further application of proteins. In the present study, molecular dynamics (MD of a thermostable Geobacillus zalihae T1 lipase was performed in different chain length polar organic solvents (methanol, ethanol, propanol, butanol, and pentanol and water mixture systems to a concentration of 50%. On the basis of the MD results, the structural deviations of the backbone atoms elucidated the dynamic effects of water/organic solvent mixtures on the equilibrium state of the protein simulations in decreasing solvent polarity. The results show that the solvent mixture gives rise to deviations in enzyme structure from the native one simulated in water. The drop in the flexibility in H2O, MtOH, EtOH and PrOH simulation mixtures shows that greater motions of residues were influenced in BtOH and PtOH simulation mixtures. Comparing the root mean square fluctuations value with the accessible solvent area (SASA for every residue showed an almost correspondingly high SASA value of residues to high flexibility and low SASA value to low flexibility. The study further revealed that the organic solvents influenced the formation of more hydrogen bonds in MtOH, EtOH and PrOH and thus, it is assumed that increased intraprotein hydrogen bonding is ultimately correlated to the stability of the protein. However, the solvent accessibility analysis showed that in all solvent systems, hydrophobic residues were exposed and polar residues tended to be buried away from the solvent. Distance variation of the tetrahedral intermediate packing of the active pocket was not conserved in organic solvent

  20. Polarizable Force Field for DNA Based on the Classical Drude Oscillator: I. Refinement Using Quantum Mechanical Base Stacking and Conformational Energetics.

    Science.gov (United States)

    Lemkul, Justin A; MacKerell, Alexander D

    2017-05-09

    Empirical force fields seek to relate the configuration of a set of atoms to its energy, thus yielding the forces governing its dynamics, using classical physics rather than more expensive quantum mechanical calculations that are computationally intractable for large systems. Most force fields used to simulate biomolecular systems use fixed atomic partial charges, neglecting the influence of electronic polarization, instead making use of a mean-field approximation that may not be transferable across environments. Recent hardware and software developments make polarizable simulations feasible, and to this end, polarizable force fields represent the next generation of molecular dynamics simulation technology. In this work, we describe the refinement of a polarizable force field for DNA based on the classical Drude oscillator model by targeting quantum mechanical interaction energies and conformational energy profiles of model compounds necessary to build a complete DNA force field. The parametrization strategy employed in the present work seeks to correct weak base stacking in A- and B-DNA and the unwinding of Z-DNA observed in the previous version of the force field, called Drude-2013. Refinement of base nonbonded terms and reparametrization of dihedral terms in the glycosidic linkage, deoxyribofuranose rings, and important backbone torsions resulted in improved agreement with quantum mechanical potential energy surfaces. Notably, we expand on previous efforts by explicitly including Z-DNA conformational energetics in the refinement.

  1. Improvements to robotics-inspired conformational sampling in rosetta.

    Directory of Open Access Journals (Sweden)

    Amelie Stein

    Full Text Available To accurately predict protein conformations in atomic detail, a computational method must be capable of sampling models sufficiently close to the native structure. All-atom sampling is difficult because of the vast number of possible conformations and extremely rugged energy landscapes. Here, we test three sampling strategies to address these difficulties: conformational diversification, intensification of torsion and omega-angle sampling and parameter annealing. We evaluate these strategies in the context of the robotics-based kinematic closure (KIC method for local conformational sampling in Rosetta on an established benchmark set of 45 12-residue protein segments without regular secondary structure. We quantify performance as the fraction of sub-Angstrom models generated. While improvements with individual strategies are only modest, the combination of intensification and annealing strategies into a new "next-generation KIC" method yields a four-fold increase over standard KIC in the median percentage of sub-Angstrom models across the dataset. Such improvements enable progress on more difficult problems, as demonstrated on longer segments, several of which could not be accurately remodeled with previous methods. Given its improved sampling capability, next-generation KIC should allow advances in other applications such as local conformational remodeling of multiple segments simultaneously, flexible backbone sequence design, and development of more accurate energy functions.

  2. A Hub Location Problem with Fully Interconnected Backbone and Access Networks

    DEFF Research Database (Denmark)

    Thomadsen, Tommy; Larsen, Jesper

    2007-01-01

    This paper considers the design of two-layered fully interconnected networks. A two-layered network consists of clusters of nodes, each defining an access network and a backbone network. We consider the integrated problem of determining the access networks and the backbone network simultaneously....

  3. Thin Films Formed from Conjugated Polymers with Ionic, Water-Soluble Backbones

    NARCIS (Netherlands)

    Voortman, Thomas P; Chiechi, Ryan C

    2015-01-01

    This paper compares the morphologies of films of conjugated polymers in which the backbone (main chain) and pendant groups are varied between ionic/hydrophilic and aliphatic/hydrophobic. We observe that conjugated polymers in which the pendant groups and backbone are matched, either ionic-ionic or

  4. Combining Rosetta with molecular dynamics (MD): A benchmark of the MD-based ensemble protein design.

    Science.gov (United States)

    Ludwiczak, Jan; Jarmula, Adam; Dunin-Horkawicz, Stanislaw

    2018-02-14

    Computational protein design is a set of procedures for computing amino acid sequences that will fold into a specified structure. Rosetta Design, a commonly used software for protein design, allows for the effective identification of sequences compatible with a given backbone structure, while molecular dynamics (MD) simulations can thoroughly sample near-native conformations. We benchmarked a procedure in which Rosetta design is started on MD-derived structural ensembles and showed that such a combined approach generates 20-30% more diverse sequences than currently available methods with only a slight increase in computation time. Importantly, the increase in diversity is achieved without a loss in the quality of the designed sequences assessed by their resemblance to natural sequences. We demonstrate that the MD-based procedure is also applicable to de novo design tasks started from backbone structures without any sequence information. In addition, we implemented a protocol that can be used to assess the stability of designed models and to select the best candidates for experimental validation. In sum our results demonstrate that the MD ensemble-based flexible backbone design can be a viable method for protein design, especially for tasks that require a large pool of diverse sequences. Copyright © 2018 Elsevier Inc. All rights reserved.

  5. The amide III vibrational circular dichroism band as a probe to detect conformational preferences of alanine dipeptide in water.

    Science.gov (United States)

    Mirtič, Andreja; Merzel, Franci; Grdadolnik, Jože

    2014-07-01

    The conformational preferences of blocked alanine dipeptide (ADP), Ac-Ala-NHMe, in aqueous solution were studied using vibrational circular dichroism (VCD) together with density functional theory (DFT) calculations. DFT calculations of three most representative conformations of ADP surrounded by six explicit water molecules immersed in a dielectric continuum have proven high sensitivity of amide III VCD band shape that is characteristic for each conformation of the peptide backbone. The polyproline II (PII ) and αR conformation of ADP are associated with a positive VCD band while β conformation has a negative VCD band in amide III region. Knowing this spectral characteristic of each conformation allows us to assign the experimental amide III VCD spectrum of ADP. Moreover, the amide III region of the VCD spectrum was used to determine the relative populations of conformations of ADP in water. Based on the interpretation of the amide III region of VCD spectrum we have shown that dominant conformation of ADP in water is PII which is stabilized by hydrogen bonded water molecules between CO and NH groups on the peptide backbone. Copyright © 2014 Wiley Periodicals, Inc.

  6. Conformally Coupled Inflation

    Directory of Open Access Journals (Sweden)

    Valerio Faraoni

    2013-07-01

    Full Text Available A massive scalar field in a curved spacetime can propagate along the light cone, a causal pathology, which can, in principle, be eliminated only if the scalar couples conformally to the Ricci curvature of spacetime. This property mandates conformal coupling for the field driving inflation in the early universe. During slow-roll inflation, this coupling can cause super-acceleration and, as a signature, a blue spectrum of primordial gravitational waves.

  7. Delineating the conformal window

    DEFF Research Database (Denmark)

    Frandsen, Mads Toudal; Pickup, Thomas; Teper, Michael

    2011-01-01

    We identify and characterise the conformal window in gauge theories relevant for beyond the standard model building, e.g. Technicolour, using the criteria of metric confinement and causal analytic couplings, which are known to be consistent with the phase diagram of supersymmetric QCD from Seiberg...... duality. Using these criteria we find perturbation theory to be consistent throughout the predicted conformal window for several of these gauge theories and we discuss recent lattice results in the light of our findings....

  8. Conformable variational iteration method

    Directory of Open Access Journals (Sweden)

    Omer Acan

    2017-02-01

    Full Text Available In this study, we introduce the conformable variational iteration method based on new defined fractional derivative called conformable fractional derivative. This new method is applied two fractional order ordinary differential equations. To see how the solutions of this method, linear homogeneous and non-linear non-homogeneous fractional ordinary differential equations are selected. Obtained results are compared the exact solutions and their graphics are plotted to demonstrate efficiency and accuracy of the method.

  9. Quantum massive conformal gravity

    Energy Technology Data Exchange (ETDEWEB)

    Faria, F.F. [Universidade Estadual do Piaui, Centro de Ciencias da Natureza, Teresina, PI (Brazil)

    2016-04-15

    We first find the linear approximation of the second plus fourth order derivative massive conformal gravity action. Then we reduce the linearized action to separated second order derivative terms, which allows us to quantize the theory by using the standard first order canonical quantization method. It is shown that quantum massive conformal gravity is renormalizable but has ghost states. A possible decoupling of these ghost states at high energies is discussed. (orig.)

  10. Local supertwistors and N=2 conformal supergravity

    International Nuclear Information System (INIS)

    Merkulov, S.A.

    1989-01-01

    N = 2 sypersymmetric extension of the local twistor theory is formulated. A supertwistor superconnection determined by the superconformal structure of the base superspace is introduced on the bundle of N = 2 local supertwistors. It is proved that the Yang - Mills equations for this superconnection coincide exactly with the Bach equations describing the dynamics of N 2 conformal supergravity

  11. Detecting the Significant Flux Backbone of Escherichia coli metabolism.

    Science.gov (United States)

    Güell, Oriol; Sagués, Francesc; Serrano, M Ángeles

    2017-05-01

    The heterogeneity of computationally predicted reaction fluxes in metabolic networks within a single flux state can be exploited to detect their significant flux backbone. Here, we disclose the backbone of Escherichia coli, and compare it with the backbones of other bacteria. We find that, in general, the core of the backbones is mainly composed of reactions in energy metabolism corresponding to ancient pathways. In E. coli, the synthesis of nucleotides and the metabolism of lipids form smaller cores which rely critically on energy metabolism. Moreover, the consideration of different media leads to the identification of pathways sensitive to environmental changes. The metabolic backbone of an organism is thus useful to trace simultaneously both its evolution and adaptation fingerprints. © 2017 The Authors FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

  12. Conformational transitions of flanking purines in HIV-1 RNA dimerization initiation site kissing complexes studied by charmm explicit solvent molecular dynamics

    Czech Academy of Sciences Publication Activity Database

    Sarzynska, J.; Réblová, Kamila; Šponer, Jiří; Kulinski, T.

    2008-01-01

    Roč. 89, č. 9 (2008), s. 732-746 ISSN 0006-3525 R&D Projects: GA MŠk(CZ) LC06030; GA AV ČR(CZ) 1QS500040581 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : molecular dynamics * RNA * force field Subject RIV: BO - Biophysics Impact factor: 2.823, year: 2008

  13. The dominant folding route minimizes backbone distortion in SH3.

    Directory of Open Access Journals (Sweden)

    Heiko Lammert

    Full Text Available Energetic frustration in protein folding is minimized by evolution to create a smooth and robust energy landscape. As a result the geometry of the native structure provides key constraints that shape protein folding mechanisms. Chain connectivity in particular has been identified as an essential component for realistic behavior of protein folding models. We study the quantitative balance of energetic and geometrical influences on the folding of SH3 in a structure-based model with minimal energetic frustration. A decomposition of the two-dimensional free energy landscape for the folding reaction into relevant energy and entropy contributions reveals that the entropy of the chain is not responsible for the folding mechanism. Instead the preferred folding route through the transition state arises from a cooperative energetic effect. Off-pathway structures are penalized by excess distortion in local backbone configurations and contact pair distances. This energy cost is a new ingredient in the malleable balance of interactions that controls the choice of routes during protein folding.

  14. 1H, 15N and 13C backbone resonance assignments of pentaerythritol tetranitrate reductase from Enterobacter cloacae PB2.

    Science.gov (United States)

    Iorgu, Andreea I; Baxter, Nicola J; Cliff, Matthew J; Waltho, Jonathan P; Hay, Sam; Scrutton, Nigel S

    2018-04-01

    Pentaerythritol tetranitrate reductase (PETNR) is a flavoenzyme possessing a broad substrate specificity and is a member of the Old Yellow Enzyme family of oxidoreductases. As well as having high potential as an industrial biocatalyst, PETNR is an excellent model system for studying hydrogen transfer reactions. Mechanistic studies performed with PETNR using stopped-flow methods have shown that tunneling contributes towards hydride transfer from the NAD(P)H coenzyme to the flavin mononucleotide (FMN) cofactor and fast protein dynamics have been inferred to facilitate this catalytic step. Herein, we report the near-complete 1 H, 15 N and 13 C backbone resonance assignments of PETNR in a stoichiometric complex with the FMN cofactor in its native oxidized form, which were obtained using heteronuclear multidimensional NMR spectroscopy. A total of 97% of all backbone resonances were assigned, with 333 out of a possible 344 residues assigned in the 1 H- 15 N TROSY spectrum. This is the first report of an NMR structural study of a flavoenzyme from the Old Yellow Enzyme family and it lays the foundation for future investigations of functional dynamics in hydride transfer catalytic mechanism.

