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Sample records for binding mode prediction

  1. Predicting bioactive conformations and binding modes of macrocycles

    Science.gov (United States)

    Anighoro, Andrew; de la Vega de León, Antonio; Bajorath, Jürgen

    2016-10-01

    Macrocyclic compounds experience increasing interest in drug discovery. It is often thought that these large and chemically complex molecules provide promising candidates to address difficult targets and interfere with protein-protein interactions. From a computational viewpoint, these molecules are difficult to treat. For example, flexible docking of macrocyclic compounds is hindered by the limited ability of current docking approaches to optimize conformations of extended ring systems for pose prediction. Herein, we report predictions of bioactive conformations of macrocycles using conformational search and binding modes using docking. Conformational ensembles generated using specialized search technique of about 70 % of the tested macrocycles contained accurate bioactive conformations. However, these conformations were difficult to identify on the basis of conformational energies. Moreover, docking calculations with limited ligand flexibility starting from individual low energy conformations rarely yielded highly accurate binding modes. In about 40 % of the test cases, binding modes were approximated with reasonable accuracy. However, when conformational ensembles were subjected to rigid body docking, an increase in meaningful binding mode predictions to more than 50 % of the test cases was observed. Electrostatic effects did not contribute to these predictions in a positive or negative manner. Rather, achieving shape complementarity at macrocycle-target interfaces was a decisive factor. In summary, a combined computational protocol using pre-computed conformational ensembles of macrocycles as a starting point for docking shows promise in modeling binding modes of macrocyclic compounds.

  2. A 3D-QSAR-driven approach to binding mode and affinity prediction

    DEFF Research Database (Denmark)

    Tosco, Paolo; Balle, Thomas

    2012-01-01

    A method for predicting the binding mode of a series of ligands is proposed. The procedure relies on three-dimensional quantitative structure-activity relationships (3D-QSAR) and does not require structural knowledge of the binding site. Candidate alignments are automatically built and ranked...... according to a consensus scoring function. 3D-QSAR analysis based on the selected binding mode enables affinity prediction of new drug candidates having less than 10 rotatable bonds....

  3. Accuracy of binding mode prediction with a cascadic stochastic tunneling method.

    Science.gov (United States)

    Fischer, Bernhard; Basili, Serena; Merlitz, Holger; Wenzel, Wolfgang

    2007-07-01

    We investigate the accuracy of the binding modes predicted for 83 complexes of the high-resolution subset of the ASTEX/CCDC receptor-ligand database using the atomistic FlexScreen approach with a simple forcefield-based scoring function. The median RMS deviation between experimental and predicted binding mode was just 0.83 A. Over 80% of the ligands dock within 2 A of the experimental binding mode, for 60 complexes the docking protocol locates the correct binding mode in all of ten independent simulations. Most docking failures arise because (a) the experimental structure clashed in our forcefield and is thus unattainable in the docking process or (b) because the ligand is stabilized by crystal water.

  4. Binding mode and free energy prediction of fisetin/β-cyclodextrin inclusion complexes

    Directory of Open Access Journals (Sweden)

    Bodee Nutho

    2014-11-01

    Full Text Available In the present study, our aim is to investigate the preferential binding mode and encapsulation of the flavonoid fisetin in the nano-pore of β-cyclodextrin (β-CD at the molecular level using various theoretical approaches: molecular docking, molecular dynamics (MD simulations and binding free energy calculations. The molecular docking suggested four possible fisetin orientations in the cavity through its chromone or phenyl ring with two different geometries of fisetin due to the rotatable bond between the two rings. From the multiple MD results, the phenyl ring of fisetin favours its inclusion into the β-CD cavity, whilst less binding or even unbinding preference was observed in the complexes where the larger chromone ring is located in the cavity. All MM- and QM-PBSA/GBSA free energy predictions supported the more stable fisetin/β-CD complex of the bound phenyl ring. Van der Waals interaction is the key force in forming the complexes. In addition, the quantum mechanics calculations with M06-2X/6-31G(d,p clearly showed that both solvation effect and BSSE correction cannot be neglected for the energy determination of the chosen system.

  5. Binding Energy Distribution Analysis Method: Hamiltonian Replica Exchange with Torsional Flattening for Binding Mode Prediction and Binding Free Energy Estimation.