  15. Multiple molecular dynamics simulation of the isoforms of human translation elongation factor 1A reveals reversible fluctuations between "open" and "closed" conformations and suggests specific for eEF1A1 affinity for Ca2+-calmodulin

    Directory of Open Access Journals (Sweden)

    Negrutskii Boris S

    2008-01-01

    Full Text Available Abstract Background Eukaryotic translation elongation factor eEF1A directs the correct aminoacyl-tRNA to ribosomal A-site. In addition, eEF1A is involved in carcinogenesis and apoptosis and can interact with large number of non-translational ligands. There are two isoforms of eEF1A, which are 98% similar. Despite the strong similarity, the isoforms differ in some properties. Importantly, the appearance of eEF1A2 in tissues in which the variant is not normally expressed can be coupled to cancer development. We reasoned that the background for the functional difference of eEF1A1 and eEF1A2 might lie in changes of dynamics of the isoforms. Results It has been determined by multiple MD simulation that eEF1A1 shows increased reciprocal flexibility of structural domains I and II and less average distance between the domains, while increased non-correlated diffusive atom motions within protein domains characterize eEF1A2. The divergence in the dynamic properties of eEF1A1 and eEF1A2 is caused by interactions of amino acid residues that differ between the two variants with neighboring residues and water environment. The main correlated motion of both protein isoforms is the change in proximity of domains I and II which can lead to disappearance of the gap between the domains and transition of the protein into a "closed" conformation. Such a transition is reversible and the protein can adopt an "open" conformation again. This finding is in line with our earlier experimental observation that the transition between "open" and "closed" conformations of eEF1A could be essential for binding of tRNA and/or other biological ligands. The putative calmodulin-binding region Asn311-Gly327 is less flexible in eEF1A1 implying its increased affinity for calmodulin. The ability of eEF1A1 rather than eEF1A2 to interact with Ca2+/calmodulin is shown experimentally in an ELISA-based test. Conclusion We have found that reversible transitions between "open" and "close

  16. NMR backbone resonance assignments of the N, P domains of CopA, a copper-transporting ATPase, in the apo and ligand bound states.

    Science.gov (United States)

    Meng, Dan; Bruschweiler-Li, Lei; Zhang, Fengli; Brüschweiler, Rafael

    2015-04-01

    Copper-transporting ATPase, a member of P-type ATPase family, plays a key role in the homeostasis of cellular copper levels. Here, the backbone assignments of the directly connected N and P domains (292 residues, 31 kDa) of Cu-transporting ATPase in the ligand free and the AMPPCP-bound states are reported in solution. The NMR assignments pave the way for binding and dynamics studies of this enzyme to better understand its function.

  17. A New Method to Determine the Transmembrane Conformation of Substrates in Intramembrane Proteolysis by Deep-UV Resonance Raman Spectroscopy.

    Science.gov (United States)

    Cooley, J W; Abdine, A; Brown, M; Chavez, J; Lada, B; JiJi, R D; Ubarretxena-Belandia, I

    2017-01-01

    We present a new method based on deep-UV resonance Raman spectroscopy to determine the backbone conformation of intramembrane protease substrates. The classical amide vibrational modes reporting on the conformation of just the transmembrane region of the substrate can be resolved from solvent exchangeable regions outside the detergent micelle by partial deuteration of the solvent. In the presence of isotopically triple-labeled intramembrane protease, these amide modes can be accurately measured to monitor the transmembrane conformation of the substrate during intramembrane proteolysis. © 2017 Elsevier Inc. All rights reserved.

  18. Conformal invariance of curvature perturbation

    CERN Document Server

    Gong, Jinn-Ouk; Park, Wan Il; Sasaki, Misao; Song, Yong-Seon

    2011-01-01

    We show that in the single component situation all perturbation variables in the comoving gauge are conformally invariant to all perturbation orders. Generally we identify a special time slicing, the uniform-conformal transformation slicing, where all perturbations are again conformally invariant to all perturbation orders. We apply this result to the delta N formalism, and show its conformal invariance.

  19. Conformity and statistical tolerancing

    Science.gov (United States)

    Leblond, Laurent; Pillet, Maurice

    2018-02-01

    Statistical tolerancing was first proposed by Shewhart (Economic Control of Quality of Manufactured Product, (1931) reprinted 1980 by ASQC), in spite of this long history, its use remains moderate. One of the probable reasons for this low utilization is undoubtedly the difficulty for designers to anticipate the risks of this approach. The arithmetic tolerance (worst case) allows a simple interpretation: conformity is defined by the presence of the characteristic in an interval. Statistical tolerancing is more complex in its definition. An interval is not sufficient to define the conformance. To justify the statistical tolerancing formula used by designers, a tolerance interval should be interpreted as the interval where most of the parts produced should probably be located. This tolerance is justified by considering a conformity criterion of the parts guaranteeing low offsets on the latter characteristics. Unlike traditional arithmetic tolerancing, statistical tolerancing requires a sustained exchange of information between design and manufacture to be used safely. This paper proposes a formal definition of the conformity, which we apply successively to the quadratic and arithmetic tolerancing. We introduce a concept of concavity, which helps us to demonstrate the link between tolerancing approach and conformity. We use this concept to demonstrate the various acceptable propositions of statistical tolerancing (in the space decentring, dispersion).

  20. Axiomatic conformal field theory

    International Nuclear Information System (INIS)

    Gaberdiel, M.R.; Goddard, P.

    2000-01-01

    A new rigourous approach to conformal field theory is presented. The basic objects are families of complex-valued amplitudes, which define a meromorphic conformal field theory (or chiral algebra) and which lead naturally to the definition of topological vector spaces, between which vertex operators act as continuous operators. In fact, in order to develop the theory, Moebius invariance rather than full conformal invariance is required but it is shown that every Moebius theory can be extended to a conformal theory by the construction of a Virasoro field. In this approach, a representation of a conformal field theory is naturally defined in terms of a family of amplitudes with appropriate analytic properties. It is shown that these amplitudes can also be derived from a suitable collection of states in the meromorphic theory. Zhu's algebra then appears naturally as the algebra of conditions which states defining highest weight representations must satisfy. The relationship of the representations of Zhu's algebra to the classification of highest weight representations is explained. (orig.)

  1. Microscopic insights into the NMR relaxation based protein conformational entropy meter

    Science.gov (United States)

    Kasinath, Vignesh; Sharp, Kim A.; Wand, A. Joshua

    2013-01-01

    Conformational entropy is a potentially important thermodynamic parameter contributing to protein function. Quantitative measures of conformational entropy are necessary for an understanding of its role but have been difficult to obtain. An empirical method that utilizes changes in conformational dynamics as a proxy for changes in conformational entropy has recently been introduced. Here we probe the microscopic origins of the link between conformational dynamics and conformational entropy using molecular dynamics simulations. Simulation of seven pro! teins gave an excellent correlation with measures of side-chain motion derived from NMR relaxation. The simulations show that the motion of methyl-bearing side-chains are sufficiently coupled to that of other side chains to serve as excellent reporters of the overall side-chain conformational entropy. These results tend to validate the use of experimentally accessible measures of methyl motion - the NMR-derived generalized order parameters - as a proxy from which to derive changes in protein conformational entropy. PMID:24007504

  2. Proton Beam Therapy Versus Conformal Photon Radiation Therapy for Childhood Craniopharyngioma: Multi-institutional Analysis of Outcomes, Cyst Dynamics, and Toxicity

    Energy Technology Data Exchange (ETDEWEB)

    Bishop, Andrew J. [Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas (United States); Greenfield, Brad [Department of Radiation Oncology, Baylor College of Medicine, Houston, Texas (United States); Mahajan, Anita [Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas (United States); Paulino, Arnold C. [Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas (United States); Department of Radiation Oncology, Baylor College of Medicine, Houston, Texas (United States); Okcu, M. Fatih [Department of Pediatrics, Texas Children' s Cancer and Hematology Center, Baylor College of Medicine, Houston, Texas (United States); Allen, Pamela K. [Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas (United States); Chintagumpala, Murali [Department of Pediatrics, Texas Children' s Cancer and Hematology Center, Baylor College of Medicine, Houston, Texas (United States); Kahalley, Lisa S. [Section of Psychology, Texas Children' s Cancer and Hematology Center, Baylor College of Medicine, Houston, Texas (United States); McAleer, Mary F.; McGovern, Susan L. [Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas (United States); Whitehead, William E. [Department of Neurosurgery, Texas Children' s Cancer and Hematology Center, Baylor College of Medicine, Houston, Texas (United States); Grosshans, David R., E-mail: dgrossha@mdanderson.org [Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas (United States)

    2014-10-01

    Purpose: We compared proton beam therapy (PBT) with intensity modulated radiation therapy (IMRT) for pediatric craniopharyngioma in terms of disease control, cyst dynamics, and toxicity. Methods and Materials: We reviewed records from 52 children treated with PBT (n=21) or IMRT (n=31) at 2 institutions from 1996-2012. Endpoints were overall survival (OS), disease control, cyst dynamics, and toxicity. Results: At 59.6 months' median follow-up (PBT 33 mo vs IMRT 106 mo; P<.001), the 3-year outcomes were 96% for OS, 95% for nodular failure-free survival and 76% for cystic failure-free survival. Neither OS nor disease control differed between treatment groups (OS P=.742; nodular failure-free survival P=.546; cystic failure-free survival P=.994). During therapy, 40% of patients had cyst growth (20% requiring intervention); immediately after therapy, 17 patients (33%) had cyst growth (transient in 14), more commonly in the IMRT group (42% vs 19% PBT; P=.082); and 27% experienced late cyst growth (32% IMRT, 19% PBT; P=.353), with intervention required in 40%. Toxicity did not differ between groups. On multivariate analysis, cyst growth was related to visual and hypothalamic toxicity (P=.009 and .04, respectively). Patients given radiation as salvage therapy (for recurrence) rather than adjuvant therapy had higher rates of visual and endocrine (P=.017 and .024, respectively) dysfunction. Conclusions: Survival and disease-control outcomes were equivalent for PBT and IMRT. Cyst growth is common, unpredictable, and should be followed during and after therapy, because it contributes to late toxicity. Delaying radiation therapy until recurrence may result in worse visual and endocrine function.

  3. The Effect of Conformational Variability of Phosphotriesterase upon N-acyl-L-homoserine Lactone and Paraoxon Binding: Insights from Molecular Dynamics Studies

    Directory of Open Access Journals (Sweden)

    Dongling Zhan

    2013-12-01

    Full Text Available The organophosphorous hydrolase (PTE from Brevundimonas diminuta is capable of degrading extremely toxic organophosphorous compounds with a high catalytic turnover and broad substrate specificity. Although the natural substrate for PTE is unknown, its loop remodeling (loop 7-2/H254R led to the emergence of a homoserine lactonase (HSL activity that is undetectable in PTE (kcat/km values of up to 2 × 104, with only a minor decrease in PTE paraoxonase activity. In this study, homology modeling and molecular dynamics simulations have been undertaken seeking to explain the reason for the substrate specificity for the wild-type and the loop 7-2/H254R variant. The cavity volume estimated results showed that the active pocket of the variant was almost two fold larger than that of the wild-type (WT enzyme. pKa calculations for the enzyme (the WT and the variant showed a significant pKa shift from WT standard values (ΔpKa = 3.5 units for the His254residue (in the Arg254 variant. Molecular dynamics simulations indicated that the displacement of loops 6 and 7 over the active site in loop 7-2/H254R variant is useful for N-acyl-L-homoserine lactone (C4-HSL with a large aliphatic chain to site in the channels easily. Thence the expanding of the active pocket is beneficial to C4-HSL binding and has a little effect on paraoxon binding. Our results provide a new theoretical contribution of loop remodeling to the rapid divergence of new enzyme functions.

  4. Conformational analysis of Infectious bursal disease virus (IBDV derived cell penetrating peptide (CPP analogs

    Directory of Open Access Journals (Sweden)

    Vinay G. Joshi

    2013-12-01

    Full Text Available Aim: This study was designed to develop peptide analogs of Infectious Bursal Disease (IBD virus VP5 protein segment having cell penetrating ability to improve their interaction with cargo molecule (Nucleic acid without affecting the backbone conformation. Materials and Methods: IBDV VP5 protein segment designated as RATH peptide were synthesized using solid phase peptide synthesis and their solution conformation was elucidated using CD spectroscopy in polar (water and apolar (TFE solvents. Cell penetrating ability of RATH-CONH2 was observed using FITC labeled peptide internalization in to HeLa cells under fluorescent microscopy. The efficacy of RATH analog interactions with nucleic acids was evaluated using FITC labeled oligonucleotides by fluorescence spectroscopy and plasmid constructs in gel retardation assay. Results: CD spectra of RATH analogs in water and apolar trifluroethanol (TFE helped to compare their secondary structures which were almost similar with dominant beta conformations suggesting successful induction of positive charge in the analogs without affecting back bone conformation of CPP designed. Cell penetrating ability of RATH CONH2 in HeLa cell was more than 90%. The fluorescence spectroscopy and plasmid constructs in gel retardation assay demonstrated successful interaction of amide analogs with nucleic acid. Conclusion: Intentional changes made in IBDV derived peptide RATH COOH to RATH CONH2 did not showed major changes in backbone conformation and such modifications may help to improve the cationic charge in most CPPs to interact with nucleic acid. [Vet World 2013; 6(6.000: 307-312

  5. Algebraic conformal field theory

    International Nuclear Information System (INIS)

    Fuchs, J.; Nationaal Inst. voor Kernfysica en Hoge-Energiefysica

    1991-11-01

    Many conformal field theory features are special versions of structures which are present in arbitrary 2-dimensional quantum field theories. So it makes sense to describe 2-dimensional conformal field theories in context of algebraic theory of superselection sectors. While most of the results of the algebraic theory are rather abstract, conformal field theories offer the possibility to work out many formulae explicitly. In particular, one can construct the full algebra A-bar of global observables and the endomorphisms of A-bar which represent the superselection sectors. Some explicit results are presented for the level 1 so(N) WZW theories; the algebra A-bar is found to be the enveloping algebra of a Lie algebra L-bar which is an extension of the chiral symmetry algebra of the WZW theory. (author). 21 refs., 6 figs

  6. Computational Protein Design Under a Given Backbone Structure with the ABACUS Statistical Energy Function.

    Science.gov (United States)

    Xiong, Peng; Chen, Quan; Liu, Haiyan

    2017-01-01

    An important objective of computational protein design is to identify amino acid sequences that stably fold into a given backbone structure. A general approach to this problem is to minimize an energy function in the sequence space. We have previously reported a method to derive statistical energies for fixed-backbone protein design and showed that it led to de novo proteins that fold as expected. Here, we present the usage of the program that implements this method, which we now name as ABACUS (A Backbone-based Amino aCid Usage Survey).

  7. Killing tensors and conformal Killing tensors from conformal Killing vectors

    International Nuclear Information System (INIS)

    Rani, Raffaele; Edgar, S Brian; Barnes, Alan

    2003-01-01

    Koutras has proposed some methods to construct reducible proper conformal Killing tensors and Killing tensors (which are, in general, irreducible) when a pair of orthogonal conformal Killing vectors exist in a given space. We give the completely general result demonstrating that this severe restriction of orthogonality is unnecessary. In addition, we correct and extend some results concerning Killing tensors constructed from a single conformal Killing vector. A number of examples demonstrate that it is possible to construct a much larger class of reducible proper conformal Killing tensors and Killing tensors than permitted by the Koutras algorithms. In particular, by showing that all conformal Killing tensors are reducible in conformally flat spaces, we have a method of constructing all conformal Killing tensors, and hence all the Killing tensors (which will in general be irreducible) of conformally flat spaces using their conformal Killing vectors

  8. Nonperturbative results for two-index conformal windows

    DEFF Research Database (Denmark)

    Bergner, Georg; Ryttov, Thomas A.; Sannino, Francesco

    2015-01-01

    Via large and small $N_c$ relations we derive nonperturbative results about the conformal window of two-index theories. Using Schwinger-Dyson methods as well as four-loops results we estimate subleading corrections and show that naive large number of colors extrapolations are unreliable when $N......_c$ is less than about six. Nevertheless useful nonperturbative inequalities for the size of the conformal windows, for any number of colors, can be derived. By further observing that the adjoint conformal window is independent of the number of colors we argue, among other things, that: The large $N_c$ two......-index conformal window is twice the conformal window of the adjoint representation (which can be determined at small $N_c$) expressed in terms of Dirac fermions; Lattice results for adjoint matter can be used to provide independent information on the conformal dynamics of two-index theories such as SU...

  9. Charged conformal Killing spinors

    Energy Technology Data Exchange (ETDEWEB)

    Lischewski, Andree, E-mail: lischews@mathematik.hu-berlin.de [Humboldt-Universität zu Berlin, Institut für Mathematik, Rudower Chaussee 25, Room 1.310, D12489 Berlin (Germany)

    2015-01-15

    We study the twistor equation on pseudo-Riemannian Spin{sup c}-manifolds whose solutions we call charged conformal Killing spinors (CCKSs). We derive several integrability conditions for the existence of CCKS and study their relations to spinor bilinears. A construction principle for Lorentzian manifolds admitting CCKS with nontrivial charge starting from CR-geometry is presented. We obtain a partial classification result in the Lorentzian case under the additional assumption that the associated Dirac current is normal conformal and complete the classification of manifolds admitting CCKS in all dimensions and signatures ≤5 which has recently been initiated in the study of supersymmetric field theories on curved space.

  10. Conformal field theory

    CERN Document Server

    Ketov, Sergei V

    1995-01-01

    Conformal field theory is an elegant and powerful theory in the field of high energy physics and statistics. In fact, it can be said to be one of the greatest achievements in the development of this field. Presented in two dimensions, this book is designed for students who already have a basic knowledge of quantum mechanics, field theory and general relativity. The main idea used throughout the book is that conformal symmetry causes both classical and quantum integrability. Instead of concentrating on the numerous applications of the theory, the author puts forward a discussion of the general

  11. A Synthetic HIV-1 Subtype C Backbone Generates Comparable PR and RT Resistance Profiles to a Subtype B Backbone in a Recombinant Virus Assay

    Science.gov (United States)

    Nauwelaers, David; Van Houtte, Margriet; Winters, Bart; Steegen, Kim; Van Baelen, Kurt; Chi, Ellen; Zhou, Mimi; Steiner, Derek; Bonesteel, Rachelle; Aston, Colin; Stuyver, Lieven J.

    2011-01-01

    In order to determine phenotypic protease and reverse transcriptase inhibitor-associated resistance in HIV subtype C virus, we have synthetically constructed an HIV-1 subtype C (HIV-1-C) viral backbone for use in a recombinant virus assay. The in silico designed viral genome was divided into 4 fragments, which were chemically synthesized and joined together by conventional subcloning. Subsequently, gag-protease-reverse-transcriptase (GPRT) fragments from 8 HIV-1 subtype C-infected patient samples were RT-PCR-amplified and cloned into the HIV-1-C backbone (deleted for GPRT) using In-Fusion reagents. Recombinant viruses (1 to 5 per patient sample) were produced in MT4-eGFP cells where cyto-pathogenic effect (CPE), p24 and Viral Load (VL) were monitored. The resulting HIV-1-C recombinant virus stocks (RVS) were added to MT4-eGFP cells in the presence of serial dilutions of antiretroviral drugs (PI, NNRTI, NRTI) to determine the fold-change in IC50 compared to the IC50 of wild-type HIV-1 virus. Additionally, viral RNA was extracted from the HIV-1-C RVS and the amplified GPRT products were used to generate recombinant virus in a subtype B backbone. Phenotypic resistance profiles in a subtype B and subtype C backbone were compared. The following observations were made: i) functional, infectious HIV-1 subtype C viruses were generated, confirmed by VL and p24 measurements; ii) their rate of infection was slower than viruses generated in the subtype B backbone; iii) they did not produce clear CPE in MT4 cells; and iv) drug resistance profiles generated in both backbones were very similar, including re-sensitizing effects like M184V on AZT. PMID:21629677

  12. A synthetic HIV-1 subtype C backbone generates comparable PR and RT resistance profiles to a subtype B backbone in a recombinant virus assay.

    Directory of Open Access Journals (Sweden)

    David Nauwelaers

    Full Text Available In order to determine phenotypic protease and reverse transcriptase inhibitor-associated resistance in HIV subtype C virus, we have synthetically constructed an HIV-1 subtype C (HIV-1-C viral backbone for use in a recombinant virus assay. The in silico designed viral genome was divided into 4 fragments, which were chemically synthesized and joined together by conventional subcloning. Subsequently, gag-protease-reverse-transcriptase (GPRT fragments from 8 HIV-1 subtype C-infected patient samples were RT-PCR-amplified and cloned into the HIV-1-C backbone (deleted for GPRT using In-Fusion reagents. Recombinant viruses (1 to 5 per patient sample were produced in MT4-eGFP cells where cyto-pathogenic effect (CPE, p24 and Viral Load (VL were monitored. The resulting HIV-1-C recombinant virus stocks (RVS were added to MT4-eGFP cells in the presence of serial dilutions of antiretroviral drugs (PI, NNRTI, NRTI to determine the fold-change in IC50 compared to the IC50 of wild-type HIV-1 virus. Additionally, viral RNA was extracted from the HIV-1-C RVS and the amplified GPRT products were used to generate recombinant virus in a subtype B backbone. Phenotypic resistance profiles in a subtype B and subtype C backbone were compared. The following observations were made: i functional, infectious HIV-1 subtype C viruses were generated, confirmed by VL and p24 measurements; ii their rate of infection was slower than viruses generated in the subtype B backbone; iii they did not produce clear CPE in MT4 cells; and iv drug resistance profiles generated in both backbones were very similar, including re-sensitizing effects like M184V on AZT.

  13. A synthetic HIV-1 subtype C backbone generates comparable PR and RT resistance profiles to a subtype B backbone in a recombinant virus assay.

    Science.gov (United States)

    Nauwelaers, David; Van Houtte, Margriet; Winters, Bart; Steegen, Kim; Van Baelen, Kurt; Chi, Ellen; Zhou, Mimi; Steiner, Derek; Bonesteel, Rachelle; Aston, Colin; Stuyver, Lieven J

    2011-01-01

    In order to determine phenotypic protease and reverse transcriptase inhibitor-associated resistance in HIV subtype C virus, we have synthetically constructed an HIV-1 subtype C (HIV-1-C) viral backbone for use in a recombinant virus assay. The in silico designed viral genome was divided into 4 fragments, which were chemically synthesized and joined together by conventional subcloning. Subsequently, gag-protease-reverse-transcriptase (GPRT) fragments from 8 HIV-1 subtype C-infected patient samples were RT-PCR-amplified and cloned into the HIV-1-C backbone (deleted for GPRT) using In-Fusion reagents. Recombinant viruses (1 to 5 per patient sample) were produced in MT4-eGFP cells where cyto-pathogenic effect (CPE), p24 and Viral Load (VL) were monitored. The resulting HIV-1-C recombinant virus stocks (RVS) were added to MT4-eGFP cells in the presence of serial dilutions of antiretroviral drugs (PI, NNRTI, NRTI) to determine the fold-change in IC50 compared to the IC50 of wild-type HIV-1 virus. Additionally, viral RNA was extracted from the HIV-1-C RVS and the amplified GPRT products were used to generate recombinant virus in a subtype B backbone. Phenotypic resistance profiles in a subtype B and subtype C backbone were compared. The following observations were made: i) functional, infectious HIV-1 subtype C viruses were generated, confirmed by VL and p24 measurements; ii) their rate of infection was slower than viruses generated in the subtype B backbone; iii) they did not produce clear CPE in MT4 cells; and iv) drug resistance profiles generated in both backbones were very similar, including re-sensitizing effects like M184V on AZT.

  14. Probing the role of backbone hydrogen bonds in protein-peptide interactions by amide-to-ester mutations

    DEFF Research Database (Denmark)

    Eildal, Jonas N N; Hultqvist, Greta; Balle, Thomas

    2013-01-01

    of the protein ligand, the role of the backbone hydrogen bonds in the binding reaction is not known. Using amide-to-ester substitutions to perturb the backbone hydrogen-bonding pattern, we have systematically probed putative backbone hydrogen bonds between four different PDZ domains and peptides corresponding...

  15. Cosmological particle creation in conformal gravity

    International Nuclear Information System (INIS)

    Berezin, Victor; Dokuchaev, Vyacheslav; Eroshenko, Yury

    2016-01-01

    We constructed the conformally invariant model for scalar particle creation induced by strong gravitational fields. Starting from the “usual” hydrodynamical description of the particle motion written in the Eulerian coordinates we substituted the particle number conservation law (which enters the formalism) by “the particle creation law”, proportional to the square of the Weyl tensor (following the famous result by Ya. B. Zel‘dovich and A. A. Starobinsky). Then, demanding the conformal invariance of the whole dynamical system, we have got both the (Weyl)-conformal gravity and the Einstein–Hilbert–dilaton gravity action integral. Thus, we obtained something like the induced gravity suggested first by A. D. Sakharov. It is shown that the resulting system is self-consistent. Some future developments of the theory are discussed in the concluding Chapter

  16. Focused conformational sampling in proteins

    Science.gov (United States)

    Bacci, Marco; Langini, Cassiano; Vymětal, Jiří; Caflisch, Amedeo; Vitalis, Andreas

    2017-11-01

    A detailed understanding of the conformational dynamics of biological molecules is difficult to obtain by experimental techniques due to resolution limitations in both time and space. Computer simulations avoid these in theory but are often too short to sample rare events reliably. Here we show that the progress index-guided sampling (PIGS) protocol can be used to enhance the sampling of rare events in selected parts of biomolecules without perturbing the remainder of the system. The method is very easy to use as it only requires as essential input a set of several features representing the parts of interest sufficiently. In this feature space, new states are discovered by spontaneous fluctuations alone and in unsupervised fashion. Because there are no energetic biases acting on phase space variables or projections thereof, the trajectories PIGS generates can be analyzed directly in the framework of transition networks. We demonstrate the possibility and usefulness of such focused explorations of biomolecules with two loops that are part of the binding sites of bromodomains, a family of epigenetic "reader" modules. This real-life application uncovers states that are structurally and kinetically far away from the initial crystallographic structures and are also metastable. Representative conformations are intended to be used in future high-throughput virtual screening campaigns.

  17. Conformational properties of pyrethroids

    Science.gov (United States)

    Mullaley, Anne; Taylor, Robin

    1994-04-01

    X-ray database searches and theoretical potential-energy calculations indicate that the acid moieties of pyrethroid cyclopropanecarboxylate esters adopt a well-defined, relatively inflexible conformation. In contrast, the alcohol moieties can exist in many low-energy geometries. One of the least conformationally flexible pyrethroid alcohols is 4-phenylindan-2-ol. The approximate overall conformation adopted at the biological binding site by insecticidal esters of this alcohol can be deduced with reasonable confidence by molecular modelling. Graphics superposition of a variety of pyrethroid acids suggests the existence of a large but rather narrow pocket at the binding site, in which substituents at the 3-position of the cyclopropane ring can be accommodated. This pocket is asymmetric with respect to the plane of the cyclopropane ring, extending further on the side remote from the ester group. The effects of α-substitution on the insecticidal activity of pyrethroid esters may be due to the influence of substituents on the preferred conformations of the molecules. This hypothesis rationalises the paradoxical dependence on absolute stereochemistry of the activities of various allylbenzyl and cinnamyl alcohol derivatives.

  18. Conformal special relativity

    International Nuclear Information System (INIS)

    Maia, M.D.

    2006-01-01

    It is shown that the information loss/recovery theorem based on the ADS/CFT correspondence is not consistent with the stability of the Schwarzschild or Reissner-Nordstrom black holes. Nonetheless, the conformal invariance of Yang-Mills theory points to new relativity principle compatible with quantum unitarity near those black holes

  19. Animal culture: chimpanzee conformity?

    Science.gov (United States)

    van Schaik, Carel P

    2012-05-22

    Culture-like phenomena in wild animals have received much attention, but how good is the evidence and how similar are they to human culture? New data on chimpanzees suggest their culture may even have an element of conformity. Copyright © 2012 Elsevier Ltd. All rights reserved.