    Science.gov (United States)

    Mentes, Ahmet; Deng, Nan-Jie; Vijayan, R S K; Xia, Junchao; Gallicchio, Emilio; Levy, Ronald M

    2016-05-10

    Molecular dynamics modeling of complex biological systems is limited by finite simulation time. The simulations are often trapped close to local energy minima separated by high energy barriers. Here, we introduce Hamiltonian replica exchange (H-REMD) with torsional flattening in the Binding Energy Distribution Analysis Method (BEDAM), to reduce energy barriers along torsional degrees of freedom and accelerate sampling of intramolecular degrees of freedom relevant to protein-ligand binding. The method is tested on a standard benchmark (T4 Lysozyme/L99A/p-xylene complex) and on a library of HIV-1 integrase complexes derived from the SAMPL4 blind challenge. We applied the torsional flattening strategy to 26 of the 53 known binders to the HIV Integrase LEDGF site found to have a binding energy landscape funneled toward the crystal structure. We show that our approach samples the conformational space more efficiently than the original method without flattening when starting from a poorly docked pose with incorrect ligand dihedral angle conformations. In these unfavorable cases convergence to a binding pose within 2-3 Å from the crystallographic pose is obtained within a few nanoseconds of the Hamiltonian replica exchange simulation. We found that torsional flattening is insufficient in cases where trapping is due to factors other than torsional energy, such as the formation of incorrect intramolecular hydrogen bonds and stacking. Work is in progress to generalize the approach to handle these cases and thereby make it more widely applicable.

  6. Alkaloid metabolite profiles by GC/MS and acetylcholinesterase inhibitory activities with binding-mode predictions of five Amaryllidaceae plants.

    Science.gov (United States)

    Cortes, Natalie; Alvarez, Rafael; Osorio, Edison H; Alzate, Fernando; Berkov, Strahil; Osorio, Edison

    2015-01-01

    Acetylcholinesterase (AChE) enzymatic inhibition is an important target for the management of Alzheimer disease (AD) and AChE inhibitors are the mainstay drugs for its treatment. In order to discover new sources of potent AChE inhibitors, a combined strategy is presented based on AChE-inhibitory activity and chemical profiles by GC/MS, together with in silico studies. The combined strategy was applied on alkaloid extracts of five Amaryllidaceae species that grow in Colombia. Fifty-seven alkaloids were detected using GC/MS, and 21 of them were identified by comparing their mass-spectral fragmentation patterns with standard reference spectra in commercial and private library databases. The alkaloid extracts of Zephyranthes carinata exhibited a high level of inhibitory activity (IC50 = 5.97 ± 0.24 μg/mL). Molecular modeling, which was performed using the structures of some of the alkaloids present in this extract and the three-dimensional crystal structures of AChE derived from Torpedo californica, disclosed their binding configuration in the active site of this AChE. The results suggested that the alkaloids 3-epimacronine and lycoramine might be of interest for AChE inhibition. Although the galanthamine group is known for its potential utility in treating AD, the tazettine-type alkaloids should be evaluated to find more selective compounds of potential benefit for AD.

  7. Multiple binding modes of ibuprofen in human serum albumin identified by absolute binding free energy calculations

    KAUST Repository

    Evoli, Stefania

    2016-11-10

    Human serum albumin possesses multiple binding sites and transports a wide range of ligands that include the anti-inflammatory drug ibuprofen. A complete map of the binding sites of ibuprofen in albumin is difficult to obtain in traditional experiments, because of the structural adaptability of this protein in accommodating small ligands. In this work, we provide a set of predictions covering the geometry, affinity of binding and protonation state for the pharmaceutically most active form (S-isomer) of ibuprofen to albumin, by using absolute binding free energy calculations in combination with classical molecular dynamics (MD) simulations and molecular docking. The most favorable binding modes correctly reproduce several experimentally identified binding locations, which include the two Sudlow\\'s drug sites (DS2 and DS1) and the fatty acid binding sites 6 and 2 (FA6 and FA2). Previously unknown details of the binding conformations were revealed for some of them, and formerly undetected binding modes were found in other protein sites. The calculated binding affinities exhibit trends which seem to agree with the available experimental data, and drastically degrade when the ligand is modeled in a protonated (neutral) state, indicating that ibuprofen associates with albumin preferentially in its charged form. These findings provide a detailed description of the binding of ibuprofen, help to explain a wide range of results reported in the literature in the last decades, and demonstrate the possibility of using simulation methods to predict ligand binding to albumin.