  20. Conformal Dirac structures

    International Nuclear Information System (INIS)

    Wade, A.

    2000-07-01

    The Courant bracket defined originally on the sections of a vector bundle TM +T*M → M is extended to the direct sum of the 1-jet vector bundle and its dual. The extended bracket allows one to interpret many structures encountered in differential geometry, in terms of Dirac structures. We give a new approach to conformal Jacobi structures. (author)

  1. Technidilaton at the conformal edge

    Science.gov (United States)

    Hashimoto, Michio; Yamawaki, Koichi

    2011-01-01

    Technidilaton (TD) was proposed long ago in the technicolor near criticality/conformality. To reveal the critical behavior of TD, we explicitly compute the nonperturbative contributions to the scale anomaly ⟨θμμ⟩ and to the technigluon condensate ⟨αGμν2⟩, which are generated by the dynamical mass m of the technifermions. Our computation is based on the (improved) ladder Schwinger-Dyson equation, with the gauge coupling α replaced by the two-loop running coupling α(μ) having the Caswell-Banks-Zaks infrared fixed point α*: α(μ)≃α=α* for the infrared region mHaba-Matsuzaki-Yamawaki. The decoupled TD can be a candidate of dark matter.

  2. The nucleotide exchange factor Ric-8A is a chaperone for the conformationally dynamic nucleotide-free state of Gαi1.

    Directory of Open Access Journals (Sweden)

    Celestine J Thomas

    Full Text Available Heterotrimeric G protein α subunits are activated upon exchange of GDP for GTP at the nucleotide binding site of Gα, catalyzed by guanine nucleotide exchange factors (GEFs. In addition to transmembrane G protein-coupled receptors (GPCRs, which act on G protein heterotrimers, members of the family cytosolic proteins typified by mammalian Ric-8A are GEFs for Gi/q/12/13-class Gα subunits. Ric-8A binds to Gα•GDP, resulting in the release of GDP. The Ric-8A complex with nucleotide-free Gαi1 is stable, but dissociates upon binding of GTP to Gαi1. To gain insight into the mechanism of Ric-8A-catalyzed GDP release from Gαi1, experiments were conducted to characterize the physical state of nucleotide-free Gαi1 (hereafter referred to as Gαi1[ ] in solution, both as a monomeric species, and in the complex with Ric-8A. We found that Ric-8A-bound, nucleotide-free Gαi1 is more accessible to trypsinolysis than Gαi1•GDP, but less so than Gαi1[ ] alone. The TROSY-HSQC spectrum of [(15N]Gαi1[ ] bound to Ric-8A shows considerable loss of peak intensity relative to that of [(15N]Gαi1•GDP. Hydrogen-deuterium exchange in Gαi1[ ] bound to Ric-8A is 1.5-fold more extensive than in Gαi1•GDP. Differential scanning calorimetry shows that both Ric-8A and Gαi1•GDP undergo cooperative, irreversible unfolding transitions at 47° and 52°, respectively, while nucleotide-free Gαi1 shows a broad, weak transition near 35°. The unfolding transition for Ric-8A:Gαi1[ ] is complex, with a broad transition that peaks at 50°, suggesting that both Ric-8A and Gαi1[ ] are stabilized within the complex, relative to their respective free states. The C-terminus of Gαi1 is shown to be a critical binding element for Ric-8A, as is also the case for GPCRs, suggesting that the two types of GEF might promote nucleotide exchange by similar mechanisms, by acting as chaperones for the unstable and dynamic nucleotide-free state of Gα.

  3. Molecular modeling and molecular dynamics simulation study of archaeal leucyl-tRNA synthetase in complex with different mischarged tRNA in editing conformation.

    Science.gov (United States)

    Rayevsky, A V; Sharifi, M; Tukalo, M A

    2017-09-01

    Aminoacyl-tRNA synthetases (aaRSs) play important roles in maintaining the accuracy of protein synthesis. Some aaRSs accomplish this via editing mechanisms, among which leucyl-tRNA synthetase (LeuRS) edits non-cognate amino acid norvaline mainly by post-transfer editing. However, the molecular basis for this pathway for eukaryotic and archaeal LeuRS remain unclear. In this study, a complex of archaeal P. horikoshii LeuRS (PhLeuRS) with misacylated tRNA Leu was modeled wherever tRNA's acceptor stem was oriented directly into the editing site. To understand the distinctive features of organization we reconstructed a complex of PhLeuRS with tRNA and visualize post-transfer editing interactions mode by performing molecular dynamics (MD) simulation studies. To study molecular basis for substrate selectivity by PhLeuRS's editing site we utilized MD simulation of the entire LeuRS complexes using a diverse charged form of tRNAs, namely norvalyl-tRNA Leu and isoleucyl-tRNA Leu . In general, the editing site organization of LeuRS from P.horikoshii has much in common with bacterial LeuRS. The MD simulation results revealed that the post-transfer editing substrate norvalyl-A76, binds more strongly than isoleucyl-A76. Moreover, the branched side chain of isoleucine prevents water molecules from being closer and hence the hydrolysis reaction slows significantly. To investigate a possible mechanism of the post-transfer editing reaction, by PhLeuRS we have determined that two water molecules (the attacking and assisting water molecules) are localized near the carbonyl group of the amino acid to be cleaved off. These water molecules approach the substrate from the opposite side to that observed for Thermus thermophilus LeuRS (TtLeuRS). Based on the results obtained, it was suggested that the post-transfer editing mechanism of PhLeuRS differs from that of prokaryotic TtLeuRS. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Evolution of Conformity in Social Dilemmas.

    Science.gov (United States)

    Dong, Yali; Li, Cong; Tao, Yi; Zhang, Boyu

    2015-01-01

    People often deviate from their individual Nash equilibrium strategy in game experiments based on the prisoner's dilemma (PD) game and the public goods game (PGG), whereas conditional cooperation, or conformity, is supported by the data from these experiments. In a complicated environment with no obvious "dominant" strategy, conformists who choose the average strategy of the other players in their group could be able to avoid risk by guaranteeing their income will be close to the group average. In this paper, we study the repeated PD game and the repeated m-person PGG, where individuals' strategies are restricted to the set of conforming strategies. We define a conforming strategy by two parameters, initial action in the game and the influence of the other players' choices in the previous round. We are particularly interested in the tit-for-tat (TFT) strategy, which is the well-known conforming strategy in theoretical and empirical studies. In both the PD game and the PGG, TFT can prevent the invasion of non-cooperative strategy if the expected number of rounds exceeds a critical value. The stability analysis of adaptive dynamics shows that conformity in general promotes the evolution of cooperation, and that a regime of cooperation can be established in an AllD population through TFT-like strategies. These results provide insight into the emergence of cooperation in social dilemma games.

  5. Chemical crosslinking and mass spectrometry studies of the structure and dynamics of membrane proteins and receptors.

    Energy Technology Data Exchange (ETDEWEB)

    Haskins, William E.; Leavell, Michael D.; Lane, Pamela; Jacobsen, Richard B.; Hong, Joohee; Ayson, Marites J.; Wood, Nichole L.; Schoeniger, Joseph S.; Kruppa, Gary Hermann; Sale, Kenneth L.; Young, Malin M.; Novak, Petr

    2005-03-01

    Membrane proteins make up a diverse and important subset of proteins for which structural information is limited. In this study, chemical cross-linking and mass spectrometry were used to explore the structure of the G-protein-coupled photoreceptor bovine rhodopsin in the dark-state conformation. All experiments were performed in rod outer segment membranes using amino acid 'handles' in the native protein sequence and thus minimizing perturbations to the native protein structure. Cysteine and lysine residues were covalently cross-linked using commercially available reagents with a range of linker arm lengths. Following chemical digestion of cross-linked protein, cross-linked peptides were identified by accurate mass measurement using liquid chromatography-fourier transform mass spectrometry and an automated data analysis pipeline. Assignments were confirmed and, if necessary, resolved, by tandem MS. The relative reactivity of lysine residues participating in cross-links was evaluated by labeling with NHS-esters. A distinct pattern of cross-link formation within the C-terminal domain, and between loop I and the C-terminal domain, emerged. Theoretical distances based on cross-linking were compared to inter-atomic distances determined from the energy-minimized X-ray crystal structure and Monte Carlo conformational search procedures. In general, the observed cross-links can be explained by re-positioning participating side-chains without significantly altering backbone structure. One exception, between C3 16 and K325, requires backbone motion to bring the reactive atoms into sufficient proximity for cross-linking. Evidence from other studies suggests that residues around K325 for a region of high backbone mobility. These findings show that cross-linking studies can provide insight into the structural dynamics of membrane proteins in their native environment.

  6. Twisting Right to Left: A…A Mismatch in a CAG Trinucleotide Repeat Overexpansion Provokes Left-Handed Z-DNA Conformation

    Science.gov (United States)

    2015-01-01

    Conformational polymorphism of DNA is a major causative factor behind several incurable trinucleotide repeat expansion disorders that arise from overexpansion of trinucleotide repeats located in coding/non-coding regions of specific genes. Hairpin DNA structures that are formed due to overexpansion of CAG repeat lead to Huntington’s disorder and spinocerebellar ataxias. Nonetheless, DNA hairpin stem structure that generally embraces B-form with canonical base pairs is poorly understood in the context of periodic noncanonical A…A mismatch as found in CAG repeat overexpansion. Molecular dynamics simulations on DNA hairpin stems containing A…A mismatches in a CAG repeat overexpansion show that A…A dictates local Z-form irrespective of starting glycosyl conformation, in sharp contrast to canonical DNA duplex. Transition from B-to-Z is due to the mechanistic effect that originates from its pronounced nonisostericity with flanking canonical base pairs facilitated by base extrusion, backbone and/or base flipping. Based on these structural insights we envisage that such an unusual DNA structure of the CAG hairpin stem may have a role in disease pathogenesis. As this is the first study that delineates the influence of a single A…A mismatch in reversing DNA helicity, it would further have an impact on understanding DNA mismatch repair. PMID:25876062

  7. Twisting right to left: A…A mismatch in a CAG trinucleotide repeat overexpansion provokes left-handed Z-DNA conformation.

    Directory of Open Access Journals (Sweden)

    Noorain Khan

    2015-04-01

    Full Text Available Conformational polymorphism of DNA is a major causative factor behind several incurable trinucleotide repeat expansion disorders that arise from overexpansion of trinucleotide repeats located in coding/non-coding regions of specific genes. Hairpin DNA structures that are formed due to overexpansion of CAG repeat lead to Huntington's disorder and spinocerebellar ataxias. Nonetheless, DNA hairpin stem structure that generally embraces B-form with canonical base pairs is poorly understood in the context of periodic noncanonical A…A mismatch as found in CAG repeat overexpansion. Molecular dynamics simulations on DNA hairpin stems containing A…A mismatches in a CAG repeat overexpansion show that A…A dictates local Z-form irrespective of starting glycosyl conformation, in sharp contrast to canonical DNA duplex. Transition from B-to-Z is due to the mechanistic effect that originates from its pronounced nonisostericity with flanking canonical base pairs facilitated by base extrusion, backbone and/or base flipping. Based on these structural insights we envisage that such an unusual DNA structure of the CAG hairpin stem may have a role in disease pathogenesis. As this is the first study that delineates the influence of a single A…A mismatch in reversing DNA helicity, it would further have an impact on understanding DNA mismatch repair.

  8. Green IGP Link Weights for Energy-efficiency and Load-balancing in IP Backbone Networks

    OpenAIRE

    Francois, Frederic; Wang, Ning; Moessner, Klaus; Georgoulas, Stylianos; Xu, Ke

    2013-01-01

    The energy consumption of backbone networks has become a primary concern for network operators and regulators due to the pervasive deployment of wired backbone networks to meet the requirements of bandwidth-hungry applications. While traditional optimization of IGP link weights has been used in IP based load-balancing operations, in this paper we introduce a novel link weight setting algorithm, the Green Load-balancing Algorithm (GLA), which is able to jointly optimize both energy efficiency ...

  9. Molecular Dynamics and Electron Density Studies of Siderophores and Peptides.

    Science.gov (United States)

    Fidelis, Krzysztof Andrzej

    1990-08-01

    The dissertation comprises three separate studies of siderophores and peptides. In the first of these studies the relative potential energies for a series of diastereomers of a siderophore neocoprogen I are evaluated with molecular mechanics force field methods. Charges on the hydroxamate moiety are determined with a synthetic model siderophore compound using valence population refinements, and alternatively, with the theoretical ab initio/ESP calculations. The single diastereomer found in the crystal structure is among four characterized by the low potential energy, while prevalence of Delta vs. Lambda configuration about the iron is found to be a property of the entire series. In the second study the crystal structure of a ferrichrome siderophore ferrirhodin is reported. The crystal structure conformation of the molecular backbone as well as the iron coordination geometry compare well with other ferrichrome structures. The differences between the acyl groups of ferrirubin and ferrirhodin are explored using the methods of molecular mechanics. The third study a 300 ps, 300 K, in vacuo molecular dynamics simulation of didemnin A and B yields distinct molecular conformers, which are different from the one found in the crystal structure or modeled in solution, using the Nuclear Overhauser Effect data. Evaluations of the relative potential energy are performed with short 10 ps simulations in solution. Didemnins are natural depsipeptides isolated from a Caribbean tunicate and characterized by particularly potent antiproliferative and immunomodulatory activity. Conformationally rigid and flexible regions of the molecule are described. A short review of the molecular mechanics methodology is given in the introduction.

  10. Characterization of mu s-ms dynamics of proteins using a combined analysis of N-15 NMR relaxation and chemical shift: Conformational exchange in plastocyanin induced by histidine protonations

    DEFF Research Database (Denmark)

    Hass, M. A. S.; Thuesen, Marianne Hallberg; Christensen, Hans Erik Mølager

    2004-01-01

    variabilis (A.v. PCu) (Ma, L.; Hass, M. A. S.; Vierick, N.; Kristensen, S. M.; Ulstrup, J.; Led, J. J. Biochemistry 2003, 42, 320-330). The R-1 and R-2 relaxation rates of the backbone N-15 nuclei were measured at a series of pH and temperatures on an 15N labeled sample of A.v. PCu, and the 15 N chemical...