  8. Molecular modeling of human APOBEC3G to predict the binding modes of the inhibitor compounds IMB26 and IMB35

    Directory of Open Access Journals (Sweden)

    Zhixin Zhang

    2013-07-01

    Full Text Available APOBEC3G(A3G is a host cytidine deaminase that incorporates into HIV-1 virions and efficiently inhibits viral replication. The virally encoded protein Vif binds to A3G and induces its degradation, thereby counteracting the antiviral activity of A3G. Vif-mediated A3G degradation clearly represents a potential target for anti-HIV drug development. Currently, there is an urgent need for understanding the three dimensional structure of full-length A3G. In this work, we use a homology modeling approach to propose a structure for A3G based on the crystal structure of APOBEC2 (APO2 and the catalytic domain structure of A3G. Two compounds, IMB26 and IMB35, which have been shown to bind to A3G and block degradation by Vif, were docked into the A3G model and the binding modes were generated for further analysis. The results may be used to design or optimize molecules targeting Vif–A3G interaction, and lead to the development of novel anti-HIV drugs.

  9. Observation of Protein Structural Vibrational Mode Sensitivity to Ligand Binding

    Science.gov (United States)

    Niessen, Katherine; Xu, Mengyang; Snell, Edward; Markelz, Andrea

    2014-03-01

    We report the first measurements of the dependence of large-scale protein intramolecular vibrational modes on ligand binding. These collective vibrational modes in the terahertz (THz) frequency range (5-100 cm-1) are of great interest due to their predicted relation to protein function. Our technique, Crystals Anisotropy Terahertz Microscopy (CATM), allows for room temperature, table-top measurements of the optically active intramolecular modes. CATM measurements have revealed surprisingly narrowband features. CATM measurements are performed on single crystals of chicken egg-white lysozyme (CEWL) as well as CEWL bound to tri-N-acetylglucosamine (CEWL-3NAG) inhibitor. We find narrow band resonances that dramatically shift with binding. Quasiharmonic calculations are performed on CEWL and CEWL-3NAG proteins with CHARMM using normal mode analysis. The expected CATM response of the crystals is then calculated by summing over all protein orientations within the unit cell. We will compare the CATM measurements with the calculated results and discuss the changes which arise with protein-ligand binding. This work is supported by NSF grant MRI 2 grant DBI2959989.

  10. Landscape of protein-small ligand binding modes.

    Science.gov (United States)

    Kasahara, Kota; Kinoshita, Kengo

    2016-09-01

    Elucidating the mechanisms of specific small-molecule (ligand) recognition by proteins is a long-standing conundrum. While the structures of these molecules, proteins and ligands, have been extensively studied, protein-ligand interactions, or binding modes, have not been comprehensively analyzed. Although methods for assessing similarities of binding site structures have been extensively developed, the methods for the computational treatment of binding modes have not been well established. Here, we developed a computational method for encoding the information about binding modes as graphs, and assessing their similarities. An all-against-all comparison of 20,040 protein-ligand complexes provided the landscape of the protein-ligand binding modes and its relationships with protein- and chemical spaces. While similar proteins in the same SCOP Family tend to bind relatively similar ligands with similar binding modes, the correlation between ligand and binding similarities was not very high (R(2)  = 0.443). We found many pairs with novel relationships, in which two evolutionally distant proteins recognize dissimilar ligands by similar binding modes (757,474 pairs out of 200,790,780 pairs were categorized into this relationship, in our dataset). In addition, there were an abundance of pairs of homologous proteins binding to similar ligands with different binding modes (68,217 pairs). Our results showed that many interesting relationships between protein-ligand complexes are still hidden in the structure database, and our new method for assessing binding mode similarities is effective to find them.

  11. The Binding Mode Prediction and Similar Ligand Potency in the Active Site of Vitamin D Receptor with QM/MM Interaction, MESP, and MD Simulation.

    Science.gov (United States)

    Selvaraman, Nagamani; Selvam, Saravana Kumar; Muthusamy, Karthikeyan

    2016-08-01

    Non-secosteroidal ligands are well-known vitamin D receptor (VDR) agonists. In this study, we described a combined QM/MM to define the protein-ligand interaction energy a strong positive correlation in both QM-MM interaction energy and binding free energy against the biological activity. The molecular dynamics simulation study was performed, and specific interactions were extensively studied. The molecular docking results and surface analysis shed light on steric and electrostatic complementarities of these non-secosteroidal ligands to VDR. Finally, the drug likeness properties were also calculated and found within the acceptable range. The results show that bulky group substitutions in side chain decrease the VDR activity, whereas a small substitution increased it. Functional analyses of H393A and H301A mutations substantiate their roles in the VDR agonistic and antagonistic activities. Apart from the His393 and His301, two other amino acids in the hinge region viz. Ser233 and Arg270 acted as an electron donor/acceptor specific to the agonist in the distinct ligand potency. The results from this study disclose the binding mechanism of VDR agonists and structural modifications required to improve the selectivity.