  11. Density functional MO calculation for stacked DNA base-pairs with backbones.

    Science.gov (United States)

    Kurita, N; Kobayashi, K

    2000-05-01

    In order to elucidate the effect of the sugar and phosphate backbones on the stable structure and electronic properties of stacked DNA base-pairs, we performed ab initio molecular orbital (MO) calculations based on the density functional theory and Slater-type basis set. As a model cluster for stacked base-pairs, we employed three isomers for the dimer unit of stacked guanine-cytosine pairs composed with backbones as well as base-pairs. These structures were fully optimized and their electronic properties were self-consistently investigated. By including the backbones, the difference in total energy among the isomers was largely enhanced, while the trend in relative stability was not changed. The effect of backbones on the electronic properties is remarkable: the MOs with the character of the PO4 parts of backbones appear just below the highest-occupied MO. This result indicates that the PO4 parts might play a rule as a reaction site in chemical processes concerning DNA. Therefore, we conclude that the DNA backbones are indispensable for investigating the stability and electronic properties of the stacked DNA base-pairs.

  12. Transportation Conformity Training and Presentations

    Science.gov (United States)

    EPA's OTAQ has provided multiple conformity training sessions in the past to assist state and local governments in implementing conformity requirements. As training information is prepared for other venues, it will be posted on this page.

  13. Conformal boundaries of warped products

    DEFF Research Database (Denmark)

    Kokkendorff, Simon Lyngby

    2006-01-01

    In this note we prove a result on how to determine the conformal boundary of a type of warped product of two length spaces in terms of the individual conformal boundaries. In the situation, that we treat, the warping and conformal distortion functions are functions of distance to a base point....... The result is applied to produce examples of CAT(0)-spaces, where the conformal and ideal boundaries differ in interesting ways....

  14. Conformal radiotherapy: a glossary

    International Nuclear Information System (INIS)

    Dubray, B.; Giraud, P.; Beaudre, A.

    1999-01-01

    Most of the concepts and terms related to conformal radiotherapy were produced by English-speaking authors and eventually validated by international groups of experts, whose working language was also English. Therefore, a significant part of this literature is poorly accessible to the French-speaking radiation oncology community. The present paper gathers the 'official' definitions already published in French, along with propositions for the remaining terms which should be submitted to a more formal and representative validation process. (author)

  15. Conformal scalar field wormholes

    Science.gov (United States)

    Halliwell, Jonathan J.; Laflamme, Raymond

    1989-01-01

    The Euclidian Einstein equations with a cosmological constant and a conformally coupled scalar field are solved, taking the metric to be of the Robertson-Walker type. In the case Lambda = 0, solutions are found which represent a wormhole connecting two asymptotically flat Euclidian regions. In the case Lambda greater than 0, the solutions represent tunneling from a small Tolman-like universe to a large Robertson-Walker universe.

  16. Compact conformations of human protein disulfide isomerase.

    Directory of Open Access Journals (Sweden)

    Shang Yang

    Full Text Available Protein disulfide isomerase (PDI composed of four thioredoxin-like domains a, b, b', and a', is a key enzyme catalyzing oxidative protein folding in the endoplasmic reticulum. Large scale molecular dynamics simulations starting from the crystal structures of human PDI (hPDI in the oxidized and reduced states were performed. The results indicate that hPDI adopts more compact conformations in solution than in the crystal structures, which are stabilized primarily by inter-domain interactions, including the salt bridges between domains a and b' observed for the first time. A prominent feature of the compact conformations is that the two catalytic domains a and a' can locate close enough for intra-molecular electron transfer, which was confirmed by the characterization of an intermediate with a disulfide between the two domains. Mutations, which disrupt the inter-domain interactions, lead to decreased reductase activity of hPDI. Our molecular dynamics simulations and biochemical experiments reveal the intrinsic conformational dynamics of hPDI and its biological impact.

  17. Physics-based side-chain-rotamer and side-chain and backbone virtual-bond-stretching potentials for coarse-grained UNRES force field. 2. Comparison with statistical potentials and implementation

    Science.gov (United States)

    Kozłowska, Urszula; Maisuradze, Gia G.; Liwo, Adam; Scheraga, Harold A.

    2009-01-01

    Using the harmonic-approximation approach of the accompanying paper and AM1 energy surfaces of terminally-blocked amino-acid residues, we determined physics-based side-chain-rotamer potentials and the side-chain virtual-bond-deformation potentials of 19 natural amino-acid residues with side chains. The potentials were approximated by analytical formulas and implemented in the UNRES mesoscopic dynamics program. For comparison, the corresponding statistical potentials were determined from 19,682 high-resolution protein structures. The low-free-energy region of both the AM1-derived and the statistical potentials is determined by the valence geometry and the L-chirality, and its size increases with side-chain flexibility and decreases with increasing virtual-bond-angle θ. The differences between the free energies of rotamers are greater for the AM1-derived potentials compared to the statistical potentials and, for alanine and other residues with small side chains, a region corresponding to the Cax7 conformation has remarkably low free energy for the AM1-derived potentials, as opposed to the statistical potentials. These differences probably result from the interactions between neighboring residues and indicate the need for introduction of cooperative terms accounting for the coupling between side-chain-rotamer and backbone interactions. Both AM1-derived and statistical virtual-bond-deformation potentials are multimodal for flexible side chains and are topologically similar; however, the regions of minima of the statistical potentials are much narrower, which probably results from imposing restraints in structure determination. The force field with the new potentials was preliminarily optimized using the FBP WW domain (1E0L) and the engrailed homeodomain (1ENH) as training proteins and assessed to be reasonably transferable. PMID:20017135

  18. Significant role of the DNA backbone in mediating the transition origin of electronic excitations of B-DNA--implication from long range corrected TDDFT and quantified NTO analysis.

    Science.gov (United States)

    Li, Jian-Hao; Chai, Jeng-Da; Guo, Guang-Yu; Hayashi, Michitoshi

    2012-07-07

    We systematically investigate the possible complex transition origin of electronic excitations of giant molecular systems by using the recently proposed QNTO analysis [J.-H. Li, J.-D. Chai, G. Y. Guo and M. Hayashi, Chem. Phys. Lett., 2011, 514, 362.] combined with long-range corrected TDDFT calculations. Thymine (Thy) related excitations of a B-DNA biomolecule are then studied as examples, where the model systems have been constructed by extracting from the perfect or an X-ray crystal (PDB code 3BSE) B-DNA structure with at least one Thy included. In the first part, we consider the systems composed of a core molecular segment (e.g. Thy, or di-Thy) and a surrounding physical/chemical environment of interest (e.g. backbone, adjacent stacking nucleobases) in gas phase and examine how the excitation properties of the core vary in response to the environment. We find that the orbitals contributed by the DNA backbone and surrounding nucleobases often participate in a transition of Thy-related excitations affecting their composition, absorption energy, and oscillator strength. A vast number of strongly backbone-orbital involved excitations are also found at an absorption wavelength below ∼180 nm predicted by TD-ωB97X. In the second part, we take into account geometrically induced variation of the excitation properties of various B-DNA segments, e.g. di-Thy, dTpdT etc., obtained from different sources (ideal and 3BSE). It is found that the transition origin of several Thy-related excitations of these segments is sensitive to slight conformational variations, suggesting that DNA with thermal motions may from time to time exhibit very different photo-induced physical and/or chemical processes.

  19. Conformational Flexibility Is a Determinant of Permeability for Cyclosporin.

    Science.gov (United States)

    Wang, Conan K; Swedberg, Joakim E; Harvey, Peta J; Kaas, Quentin; Craik, David J

    2018-03-01

    Several cyclic peptides have been reported to have unexpectedly high membrane permeability. Of these, cyclosporin A is perhaps the most well-known example, particularly in light of its relatively high molecular weight. Observations that cyclosporin A changes conformation depending on its solvent environment led to the hypothesis that conformational dynamics is a prerequisite for its permeability; however, this hypothesis has been difficult to validate experimentally. Here, we use molecular dynamics simulations to explicitly determine the conformational behavior of cyclosporin A and other related cyclic peptides as they spontaneously transition between different environments, including through a lipid bilayer. These simulations are referenced against simulations in explicit water, chloroform, and cyclohexane and further validated against NMR experiments, measuring conformational exchange, nuclear spin relaxation, and three-dimensional structures in membrane-mimicking environments, such as in dodecylphosphocholine micelles, to build a comprehensive understanding of the role of dynamics. We find that conformational flexibility is a key determinant of the membrane permeability of cyclosporin A and similar membrane-permeable cyclic peptides, as conformationally constrained variants have limited movement into, then through, and finally out of the membrane in silico. We envisage that a better understanding of dynamics might thus provide new opportunities to modulate peptide function and enhance their delivery.

  20. Conformal Hamiltonian dynamics of general relativity

    Energy Technology Data Exchange (ETDEWEB)

    Arbuzov, A.B.; Barbashov, B.M. [Bogoliubov Laboratory of Theoretical Physics, Joint Institute for Nuclear Research, 141980 Dubna (Russian Federation); Nazmitdinov, R.G. [Bogoliubov Laboratory of Theoretical Physics, Joint Institute for Nuclear Research, 141980 Dubna (Russian Federation); Department de Fisica, Universitat de les Illes Balears, E-07122 Palma de Mallorca (Spain); Pervushin, V.N., E-mail: pervush@theor.jinr.r [Bogoliubov Laboratory of Theoretical Physics, Joint Institute for Nuclear Research, 141980 Dubna (Russian Federation); Borowiec, A. [Institute of Theoretical Physics, University of Wroclaw, Pl. Maxa Borna 9, 50-204 Wroclaw (Poland); Pichugin, K.N. [Kirensky Institute of Physics, 660036 Krasnoyarsk (Russian Federation); Zakharov, A.F. [Institute of Theoretical and Experimental Physics, B. Cheremushkinskaya str. 25, 117259 Moscow (Russian Federation)

    2010-08-09

    The General Relativity formulated with the aid of the spin connection coefficients is considered in the finite space geometry of similarity with the Dirac scalar dilaton. We show that the redshift evolution of the General Relativity describes the vacuum creation of the matter in the empty Universe at the electroweak epoch and the dilaton vacuum energy plays a role of the dark energy.

  1. Geometric decomposition of the conformation tensor in viscoelastic turbulence

    Science.gov (United States)

    Hameduddin, Ismail; Meneveau, Charles; Zaki, Tamer A.; Gayme, Dennice F.

    2018-05-01

    This work introduces a mathematical approach to analysing the polymer dynamics in turbulent viscoelastic flows that uses a new geometric decomposition of the conformation tensor, along with associated scalar measures of the polymer fluctuations. The approach circumvents an inherent difficulty in traditional Reynolds decompositions of the conformation tensor: the fluctuating tensor fields are not positive-definite and so do not retain the physical meaning of the tensor. The geometric decomposition of the conformation tensor yields both mean and fluctuating tensor fields that are positive-definite. The fluctuating tensor in the present decomposition has a clear physical interpretation as a polymer deformation relative to the mean configuration. Scalar measures of this fluctuating conformation tensor are developed based on the non-Euclidean geometry of the set of positive-definite tensors. Drag-reduced viscoelastic turbulent channel flow is then used an example case study. The conformation tensor field, obtained using direct numerical simulations, is analysed using the proposed framework.

  2. Open conformal systems and perturbations of transfer operators

    CERN Document Server

    Pollicott, Mark

    2017-01-01

    The focus of this book is on open conformal dynamical systems corresponding to the escape of a point through an open Euclidean ball. The ultimate goal is to understand the asymptotic behavior of the escape rate as the radius of the ball tends to zero. In the case of hyperbolic conformal systems this has been addressed by various authors. The conformal maps considered in this book are far more general, and the analysis correspondingly more involved. The asymptotic existence of escape rates is proved and they are calculated in the context of (finite or infinite) countable alphabets, uniformly contracting conformal graph-directed Markov systems, and in particular, conformal countable alphabet iterated function systems. These results have direct applications to interval maps, meromorphic maps and rational functions. Towards this goal the authors develop, on a purely symbolic level, a theory of singular perturbations of Perron--Frobenius (transfer) operators associated with countable alphabet subshifts of finite t...

  3. Synthesis of conformation switchable cationic polypeptides based on poly(S-propargyl-cysteine) for use as siRNA delivery.

    Science.gov (United States)

    Yi, Ling; Wang, Yisi; Lin, Guanliang; Lin, Danling; Chen, Wenliang; Huang, Yugang; Ye, Guodong

    2017-08-01

    Ring-opening polymerization of S-propargyl-cysteine-N-carboxyanhydride has been used to synthesize conformation switchable poly(S-propargyl-cysteine) starting with l-cysteine, dl- and d-cysteine. Then cationic polypeptides with different backbone chirality are obtained by nearly 100% side-chain grafting of cysteamine via thiol-yne click chemistry. The cationic polypeptides containing mixed conformations of β-sheets, β-turns and random coils are stable against pH, salt and temperature variations. The cationic polypeptides can condense siRNA at a low polypeptide/siRNA weight ratio to form nanoparticles with size depending on the backbone chirality. The cationic polypeptides derived from poly(S-propargyl-l or d-cysteine) are non-cytotoxic to HeLa and HepG2 cells, but interrupting the backbone chirality enhances the cytotoxicity sharply. The cationic polypeptides used for siRNA delivery show good transfection efficiency, but cell internalization process depends on the backbone chirality. The cationic polypeptide derived from the poly(S-propargyl-l-cysteine) is an appropriate siRNA vector with advantages of non-cytotoxicity and high transfection efficiency. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Molecular Data for a Biochemical Model of DNA Radiation Damage: Electron Impact Ionization and Dissociative Ionization of DNA Bases and Sugar-Phosphate Backbone

    Science.gov (United States)

    Dateo, Christopher E.; Fletcher, Graham D.