  12. Computational Prediction of RNA-Binding Proteins and Binding Sites.

    Science.gov (United States)

    Si, Jingna; Cui, Jing; Cheng, Jin; Wu, Rongling

    2015-01-01

    Proteins and RNA interaction have vital roles in many cellular processes such as protein synthesis, sequence encoding, RNA transfer, and gene regulation at the transcriptional and post-transcriptional levels. Approximately 6%-8% of all proteins are RNA-binding proteins (RBPs). Distinguishing these RBPs or their binding residues is a major aim of structural biology. Previously, a number of experimental methods were developed for the determination of protein-RNA interactions. However, these experimental methods are expensive, time-consuming, and labor-intensive. Alternatively, researchers have developed many computational approaches to predict RBPs and protein-RNA binding sites, by combining various machine learning methods and abundant sequence and/or structural features. There are three kinds of computational approaches, which are prediction from protein sequence, prediction from protein structure, and protein-RNA docking. In this paper, we review all existing studies of predictions of RNA-binding sites and RBPs and complexes, including data sets used in different approaches, sequence and structural features used in several predictors, prediction method classifications, performance comparisons, evaluation methods, and future directions.

  13. Computational Prediction of RNA-Binding Proteins and Binding Sites

    Directory of Open Access Journals (Sweden)

    Jingna Si

    2015-11-01

    Full Text Available Proteins and RNA interaction have vital roles in many cellular processes such as protein synthesis, sequence encoding, RNA transfer, and gene regulation at the transcriptional and post-transcriptional levels. Approximately 6%–8% of all proteins are RNA-binding proteins (RBPs. Distinguishing these RBPs or their binding residues is a major aim of structural biology. Previously, a number of experimental methods were developed for the determination of protein–RNA interactions. However, these experimental methods are expensive, time-consuming, and labor-intensive. Alternatively, researchers have developed many computational approaches to predict RBPs and protein–RNA binding sites, by combining various machine learning methods and abundant sequence and/or structural features. There are three kinds of computational approaches, which are prediction from protein sequence, prediction from protein structure, and protein-RNA docking. In this paper, we review all existing studies of predictions of RNA-binding sites and RBPs and complexes, including data sets used in different approaches, sequence and structural features used in several predictors, prediction method classifications, performance comparisons, evaluation methods, and future directions.

  14. Predicting zinc binding at the proteome level

    Directory of Open Access Journals (Sweden)

    Rosato Antonio

    2007-02-01

    Full Text Available Abstract Background Metalloproteins are proteins capable of binding one or more metal ions, which may be required for their biological function, for regulation of their activities or for structural purposes. Metal-binding properties remain difficult to predict as well as to investigate experimentally at the whole-proteome level. Consequently, the current knowledge about metalloproteins is only partial. Results The present work reports on the development of a machine learning method for the prediction of the zinc-binding state of pairs of nearby amino-acids, using predictors based on support vector machines. The predictor was trained using chains containing zinc-binding sites and non-metalloproteins in order to provide positive and negative examples. Results based on strong non-redundancy tests prove that (1 zinc-binding residues can be predicted and (2 modelling the correlation between the binding state of nearby residues significantly improves performance. The trained predictor was then applied to the human proteome. The present results were in good agreement with the outcomes of previous, highly manually curated, efforts for the identification of human zinc-binding proteins. Some unprecedented zinc-binding sites could be identified, and were further validated through structural modelling. The software implementing the predictor is freely available at: http://zincfinder.dsi.unifi.it Conclusion The proposed approach constitutes a highly automated tool for the identification of metalloproteins, which provides results of comparable quality with respect to highly manually refined predictions. The ability to model correlations between pairwise residues allows it to obtain a significant improvement over standard 1D based approaches. In addition, the method permits the identification of unprecedented metal sites, providing important hints for the work of experimentalists.

  15. Predicted metal binding sites for phytoremediation.

    Science.gov (United States)

    Sharma, Ashok; Roy, Sudeep; Tripathi, Kumar Parijat; Roy, Pratibha; Mishra, Manoj; Khan, Feroz; Meena, Abha

    2009-09-05

    Metal ion binding domains are found in proteins that mediate transport, buffering or detoxification of metal ions. The objective of the study is to design and analyze metal binding motifs against the genes involved in phytoremediation. This is being done on the basis of certain pre-requisite amino-acid residues known to bind metal ions/metal complexes in medicinal and aromatic plants (MAP's). Earlier work on MAP's have shown that heavy metals accumulated by aromatic and medicinal plants do not appear in the essential oil and that some of these species are able to grow in metal contaminated sites. A pattern search against the UniProtKB/Swiss-Prot and UniProtKB/TrEMBL databases yielded true positives in each case showing the high specificity of the motifs designed for the ions of nickel, lead, molybdenum, manganese, cadmium, zinc, iron, cobalt and xenobiotic compounds. Motifs were also studied against PDB structures. Results of the study suggested the presence of binding sites on the surface of protein molecules involved. PDB structures of proteins were finally predicted for the binding sites functionality in their respective phytoremediation usage. This was further validated through CASTp server to study its physico-chemical properties. Bioinformatics implications would help in designing strategy for developing transgenic plants with increased metal binding capacity. These metal binding factors can be used to restrict metal update by plants. This helps in reducing the possibility of metal movement into the food chain.