    2004-01-01

    As part of the database for building up a biochemical model of DNA radiation damage, electron impact ionization cross sections of sugar-phosphate backbone and DNA bases have been calculated using the improved binary-encounter dipole (iBED) model. It is found that the total ionization cross sections of C3'- and C5'-deoxyribose-phospate, two conformers of the sugar-phosphate backbone, are close to each other. Furthermore, the sum of the ionization cross sections of the separate deoxyribose and phosphate fragments is in close agreement with the C3'- and C5'-deoxyribose-phospate cross sections, differing by less than 10%. Of the four DNA bases, the ionization cross section of guanine is the largest, then in decreasing order, adenine, thymine, and cytosine. The order is in accordance with the known propensity of oxidation of the bases by ionizing radiation. Dissociative ionization (DI), a process that both ionizes and dissociates a molecule, is investigated for cytosine. The DI cross section for the formation of H and (cytosine-Hl)(+), with the cytosine ion losing H at the 1 position, is also reported. The threshold of this process is calculated to be 17.1 eV. Detailed analysis of ionization products such as in DI is important to trace the sequential steps in the biochemical process of DNA damage.

  5. Cost-effectiveness analysis of dolutegravir plus backbone compared with raltegravir plus backbone, darunavir+ritonavir plus backbone and efavirenz/tenofovir/emtricitabine in treatment naïve and experienced HIV-positive patients

    Directory of Open Access Journals (Sweden)

    Restelli U

    2017-06-01

    Full Text Available Umberto Restelli,1,2 Giuliano Rizzardini,3,4 Andrea Antinori,5 Adriano Lazzarin,6 Marzia Bonfanti,1 Paolo Bonfanti,7 Davide Croce1,2 1Centre for Research on Health Economics, Social and Health Care Management, LIUC – Università Cattaneo, Castellanza, Varese, Italy; 2School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; 3First and Second Divisions of Infectious Diseases, “Luigi Sacco” Hospital, Milan, Italy; 4School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; 5National Institute for Infectious Diseases “L Spallanzani”, Rome, 6Department of Infectious Diseases, San Raffaele Scientific Institute, 7Department of Infectious and Tropical Diseases, A Manzoni Hospital, Lecco, Italy Background: In January 2014, the European Medicines Agency issued a marketing authorization for dolutegravir (DTG, a second-generation integrase strand transfer inhibitor for HIV treatment. The study aimed at determining the incremental cost-effectiveness ratio (ICER of the use of DTG+backbone compared with raltegravir (RAL+backbone, darunavir (DRV+ritonavir(r+backbone and efavirenz/tenofovir/emtricitabine (EFV/TDF/FTC in HIV-positive treatment-naïve patients and compared with RAL+backbone in treatment-experienced patients, from the Italian National Health Service’s point of view.Materials and methods: A published Monte Carlo Individual Simulation Model (ARAMIS-DTG model was used to perform the analysis. Patients pass through mutually exclusive health states (defined in terms of diagnosis of HIV with or without opportunistic infections [OIs] and cardiovascular disease [CVD] and successive lines of therapy. The model considers costs (2014 and quality of life per monthly cycle in a lifetime horizon. Costs and quality-adjusted life years (QALYs are dependent on OI, CVD, AIDS events, adverse events and antiretroviral therapies.Results: In

  6. Side chain: backbone projections in aromatic and ASX residues from NMR cross-correlated relaxation

    Energy Technology Data Exchange (ETDEWEB)

    Voegeli, Beat, E-mail: beat.voegeli@phys.chem.ethz.ch; Riek, Roland [Swiss Federal Institute of Technology, Laboratory of Physical Chemistry (Switzerland)

    2010-02-15

    The measurements of cross-correlated relaxation rates between H{sup N}-N and C{sup {beta}}-C{sup {gamma}} intraresidual and sequential dipolar interactions is demonstrated in ASN, ASP and aromatic residues. The experiment can be used for deuterated samples and no additional knowledge such as Karplus parametrizations is required for the analysis. The data constitutes a new type of information since no other method relates the C{sup {beta}}-C{sup {gamma}} bond to H{sup N}-N. Using this method the dominant populations of rotamer states of {chi}1 can be readily cross checked provided that {phi} or {psi} are known. In addition, dynamics on all timescales can be probed. As opposed to standard dynamics analysis of isolated bonds, the presented observables depend on relative dynamics with an interesting prospect to analyze correlated fluctuations of the two torsion angles {phi} or {psi} with {chi}1. Experimental rates are compared to single conformer and ensemble representations of GB3 and ubiquitin. In particular, it is found that the recently published ubiquitin ensemble 2k39 improves the agreement obtained for 1UBQ. In general, however, input data restricting ASX and aromatic side chains in structure calculation is sparse highlighting the need for new NMR observables.

  7. Side chain: backbone projections in aromatic and ASX residues from NMR cross-correlated relaxation.

    Science.gov (United States)

    Vögeli, Beat; Riek, Roland

    2010-02-01

    The measurements of cross-correlated relaxation rates between H(N)-N and C(beta)-C(gamma) intraresidual and sequential dipolar interactions is demonstrated in ASN, ASP and aromatic residues. The experiment can be used for deuterated samples and no additional knowledge such as Karplus parametrizations is required for the analysis. The data constitutes a new type of information since no other method relates the C(beta)-C(gamma) bond to H(N)-N. Using this method the dominant populations of rotamer states of chi 1 can be readily cross checked provided that phi or psi are known. In addition, dynamics on all timescales can be probed. As opposed to standard dynamics analysis of isolated bonds, the presented observables depend on relative dynamics with an interesting prospect to analyze correlated fluctuations of the two torsion angles phi or psi with chi 1. Experimental rates are compared to single conformer and ensemble representations of GB3 and ubiquitin. In particular, it is found that the recently published ubiquitin ensemble 2k39 improves the agreement obtained for 1UBQ. In general, however, input data restricting ASX and aromatic side chains in structure calculation is sparse highlighting the need for new NMR observables.

  8. Underestimated Halogen Bonds Forming with Protein Backbone in Protein Data Bank.

    Science.gov (United States)

    Zhang, Qian; Xu, Zhijian; Shi, Jiye; Zhu, Weiliang

    2017-07-24

    Halogen bonds (XBs) are attracting increasing attention in biological systems. Protein Data Bank (PDB) archives experimentally determined XBs in biological macromolecules. However, no software for structure refinement in X-ray crystallography takes into account XBs, which might result in the weakening or even vanishing of experimentally determined XBs in PDB. In our previous study, we showed that side-chain XBs forming with protein side chains are underestimated in PDB on the basis of the phenomenon that the proportion of side-chain XBs to overall XBs decreases as structural resolution becomes lower and lower. However, whether the dominant backbone XBs forming with protein backbone are overlooked is still a mystery. Here, with the help of the ratio (R F ) of the observed XBs' frequency of occurrence to their frequency expected at random, we demonstrated that backbone XBs are largely overlooked in PDB, too. Furthermore, three cases were discovered possessing backbone XBs in high resolution structures while losing the XBs in low resolution structures. In the last two cases, even at 1.80 Å resolution, the backbone XBs were lost, manifesting the urgent need to consider XBs in the refinement process during X-ray crystallography study.

  9. Backbone NMR resonance assignments of the nucleotide binding domain of the ABC multidrug transporter LmrA from Lactococcus lactis in its ADP-bound state.

    Science.gov (United States)

    Hellmich, Ute A; Duchardt-Ferner, Elke; Glaubitz, Clemens; Wöhnert, Jens

    2012-04-01

    LmrA from Lactococcus lactis is a multidrug transporter and a member of the ATP binding cassette (ABC) transporter family. ABC transporters consist of a transmembrane domain (TMD) and a nucleotide binding domain (NBD). The NBD contains the highly conserved signature motifs of this transporter superfamily. In the case of LmrA, the TMD and the NBD are expressed as a single polypeptide. LmrA catalyzes the extrusion of hydrophobic compounds including antibiotics from the cell membrane at the expense of ATP hydrolysis. ATP binds to the NBD, where binding and hydrolysis induce conformational changes that lead to the extrusion of the substrate via the TMD. Here, we report the (1)H, (13)C and (15)N backbone chemical shift assignments of the isolated 263 amino acid containing NBD of LmrA in its ADP bound state.

  10. Mnn10 Maintains Pathogenicity in Candida albicans by Extending α-1,6-Mannose Backbone to Evade Host Dectin-1 Mediated Antifungal Immunity

    Science.gov (United States)

    Zhang, Shi Qun; Zou, Zui; Shen, Hui; Shen, Shuai Shuai; Miao, Qi; Huang, Xin; Liu, Wei; Li, Li Ping; Chen, Si Min; Yan, Lan; Zhang, Jun Dong; Zhao, Jing Jun; Xu, Guo Tong; An, Mao Mao; Jiang, Yuan Ying

    2016-01-01

    The cell wall is a dynamic structure that is important for the pathogenicity of Candida albicans. Mannan, which is located in the outermost layer of the cell wall, has been shown to contribute to the pathogenesis of C. albicans, however, the molecular mechanism by which this occurs remains unclear. Here we identified a novel α-1,6-mannosyltransferase encoded by MNN10 in C. albicans. We found that Mnn10 is required for cell wall α-1,6-mannose backbone biosynthesis and polysaccharides organization. Deletion of MNN10 resulted in significant attenuation of the pathogenesis of C. albicans in a murine systemic candidiasis model. Inhibition of α-1,6-mannose backbone extension did not, however, impact the invasive ability of C. albicans in vitro. Notably, mnn10 mutant restored the invasive capacity in athymic nude mice, which further supports the notion of an enhanced host antifungal defense related to this backbone change. Mnn10 mutant induced enhanced Th1 and Th17 cell mediated antifungal immunity, and resulted in enhanced recruitment of neutrophils and monocytes for pathogen clearance in vivo. We also demonstrated that MNN10 could unmask the surface β-(1,3)-glucan, a crucial pathogen-associated molecular pattern (PAMP) of C. albicans recognized by host Dectin-1. Our results demonstrate that mnn10 mutant could stimulate an enhanced Dectin-1 dependent immune response of macrophages in vitro, including the activation of nuclear factor-κB, mitogen-activated protein kinase pathways, and secretion of specific cytokines such as TNF-α, IL-6, IL-1β and IL-12p40. In summary, our study indicated that α-1,6-mannose backbone is critical for the pathogenesis of C. albicans via shielding β-glucan from recognition by host Dectin-1 mediated immune recognition. Moreover, our work suggests that inhibition of α-1,6-mannose extension by Mnn10 may represent a novel modality to reduce the pathogenicity of C. albicans. PMID:27144456

  11. Mnn10 Maintains Pathogenicity in Candida albicans by Extending α-1,6-Mannose Backbone to Evade Host Dectin-1 Mediated Antifungal Immunity.

    Directory of Open Access Journals (Sweden)

    Shi Qun Zhang

    2016-05-01

    Full Text Available The cell wall is a dynamic structure that is important for the pathogenicity of Candida albicans. Mannan, which is located in the outermost layer of the cell wall, has been shown to contribute to the pathogenesis of C. albicans, however, the molecular mechanism by which this occurs remains unclear. Here we identified a novel α-1,6-mannosyltransferase encoded by MNN10 in C. albicans. We found that Mnn10 is required for cell wall α-1,6-mannose backbone biosynthesis and polysaccharides organization. Deletion of MNN10 resulted in significant attenuation of the pathogenesis of C. albicans in a murine systemic candidiasis model. Inhibition of α-1,6-mannose backbone extension did not, however, impact the invasive ability of C. albicans in vitro. Notably, mnn10 mutant restored the invasive capacity in athymic nude mice, which further supports the notion of an enhanced host antifungal defense related to this backbone change. Mnn10 mutant induced enhanced Th1 and Th17 cell mediated antifungal immunity, and resulted in enhanced recruitment of neutrophils and monocytes for pathogen clearance in vivo. We also demonstrated that MNN10 could unmask the surface β-(1,3-glucan, a crucial pathogen-associated molecular pattern (PAMP of C. albicans recognized by host Dectin-1. Our results demonstrate that mnn10 mutant could stimulate an enhanced Dectin-1 dependent immune response of macrophages in vitro, including the activation of nuclear factor-κB, mitogen-activated protein kinase pathways, and secretion of specific cytokines such as TNF-α, IL-6, IL-1β and IL-12p40. In summary, our study indicated that α-1,6-mannose backbone is critical for the pathogenesis of C. albicans via shielding β-glucan from recognition by host Dectin-1 mediated immune recognition. Moreover, our work suggests that inhibition of α-1,6-mannose extension by Mnn10 may represent a novel modality to reduce the pathogenicity of C. albicans.

  12. OSI Conformance Testing for Bibliographic Applications.

    Science.gov (United States)

    Arbez, Gilbert; Swain, Leigh

    1990-01-01

    Describes the development of Open Systems Interconnection (OSI) conformance testing sites, conformance testing tools, and conformance testing services. Discusses related topics such as interoperability testing, arbitration testing, and international harmonization of conformance testing. A glossary is included. (24 references) (SD)

  13. Conformance and Deviance

    DEFF Research Database (Denmark)

    Gjerdrum Pedersen, Esben Rahbek; Neergaard, Peter; Thusgaard Pedersen, Janni

    2013-01-01

    This paper analyses how large Danish companies are responding to new governmental regulation which requires them to report on corporate social responsibility (CSR). The paper is based on an analysis of 142 company annual reports required by the new Danish regulation regarding CSR reporting, plus ...... in CSR reporting practices. Finally, it is argued that non-conformance with the new regulatory requirements is not solely about conscious resistance but may also be caused by, for example, lack of awareness, resource limitations, misinterpretations, and practical difficulties....

  14. Classical extended conformal symmetries

    International Nuclear Information System (INIS)

    Viswanathan, R.