  16. Predicting binding free energies in solution

    CERN Document Server

    Jensen, Jan H

    2015-01-01

    Recent predictions of absolute binding free energies of host-guest complexes in aqueous solution using electronic structure theory have been encouraging for some systems, while other systems remain problematic for others. In paper I summarize some of the many factors that could easily contribute 1-3 kcal/mol errors at 298 K: three-body dispersion effects, molecular symmetry, anharmonicity, spurious imaginary frequencies, insufficient conformational sampling, wrong or changing ionization states, errors in the solvation free energy of ions, and explicit solvent (and ion) effects that are not well-represented by continuum models. While the paper is primarily a synthesis of previously published work there are two new results: the adaptation of Legendre transformed free energies to electronic structure theory and a use of water clusters that maximizes error cancellation in binding free energies computed using explicit solvent molecules. While I focus on binding free energies in aqueous solution the approach also a...

  17. BindUP: a web server for non-homology-based prediction of DNA and RNA binding proteins.

    Science.gov (United States)

    Paz, Inbal; Kligun, Efrat; Bengad, Barak; Mandel-Gutfreund, Yael

    2016-07-08

    Gene expression is a multi-step process involving many layers of regulation. The main regulators of the pathway are DNA and RNA binding proteins. While over the years, a large number of DNA and RNA binding proteins have been identified and extensively studied, it is still expected that many other proteins, some with yet another known function, are awaiting to be discovered. Here we present a new web server, BindUP, freely accessible through the website http://bindup.technion.ac.il/, for predicting DNA and RNA binding proteins using a non-homology-based approach. Our method is based on the electrostatic features of the protein surface and other general properties of the protein. BindUP predicts nucleic acid binding function given the proteins three-dimensional structure or a structural model. Additionally, BindUP provides information on the largest electrostatic surface patches, visualized on the server. The server was tested on several datasets of DNA and RNA binding proteins, including proteins which do not possess DNA or RNA binding domains and have no similarity to known nucleic acid binding proteins, achieving very high accuracy. BindUP is applicable in either single or batch modes and can be applied for testing hundreds of proteins simultaneously in a highly efficient manner.

  18. THz time scale structural rearrangements and binding modes in lysozyme-ligand interactions.

    Science.gov (United States)

    Woods, K N

    2014-03-01

    Predicting the conformational changes in proteins that are relevant for substrate binding is an ongoing challenge in the aim of elucidating the functional states of proteins. The motions that are induced by protein-ligand interactions are governed by the protein global modes. Our measurements indicate that the detected changes in the global backbone motion of the enzyme upon binding reflect a shift from the large-scale collective dominant mode in the unbound state towards a functional twisting deformation that assists in closing the binding cleft. Correlated motion in lysozyme has been implicated in enzyme function in previous studies, but detailed characterization of the internal fluctuations that enable the protein to explore the ensemble of conformations that ultimately foster large-scale conformational change is yet unknown. For this reason, we use THz spectroscopy to investigate the picosecond time scale binding modes and collective structural rearrangements that take place in hen egg white lysozyme (HEWL) when bound by the inhibitor (NAG)3. These protein thermal motions correspond to fluctuations that have a role in both selecting and sampling from the available protein intrinsic conformations that communicate function. Hence, investigation of these fast, collective modes may provide knowledge about the mechanism leading to the preferred binding process in HEWL-(NAG)3. Specifically, in this work we find that the picosecond time scale hydrogen-bonding rearrangements taking place in the protein hydration shell with binding modify the packing density within the hydrophobic core on a local level. These localized, intramolecular contact variations within the protein core appear to facilitate the large cooperative movements within the interfacial region separating the α- and β- domain that mediate binding. The THz time-scale fluctuations identified in the protein-ligand system may also reveal a molecular mechanism for substrate recognition.

  19. Prediction of binding modes between protein L-isoaspartyl (D-aspartyl) O-methyltransferase and peptide substrates including isomerized aspartic acid residues using in silico analytic methods for the substrate screening.

    Science.gov (United States)

    Oda, Akifumi; Noji, Ikuhiko; Fukuyoshi, Shuichi; Takahashi, Ohgi

    2015-12-10

    Because the aspartic acid (Asp) residues in proteins are occasionally isomerized in the human body, not only l-α-Asp but also l-β-Asp, D-α-Asp and D-β-Asp are found in human proteins. In these isomerized aspartic acids, the proportion of D-β-Asp is the largest and the proportions of l-β-Asp and D-α-Asp found in human proteins are comparatively small. To explain the proportions of aspartic acid isomers, the possibility of an enzyme able to repair l-β-Asp and D-α-Asp is frequently considered. The protein L-isoaspartyl (D-aspartyl) O-methyltransferase (PIMT) is considered one of the possible repair enzymes for l-β-Asp and D-α-Asp. Human PIMT is an enzyme that recognizes both l-β-Asp and D-α-Asp, and catalyzes the methylation of their side chains. In this study, the binding modes between PIMT and peptide substrates containing l-β-Asp or D-α-Asp residues were investigated using computational protein-ligand docking and molecular dynamics simulations. The results indicate that carboxyl groups of both l-β-Asp and D-α-Asp were recognized in similar modes by PIMT and that the C-terminal regions of substrate peptides were located in similar positions on PIMT for both the l-β-Asp and D-α-Asp peptides. In contrast, for peptides containing l-α-Asp or D-β-Asp residues, which are not substrates of PIMT, the computationally constructed binding modes between PIMT and peptides greatly differed from those between PIMT and substrates. In the nonsubstrate peptides, not inter- but intra-molecular hydrogen bonds were observed, and the conformations of peptides were more rigid than those of substrates. Thus, the in silico analytical methods were able to distinguish substrates from nonsubstrates and the computational methods are expected to complement experimental analytical methods.

  20. Predicted metal binding sites for phytoremediation

    OpenAIRE

    Sharma, Ashok; Roy, Sudeep; Tripathi, Kumar Parijat; Roy, Pratibha; Mishra, Manoj; Khan, Feroz; Meena, Abha

    2009-01-01

    Metal ion binding domains are found in proteins that mediate transport, buffering or detoxification of metal ions. The objective of the study is to design and analyze metal binding motifs against the genes involved in phytoremediation. This is being done on the basis of certain pre-requisite amino-acid residues known to bind metal ions/metal complexes in medicinal and aromatic plants (MAP's). Earlier work on MAP's have shown that heavy metals accumulated by aromatic and medicinal plants do no...

  1. Predicting the Diversity of Foreign Entry Modes

    DEFF Research Database (Denmark)

    Hashai, Niron; Geisler Asmussen, Christian; Benito, Gabriel;

    2007-01-01

    diversity across value chain activities and host markets. Analyzing a sample of Israeli based firms we show that larger firms exhibit a higher degree of entry mode diversity both across value chain activities and across host markets. Higher levels of knowledge intensity are also associated with more...... diversity in firms' entry modes across both dimensions....

  2. Fast Intra Prediction Mode Decision Algorithm for HEVC

    Directory of Open Access Journals (Sweden)

    Mengmeng Zhang

    2013-10-01

    Full Text Available This paper proposes a novel fast intra-prediction algorithm that exploits the Sobel operator to replace the Hadamard transform used in the Rough Mode Decision (RMD process of intra prediction in High Efficiency Video Coding (HEVC. First, the Sobel operator is used to calculate the vector direction of each pixel. A judgment is then made on which prediction mode the vector belongs to, and a histogram is applied in the scheme to generate the statistics of prediction modes for each prediction unit. Finally, the prediction mode candidates are placed in the candidate list for the rate-distortion optimization process. Experimental results show that our proposed algorithm for RMD significantly reduces the complexity of the encoder with an acceptable degradation of quality and BD-rate compared with HM7.0.  

  3. Protein Structural Memory Influences Ligand Binding Mode(s) and Unbinding Rates.

    Science.gov (United States)