    1990-02-01

    Extensions of the Virasoro algebra are constructed as Poisson brackets of higher spin fields which appear as coefficient fields in certain covariant derivative operators of order N. These differential operators are constructed so as to be covariant under reparametrizations on fields of definite conformal dimension. Factorization of such an N-th order operator in terms of first order operators, together with the inclusion of a spin one U(1) current, is shown to lead to a two-parameter W-algebra. One of these parameters plays the role of interpolating between W-algebras based on different Lie algebras of the same rank. (author). 11 refs

  15. Hot Conformal Gauge Theories

    DEFF Research Database (Denmark)

    Mojaza, Matin; Pica, Claudio; Sannino, Francesco

    2010-01-01

    We compute the nonzero temperature free energy up to the order g^6 \\ln(1/g) in the coupling constant for vector like SU(N) gauge theories featuring matter transforming according to different representations of the underlying gauge group. The number of matter fields, i.e. flavors, is arranged...... of flavors. Surprisingly this number, if computed to the order g^2, agrees with previous predictions for the lower boundary of the conformal window for nonsupersymmetric gauge theories. The higher order results tend to predict a higher number of critical flavors. These are universal properties, i...

  16. NMR analysis of the dynamic exchange of the NS2B cofactor between open and closed conformations of the West Nile virus NS2B-NS3 protease.

    Directory of Open Access Journals (Sweden)

    Xun-Cheng Su

    Full Text Available BACKGROUND: The two-component NS2B-NS3 proteases of West Nile and dengue viruses are essential for viral replication and established targets for drug development. In all crystal structures of the proteases to date, the NS2B cofactor is located far from the substrate binding site (open conformation in the absence of inhibitor and lining the substrate binding site (closed conformation in the presence of an inhibitor. METHODS: In this work, nuclear magnetic resonance (NMR spectroscopy of isotope and spin-labeled samples of the West Nile virus protease was used to investigate the occurrence of equilibria between open and closed conformations in solution. FINDINGS: In solution, the closed form of the West Nile virus protease is the predominant conformation irrespective of the presence or absence of inhibitors. Nonetheless, dissociation of the C-terminal part of the NS2B cofactor from the NS3 protease (open conformation occurs in both the presence and the absence of inhibitors. Low-molecular-weight inhibitors can shift the conformational exchange equilibria so that over 90% of the West Nile virus protease molecules assume the closed conformation. The West Nile virus protease differs from the dengue virus protease, where the open conformation is the predominant form in the absence of inhibitors. CONCLUSION: Partial dissociation of NS2B from NS3 has implications for the way in which the NS3 protease can be positioned with respect to the host cell membrane when NS2B is membrane associated via N- and C-terminal segments present in the polyprotein. In the case of the West Nile virus protease, discovery of low-molecular-weight inhibitors that act by breaking the association of the NS2B cofactor with the NS3 protease is impeded by the natural affinity of the cofactor to the NS3 protease. The same strategy can be more successful in the case of the dengue virus NS2B-NS3 protease.

  17. A Synthetic HIV-1 Subtype C Backbone Generates Comparable PR and RT Resistance Profiles to a Subtype B Backbone in a Recombinant Virus Assay

    OpenAIRE

    Nauwelaers, David; Van Houtte, Margriet; Winters, Bart; Steegen, Kim; Van Baelen, Kurt; Chi, Ellen; Zhou, Mimi; Steiner, Derek; Bonesteel, Rachelle; Aston, Colin; Stuyver, Lieven J.

    2011-01-01

    In order to determine phenotypic protease and reverse transcriptase inhibitor-associated resistance in HIV subtype C virus, we have synthetically constructed an HIV-1 subtype C (HIV-1-C) viral backbone for use in a recombinant virus assay. The in silico designed viral genome was divided into 4 fragments, which were chemically synthesized and joined together by conventional subcloning. Subsequently, gag-protease-reverse-transcriptase (GPRT) fragments from 8 HIV-1 subtype C-infected patient sam...

  18. Impact of Backbone Fluorination on π-Conjugated Polymers in Organic Photovoltaic Devices: A Review

    Directory of Open Access Journals (Sweden)

    Nicolas Leclerc

    2016-01-01

    Full Text Available Solution-processed bulk heterojunction solar cells have experienced a remarkable acceleration in performances in the last two decades, reaching power conversion efficiencies above 10%. This impressive progress is the outcome of a simultaneous development of more advanced device architectures and of optimized semiconducting polymers. Several chemical approaches have been developed to fine-tune the optoelectronics and structural polymer parameters required to reach high efficiencies. Fluorination of the conjugated polymer backbone has appeared recently to be an especially promising approach for the development of efficient semiconducting polymers. As a matter of fact, most currently best-performing semiconducting polymers are using fluorine atoms in their conjugated backbone. In this review, we attempt to give an up-to-date overview of the latest results achieved on fluorinated polymers for solar cells and to highlight general polymer properties’ evolution trends related to the fluorination of their conjugated backbone.

  19. Wetting of nonconserved residue-backbones: A feature indicative of aggregation associated regions of proteins.

    Science.gov (United States)

    Pradhan, Mohan R; Pal, Arumay; Hu, Zhongqiao; Kannan, Srinivasaraghavan; Chee Keong, Kwoh; Lane, David P; Verma, Chandra S

    2016-02-01

    Aggregation is an irreversible form of protein complexation and often toxic to cells. The process entails partial or major unfolding that is largely driven by hydration. We model the role of hydration in aggregation using "Dehydrons." "Dehydrons" are unsatisfied backbone hydrogen bonds in proteins that seek shielding from water molecules by associating with ligands or proteins. We find that the residues at aggregation interfaces have hydrated backbones, and in contrast to other forms of protein-protein interactions, are under less evolutionary pressure to be conserved. Combining evolutionary conservation of residues and extent of backbone hydration allows us to distinguish regions on proteins associated with aggregation (non-conserved dehydron-residues) from other interaction interfaces (conserved dehydron-residues). This novel feature can complement the existing strategies used to investigate protein aggregation/complexation. © 2015 Wiley Periodicals, Inc.

  20. Supergravitational conformal Galileons

    Science.gov (United States)

    Deen, Rehan; Ovrut, Burt

    2017-08-01

    The worldvolume actions of 3+1 dimensional bosonic branes embedded in a five-dimensional bulk space can lead to important effective field theories, such as the DBI conformal Galileons, and may, when the Null Energy Condition is violated, play an essential role in cosmological theories of the early universe. These include Galileon Genesis and "bouncing" cosmology, where a pre-Big Bang contracting phase bounces smoothly to the presently observed expanding universe. Perhaps the most natural arena for such branes to arise is within the context of superstring and M -theory vacua. Here, not only are branes required for the consistency of the theory, but, in many cases, the exact spectrum of particle physics occurs at low energy. However, such theories have the additional constraint that they must be N = 1 supersymmetric. This motivates us to compute the worldvolume actions of N = 1 supersymmetric three-branes, first in flat superspace and then to generalize them to N = 1 supergravitation. In this paper, for simplicity, we begin the process, not within the context of a superstring vacuum but, rather, for the conformal Galileons arising on a co-dimension one brane embedded in a maximally symmetric AdS 5 bulk space. We proceed to N = 1 supersymmetrize the associated worldvolume theory and then generalize the results to N = 1 supergravity, opening the door to possible new cosmological scenarios

  1. Conformational analysis of the ΜΒΡ83-99 (Phe91) and ΜΒΡ83-99 (Tyr91) peptide analogues and study of their interactions with the HLA-DR2 and human TCR receptors by using Molecular Dynamics

    Science.gov (United States)

    Potamitis, C.; Matsoukas, M.-T.; Tselios, T.; Mavromoustakos, T.; Golič Grdadolnik, S.

    2011-09-01

    The two new synthetic analogues of the MBP83-99 epitope substituted at Lys91 (primary TCR contact) with Phe [MBP83-99 (Phe91)] or Tyr [MBP83-99 (Tyr91)], have been structurally elucidated using 1D and 2D high resolution NMR studies. The conformational analysis of the two altered peptide ligands (APLs) has been performed and showed that they adopt a linear and extended conformation which is in agreement with the structural requirements of the peptides that interact with the HLA-DR2 and TCR receptors. In addition, Molecular Dynamics (MD) simulations of the two analogues in complex with HLA-DR2 (DRA, DRB1*1501) and TCR were performed. Similarities and differences of the binding motif of the two analogues were observed which provide a possible explanation of their biological activity. Their differences in the binding mode in comparison with the MBP83-99 epitope may also explain their antagonistic versus agonistic activity. The obtained results clearly indicate that substitutions in crucial amino acids (TCR contacts) in combination with the specific conformational characteristics of the MBP83-99 immunodominant epitope lead to an alteration of their biological activity. These results make the rational drug design intriguing since the biological activity is very sensitive to the substitution and conformation of the mutated MBP epitopes.

  2. Conformation-independent structural comparison of macromolecules with ProSMART

    International Nuclear Information System (INIS)

    Nicholls, Robert A.; Fischer, Marcus; McNicholas, Stuart; Murshudov, Garib N.

    2014-01-01

    The Procrustes Structural Matching Alignment and Restraints Tool (ProSMART) has been developed to allow local comparative structural analyses independent of the global conformations and sequence homology of the compared macromolecules. This allows quick and intuitive visualization of the conservation of backbone and side-chain conformations, providing complementary information to existing methods. The identification and exploration of (dis)similarities between macromolecular structures can help to gain biological insight, for instance when visualizing or quantifying the response of a protein to ligand binding. Obtaining a residue alignment between compared structures is often a prerequisite for such comparative analysis. If the conformational change of the protein is dramatic, conventional alignment methods may struggle to provide an intuitive solution for straightforward analysis. To make such analyses more accessible, the Procrustes Structural Matching Alignment and Restraints Tool (ProSMART) has been developed, which achieves a conformation-independent structural alignment, as well as providing such additional functionalities as the generation of restraints for use in the refinement of macromolecular models. Sensible comparison of protein (or DNA/RNA) structures in the presence of conformational changes is achieved by enforcing neither chain nor domain rigidity. The visualization of results is facilitated by popular molecular-graphics software such as CCP4mg and PyMOL, providing intuitive feedback regarding structural conservation and subtle dissimilarities between close homologues that can otherwise be hard to identify. Automatically generated colour schemes corresponding to various residue-based scores are provided, which allow the assessment of the conservation of backbone and side-chain conformations relative to the local coordinate frame. Structural comparison tools such as ProSMART can help to break the complexity that accompanies the constantly growing

  3. Conformation-independent structural comparison of macromolecules with ProSMART

    Energy Technology Data Exchange (ETDEWEB)

    Nicholls, Robert A., E-mail: nicholls@mrc-lmb.cam.ac.uk [MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH (United Kingdom); Fischer, Marcus [University of California San Francisco, San Francisco, CA 94158 (United States); McNicholas, Stuart [University of York, Heslington, York YO10 5DD (United Kingdom); Murshudov, Garib N. [MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH (United Kingdom)

    2014-09-01

    The Procrustes Structural Matching Alignment and Restraints Tool (ProSMART) has been developed to allow local comparative structural analyses independent of the global conformations and sequence homology of the compared macromolecules. This allows quick and intuitive visualization of the conservation of backbone and side-chain conformations, providing complementary information to existing methods. The identification and exploration of (dis)similarities between macromolecular structures can help to gain biological insight, for instance when visualizing or quantifying the response of a protein to ligand binding. Obtaining a residue alignment between compared structures is often a prerequisite for such comparative analysis. If the conformational change of the protein is dramatic, conventional alignment methods may struggle to provide an intuitive solution for straightforward analysis. To make such analyses more accessible, the Procrustes Structural Matching Alignment and Restraints Tool (ProSMART) has been developed, which achieves a conformation-independent structural alignment, as well as providing such additional functionalities as the generation of restraints for use in the refinement of macromolecular models. Sensible comparison of protein (or DNA/RNA) structures in the presence of conformational changes is achieved by enforcing neither chain nor domain rigidity. The visualization of results is facilitated by popular molecular-graphics software such as CCP4mg and PyMOL, providing intuitive feedback regarding structural conservation and subtle dissimilarities between close homologues that can otherwise be hard to identify. Automatically generated colour schemes corresponding to various residue-based scores are provided, which allow the assessment of the conservation of backbone and side-chain conformations relative to the local coordinate frame. Structural comparison tools such as ProSMART can help to break the complexity that accompanies the constantly growing

  4. Ca-C backbone fragmentation dominates in electron detachment dissociation of gas-phase polypeptide polyanions

    DEFF Research Database (Denmark)

    Kjeldsen, Frank; Silivra, Oleg A; Ivonin, Igor A

    2005-01-01

    the dissociation of oxidized radical anions [M-nH]((n-1)-*. We demonstrate that C(alpha)-C cleavages, which are otherwise rarely observed in tandem mass spectrometry, can account for most of the backbone fragmentation, with even-electron x fragments dominating over radical a* ions. Ab initio calculations at the B3......Fragmentation of peptide polyanions by electron detachment dissociation (EDD) has been induced by electron irradiation of deprotonated polypeptides [M-nH](n-) with >10 eV electrons. EDD has been found to lead preferentially to a* and x fragment ions (C(alpha)-C backbone cleavage) arising from...

  5. Backbone NMR assignment of a hypothetical protein MJ0754 from Methanococcus jannaschii DSM 2661

    Directory of Open Access Journals (Sweden)

    Kwang Yeon Hwang

    2011-06-01

    Full Text Available MJ0754 is an unknown hypothetical protein from hyperthermophilic archaeon Methanococcus jannaschii DSM 2661. Here we report the protein purification and NMR spectroscopic study of the N-terminal deleted truncated form of recombinant MJ0754 protein (Δ10-MJ0754. We aquired 3D NMR spectra and assigned all the backbone chemical shifts including Cα, Cβ, CO, HN, and N of Δ10-MJ0754. The secondary structure of Δ10-MJ0754 was estimated from the assigned backbone chemical shifts. This NMR result is very useful for further structural and functional study of MJ0754 protein.