    Xu, Min; Caflisch, Amedeo; Hamm, Peter

    2016-03-01

    The binding of small molecules (e.g., natural ligands, metabolites, and drugs) to proteins governs most biochemical pathways and physiological processes. Here, we use molecular dynamics to investigate the unbinding of dimethyl sulfoxide (DMSO) from two distinct states of a small rotamase enzyme, the FK506-binding protein (FKBP). These states correspond to the FKBP protein relaxed with and without DMSO in the active site. Since the time scale of ligand unbinding (2-20 ns) is faster than protein relaxation (100 ns), a novel methodology is introduced to relax the protein without having to introduce an artificial constraint. The simulation results show that the unbinding time is an order of magnitude longer for dissociation from the DMSO-bound state (holo-relaxed). That is, the actual rate of unbinding depends on the state of the protein, with the protein having a long-lived memory. The rate thus depends on the concentration of the ligand as the apo and holo states reflect low and high concentrations of DMSO, respectively. Moreover, there are multiple binding modes in the apo-relaxed state, while a single binding mode dominates the holo-relaxed state in which DMSO acts as hydrogen bond acceptor from the backbone NH of Ile56, as in the crystal structure of the DMSO/FKBP complex. The solvent relaxes very fast (∼1 ns) close to the NH of Ile56 and with the same time scale of the protein far away from the active site. These results have implications for high-throughput docking, which makes use of a rigid structure of the protein target.

  4. Automated benchmarking of peptide-MHC class I binding predictions

    DEFF Research Database (Denmark)

    Trolle, Thomas; Metushi, Imir G.; Greenbaum, Jason;

    2015-01-01

    Motivation: Numerous in silico methods predicting peptide binding to major histocompatibility complex (MHC) class I molecules have been developed over the last decades. However, the multitude of available prediction tools makes it non-trivial for the end-user to select which tool to use for a given...... the public access to frequent, up-to-date performance evaluations of all participating tools. To overcome potential selection bias in the data included in the IEDB, a strategy was implemented that suggests a set of peptides for which different prediction methods give divergent predictions as to their binding...

  5. Predictability of the Dynamic Mode Decomposition in Coastal Processes

    Science.gov (United States)

    Wang, Ruo-Qian; Herdman, Liv; Stacey, Mark; Barnard, Patrick

    2016-11-01

    Dynamic Mode Decomposition (DMD) is a model order reduction technique that helps reduce the complexity of computational models. DMD is frequently easier to interpret physically than the Proper Orthogonal Decomposition. The DMD can also produce the eigenvalues of each mode to show the trend of the mode, establishing the rate of growth or decay, but the original DMD cannot produce the contributing weights of the modes. The challenge is selecting the important modes to build a reduced order model. DMD variants have been developed to estimate the weights of each mode. One of the popular methods is called Optimal Mode Decomposition (OMD). This method decomposes the data matrix into a product of the DMD modes, the diagonal weight matrix, and the Vandermonde matrix. The weight matrix can be used to rank the importance of the mode contributions and ultimately leads to the reduced order model for prediction and controlling purpose. We are currently applying DMD to a numerical simulation of the San Francisco Bay, which features complicated coastal geometry, multiple frequency components, and high periodicity. Since DMD defines modes with specific frequencies, we expect DMD would produce a good approximation, but the preliminary results show that the predictability of the DMD is poor if unimportant modes are dropped according to the OMD. We are currently testing other DMD variants and will report our findings in the presentation.

  6. Exploring the stability of ligand binding modes to proteins by molecular dynamics simulations

    Science.gov (United States)

    Liu, Kai; Watanabe, Etsurou; Kokubo, Hironori

    2017-02-01

    The binding mode prediction is of great importance to structure-based drug design. The discrimination of various binding poses of ligand generated by docking is a great challenge not only to docking score functions but also to the relatively expensive free energy calculation methods. Here we systematically analyzed the stability of various ligand poses under molecular dynamics (MD) simulation. First, a data set of 120 complexes was built based on the typical physicochemical properties of drug-like ligands. Three potential binding poses (one correct pose and two decoys) were selected for each ligand from self-docking in addition to the experimental pose. Then, five independent MD simulations for each pose were performed with different initial velocities for the statistical analysis. Finally, the stabilities of ligand poses under MD were evaluated and compared with the native one from crystal structure. We found that about 94% of the native poses were maintained stable during the simulations, which suggests that MD simulations are accurate enough to judge most experimental binding poses as stable properly. Interestingly, incorrect decoy poses were maintained much less and 38-44% of decoys could be excluded just by performing equilibrium MD simulations, though 56-62% of decoys were stable. The computationally-heavy binding free energy calculation can be performed only for these survived poses.