  6. Convenient and Scalable Synthesis of Fmoc-Protected Peptide Nucleic Acid Backbone

    Directory of Open Access Journals (Sweden)

    Trevor A. Feagin

    2012-01-01

    Full Text Available The peptide nucleic acid backbone Fmoc-AEG-OBn has been synthesized via a scalable and cost-effective route. Ethylenediamine is mono-Boc protected, then alkylated with benzyl bromoacetate. The Boc group is removed and replaced with an Fmoc group. The synthesis was performed starting with 50 g of Boc anhydride to give 31 g of product in 32% overall yield. The Fmoc-protected PNA backbone is a key intermediate in the synthesis of nucleobase-modified PNA monomers. Thus, improved access to this molecule is anticipated to facilitate future investigations into the chemical properties and applications of nucleobase-modified PNA.

  7. Conformal invariance in conditioned stochastic particle systems

    Science.gov (United States)

    Schütz, Gunter M.

    2017-08-01

    We consider space-time correlations in generic one-dimensional stochastic interacting particle systems with short-range interactions that undergo a fluctuation with an atypically activity of particle jumps or reactions or spin flips. We briefly review the approach in the framework of the quantum Hamiltonian formalism and present examples where the dynamics during such large fluctuations is governed not by the typical stationary dynamics, but by ballistic universality classes with dynamical exponent z=1 that are described unitary conformally invariant field theories with central charge c. For reaction-diffusion and spin flip dynamics we identify critical points (a) in the Ising universality class with c=1/2 , and (b) in the universality class of the three-states Potts model with c=4/5 . For the Ising universality class we obtain a universal scaling form for the generating function of cumulants of the jump activity. For repulsive driven diffusive systems with one conservation law the regime of an atypically high current or hopping activity is generically conformally invariant with central charge c=1 .

  8. Dimensional reduction for conformal blocks

    Science.gov (United States)

    Hogervorst, Matthijs

    2016-09-01

    We consider the dimensional reduction of a CFT, breaking multiplets of the d-dimensional conformal group SO( d + 1 , 1) up into multiplets of SO( d, 1). This leads to an expansion of d-dimensional conformal blocks in terms of blocks in d - 1 dimensions. In particular, we obtain a formula for 3 d conformal blocks as an infinite sum over 2 F 1 hypergeometric functions with closed-form coefficients.

  9. Reflections on Conformal Spectra

    CERN Multimedia

    CERN. Geneva

    2015-01-01

    We use modular invariance and crossing symmetry of conformal field theory to reveal approximate reflection symmetries in the spectral decompositions of the partition function in two dimensions in the limit of large central charge and of the four-point function in any dimension in the limit of large scaling dimensions Δ0 of external operators. We use these symmetries to motivate universal upper bounds on the spectrum and the operator product expansion coefficients, which we then derive by independent techniques. Some of the bounds for four-point functions are valid for finite Δ0 as well as for large Δ0. We discuss a similar symmetry in a large spacetime dimension limit. Finally, we comment on the analogue of the Cardy formula and sparse light spectrum condition for the four-point function. (based on 1510.08772 with Kim & Ooguri). This seminar will be given via videolink

  10. Instantons in conformal gravity

    International Nuclear Information System (INIS)

    Strominger, A.; Horowitz, G.T.; Perry, M.J.

    1984-01-01

    Fe study extrema of the general conformally invariant action: Ssub(c)=∫1/sub(α) 2 Csup(abcd)Csub(abcd)+γRsup(abcd*)Rsup(*)sub(abcd)+iTHETARsup(abcd)*Rsub(abcd). We find the first examples in four dimensions of asymptotically euclidean gravitational instantons. These have arbitrary Euler number and Hirzebruch signature. Some of these instantons represent tunneling between zero-curvature vacua that are not related by small gauge transformations. Others represent tunneling between flat space and topologically non-trivial zero-energy initial data. A general formula for the one-loop determinant is derived in terms of the renormalization group invariant masses, the volume of space-time, the Euler number and the Hirzebruch signature. (orig.)

  11. Molecular dynamics studies of protein folding and aggregation

    Science.gov (United States)

    Ding, Feng

    that globular proteins under a denaturing environment partially unfold and aggregate by forming stabilizing hydrogen bonds between the backbones of the partial folded substructures. Proteins or peptides rich in alpha-helices also aggregate into beta-rich amyloid fibrils. Upon aggregation, the protein or peptide undergoes a conformational transition from alpha-helices to beta-sheets. The transition of alpha-helix to beta-hairpin (two-stranded beta-sheet) is studied in an all-heavy-atom discrete molecular dynamics model of a polyalanine chain. An entropical driving scenario for the alpha-helix to beta-hairpin transition is discovered.

  12. Nuclear Magnetic Resonance-Based Structural Characterization and Backbone Dynamics of Recombinant Bee Venom Melittin.

    Science.gov (United States)

    Ramirez, Lisa; Shekhtman, Alexander; Pande, Jayanti

    2018-04-30

    In recent years, there has been a resurgence of interest in melittin and its variants as their therapeutic potential has become increasingly evident. Melittin is a 26-residue peptide and a toxic component of honey bee venom. The versatility of melittin in interacting with various biological substrates, such as membranes, glycosaminoglycans, and a variety of proteins, has inspired a slew of studies that aim to improve our understanding of the structural basis of such interactions. However, these studies have largely focused on melittin solutions at high concentrations (>1 mM), even though melittin is generally effective at lower (micromolar) concentrations. Here we present high-resolution nuclear magnetic resonance studies in the lower-concentration regime using a novel method to produce isotope-labeled ( 15 N and 13 C) recombinant melittin. We provide residue-specific structural characterization of melittin in dilute aqueous solution and in 2,2,2-trifluoroethanol/water mixtures, which mimic melittin structure-function and interactions in aqueous and membrane-like environments, respectively. We find that the cis-trans isomerization of Pro14 is key to changes in the secondary structure of melittin. Thus, this study provides residue-specific structural information about melittin in the free state and in a model of the substrate-bound state. These results, taken together with published work from other laboratories, reveal the peptide's structural versatility that resembles that of intrinsically disordered proteins and peptides.

  13. Dynamics of glyphosate-induced conformational changes of Mycobacterium tuberculosis 5-enolpyruvylshikimate-3-phosphate synthase (EC 2.5.1.19) determined by hydrogen-deuterium exchange and electrospray mass spectrometry.

    Science.gov (United States)

    Marques, Maurício R; Vaso, Alessandra; Neto, João Ruggiero; Fossey, Marcelo A; Oliveira, Jaim S; Basso, Luiz A; dos Santos, Diógenes S; de Azevedo Junior, Walter F; Palma, Mario S

    2008-07-15

    The enzyme 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) catalyzes the reaction between shikimate 3-phosphate and phosphoenolpyruvate to form 5-enolpyruvylshikimate 3-phosphate, an intermediate in the shikimate pathway, which leads to the biosynthesis of aromatic amino acids. EPSPS exists in an open conformation in the absence of substrates and/or inhibitors and in a closed conformation when bound to the substrate and/or inhibitor. In the present report, the H/D exchange properties of EPSPS from Mycobacterium tuberculosis ( Mt) were investigated for both enzyme conformations using ESI mass spectrometry and circular dichroism (CD). When the conformational changes identified by H/D exchanges were mapped on the 3-D structure, it was observed that the apoenzyme underwent extensive conformational changes due to glyphosate complexation, characterized by an increase in the content of alpha-helices from 40% to 57%, while the beta-sheet content decreased from 30% to 23%. These results indicate that the enzyme underwent a series of rearrangements of its secondary structure that were accompanied by a large decrease in solvent access to many different regions of the protein. This was attributed to the compaction of 71% of alpha-helices and 57% of beta-sheets as a consequence of glyphosate binding to the enzyme. Apparently, MtEPSPS undergoes a series of inhibitor-induced conformational changes, which seem to have caused synergistic effects in preventing solvent access to the core of molecule, especially in the cleft region. This may be part of the mechanism of inhibition of the enzyme, which is required to prevent the hydration of the substrate binding site and also to induce the cleft closure to avoid entrance of the substrates.

  14. On Associative Conformal Algebras of Linear Growth

    OpenAIRE

    Retakh, Alexander

    2000-01-01

    Lie conformal algebras appear in the theory of vertex algebras. Their relation is similar to that of Lie algebras and their universal enveloping algebras. Associative conformal algebras play a role in conformal representation theory. We introduce the notions of conformal identity and unital associative conformal algebras and classify finitely generated simple unital associative conformal algebras of linear growth. These are precisely the complete algebras of conformal endomorphisms of finite ...

  15. Replacement between conformity and counter-conformity in consumption decisions.

    Science.gov (United States)

    Chou, Ting-Jui; Chang, En-Chung; Dai, Qi; Wong, Veronica

    2013-02-01

    This study assessed, in a Chinese context, how self-esteem interacts with perceived similarity and uniqueness to yield cognitive dissonance, and whether the dissonance leads to self-reported conformity or counter-conformity behavior. Participants were 408 respondents from 4 major Chinese cities (M age = 33.0 yr., SD = 4.3; 48% men). Self-perceptions of uniqueness, similarity, cognitive dissonance, self-esteem and need to behave in conformity or counter-conformity were measured. A theoretical model was assessed in four situations, relating the ratings of self-esteem and perceived similarity/uniqueness to the way other people at a wedding were dressed, and the resultant cognitive dissonance and conformity/ counter-conformity behavior. Regardless of high or low self-esteem, all participants reported cognitive dissonance when they were told that they were dressed extremely similarly to or extremely differently from the other people attending the wedding. However, the conforming/counter-conforming strategies used by participants to resolve the cognitive dissonance differed. When encountering dissonance induced by the perceived extreme uniqueness of dress, participants with low self-esteem tended to say they would dress next time so as to conform with the way others were dressed, while those with high self-esteem indicated they would continue their counter-conformity in attire. When encountering dissonance induced by the perceived extreme similarity to others, both those with high and low self-esteem tended to say they would dress in an unorthodox manner to surprise other people in the future.

  16. Detecting the solution space of vertex cover by mutual determinations and backbones.

    Science.gov (United States)

    Wei, Wei; Zhang, Renquan; Guo, Binghui; Zheng, Zhiming

    2012-07-01

    To solve the combinatorial optimization problems, especially the minimal Vertex-cover problem with high efficiency, is a significant task in theoretical computer science and many other subjects. Aiming at detecting the solution space of Vertex-cover, a new structure named mutual-determination is defined and discovered for Vertex-cover on general graphs, which results in the emergence of strong correlations among the unfrozen nodes. Based on the backbones and mutual-determinations with node ranks by leaf removal, we propose a Mutual-determination and Backbone Evolution Algorithm to achieve the reduced solution graph, which provides a graphical expression of the solution space of Vertex-cover. By this algorithm, the whole solution space and detailed structures such as backbones can be obtained strictly when there is no leaf-removal core on the given graph. Compared with the current algorithms, the Mutual-determination and Backbone Evolution Algorithm performs as well as the replica symmetry one in a certain interval but has a small gap higher than the replica symmetric breaking one and has a relatively small error for the exact results. The algorithm with the mutual-determination provides a new viewpoint to solve Vertex-cover and understand the organizations of the solution spaces, and the reduced solution graph gives an alternative way to catch detailed information of the ground/steady states.

  17. Comparing the Reliability of Regular Topologies on a Backbone Network. A Case Study

    DEFF Research Database (Denmark)

    Cecilio, Sergio Labeage; Gutierrez Lopez, Jose Manuel; Riaz, M. Tahir

    2009-01-01

    The aim of this paper is to compare the reliability of regular topologies on a backbone network. The study is focused on a large-scale fiberoptic network. Different regular topological solutions as single ring, double ring or 4-Regular grid are applied to the case study, and compared in terms...

  18. “Pinning strategy”: a novel approach for predicting the backbone ...

    Indian Academy of Sciences (India)

    Prakash

    a high performance rate. For instance, prediction in ... [de Brevern A G, Etchebest C, Benros C and Hazout S 2006 “Pinning strategy”: a novel approach for predicting the backbone structure in terms of protein blocks from sequence; ..... are confronted to a dilemma: (i) the necessity to trap the main sequence determinants.

  19. High dimensional and high resolution pulse sequences for backbone resonance assignment of intrinsically disordered proteins

    Czech Academy of Sciences Publication Activity Database

    Zawadzka-Kazimierczuk, A.; Kozminski, W.; Šanderová, Hana; Krásný, Libor

    2012-01-01

    Roč. 52, č. 4 (2012), s. 329-337 ISSN 0925-2738 R&D Projects: GA ČR GA204/09/0583 Institutional research plan: CEZ:AV0Z50200510 Keywords : Intrinsically disordered proteins * Non-uniform sampling * Backbone assignment Subject RIV: EE - Microbiology, Virology Impact factor: 2.845, year: 2012

  20. Integrative technology of massage manipulations in physical rehabilitation of students with backbone pathology

    Directory of Open Access Journals (Sweden)

    V.I. Kotelevskiy

    2016-06-01

    Full Text Available Purpose:to analyze effectiveness of massage manipulations’ integrative technology in physical rehabilitation of higher educational establishments’ students with backbone pathology. Material: in the research 195 students of 19-20 years’ age participated. All students had periodical initial neurological symptoms of functional pathology and first stage osteochondrosis in different parts of backbone. We conducted a course of 10 sessions of therapeutic massage. Results: the sense of massage integrative technology is that every specialist shall have certain optimal set of skills and knowledge in technique of manipulation sessions of massage. Integrative technology of massage manipulations consists of psycho-corrective and manipulation parts. It considers psycho-somatic, mechanical and reflex rehabilitation aspects of patho-genesis of backbone functional disorders and vertebral osteochondrosis. Conclusions: depending on pathological process or backbone functional state of every person (peculiarities of his (her psycho-somatic status or, even, his (her bents. Individual approach in choice of strategy, tactic and methodological provisioning of massage session shall be used.