  7. Influence of binding energies of electrons on nuclear mass predictions

    Science.gov (United States)

    Tang, Jing; Niu, Zhong-Ming; Guo, Jian-You

    2016-07-01

    Nuclear mass contains a wealth of nuclear structure information, and has been widely employed to extract the nuclear effective interactions. The known nuclear mass is usually extracted from the experimental atomic mass by subtracting the masses of electrons and adding the binding energy of electrons in the atom. However, the binding energies of electrons are sometimes neglected in extracting the known nuclear masses. The influence of binding energies of electrons on nuclear mass predictions are carefully investigated in this work. If the binding energies of electrons are directly subtracted from the theoretical mass predictions, the rms deviations of nuclear mass predictions with respect to the known data are increased by about 200 keV for nuclei with Z, N ⩾ 8. Furthermore, by using the Coulomb energies between protons to absorb the binding energies of electrons, their influence on the rms deviations is significantly reduced to only about 10 keV for nuclei with Z, N ⩾ 8. However, the binding energies of electrons are still important for the heavy nuclei, about 150 keV for nuclei around Z = 100 and up to about 500 keV for nuclei around Z = 120. Therefore, it is necessary to consider the binding energies of electrons to reliably predict the masses of heavy nuclei at an accuracy of hundreds of keV. Supported by National Natural Science Foundation of China (11205004)

  8. ELK1 uses different DNA binding modes to regulate functionally distinct classes of target genes.

    Directory of Open Access Journals (Sweden)

    Zaneta Odrowaz

    Full Text Available Eukaryotic transcription factors are grouped into families and, due to their similar DNA binding domains, often have the potential to bind to the same genomic regions. This can lead to redundancy at the level of DNA binding, and mechanisms are required to generate specific functional outcomes that enable distinct gene expression programmes to be controlled by a particular transcription factor. Here we used ChIP-seq to uncover two distinct binding modes for the ETS transcription factor ELK1. In one mode, other ETS transcription factors can bind regulatory regions in a redundant fashion; in the second, ELK1 binds in a unique fashion to another set of genomic targets. Each binding mode is associated with different binding site features and also distinct regulatory outcomes. Furthermore, the type of binding mode also determines the control of functionally distinct subclasses of genes and hence the phenotypic response elicited. This is demonstrated for the unique binding mode where a novel role for ELK1 in controlling cell migration is revealed. We have therefore uncovered an unexpected link between the type of binding mode employed by a transcription factor, the subsequent gene regulatory mechanisms used, and the functional categories of target genes controlled.

  9. Structural insights into Cydia pomonella pheromone binding protein 2 mediated prediction of potentially active semiochemicals

    Science.gov (United States)

    Tian, Zhen; Liu, Jiyuan; Zhang, Yalin

    2016-03-01

    Given the advantages of behavioral disruption application in pest control and the damage of Cydia pomonella, due progresses have not been made in searching active semiochemicals for codling moth. In this research, 31 candidate semiochemicals were ranked for their binding potential to Cydia pomonella pheromone binding protein 2 (CpomPBP2) by simulated docking, and this sorted result was confirmed by competitive binding assay. This high predicting accuracy of virtual screening led to the construction of a rapid and viable method for semiochemicals searching. By reference to binding mode analyses, hydrogen bond and hydrophobic interaction were suggested to be two key factors in determining ligand affinity, so is the length of molecule chain. So it is concluded that semiochemicals of appropriate chain length with hydroxyl group or carbonyl group at one head tended to be favored by CpomPBP2. Residues involved in binding with each ligand were pointed out as well, which were verified by computational alanine scanning mutagenesis. Progress made in the present study helps establish an efficient method for predicting potentially active compounds and prepares for the application of high-throughput virtual screening in searching semiochemicals by taking insights into binding mode analyses.

  10. Predicting nucleic acid binding interfaces from structural models of proteins.

    Science.gov (United States)

    Dror, Iris; Shazman, Shula; Mukherjee, Srayanta; Zhang, Yang; Glaser, Fabian; Mandel-Gutfreund, Yael

    2012-02-01

    The function of DNA- and RNA-binding proteins can be inferred from the characterization and accurate prediction of their binding interfaces. However, the main pitfall of various structure-based methods for predicting nucleic acid binding function is that they are all limited to a relatively small number of proteins for which high-resolution three-dimensional structures are available. In this study, we developed a pipeline for extracting functional electrostatic patches from surfaces of protein structural models, obtained using the I-TASSER protein structure predictor. The largest positive patches are extracted from the protein surface using the patchfinder algorithm. We show that functional electrostatic patches extracted from an ensemble of structural models highly overlap the patches extracted from high-resolution structures. Furthermore, by testing our pipeline on a set of 55 known nucleic acid binding proteins for which I-TASSER produces high-quality models, we show that the method accurately identifies the nucleic acids binding interface on structural models of proteins. Employing a combined patch approach we show that patches extracted from an ensemble of models better predicts the real nucleic acid binding interfaces compared with patches extracted from independent models. Overall, these results suggest that combining information from a collection of low-resolution structural models could be a valuable approach for functional annotation. We suggest that our method will be further applicable for predicting other functional surfaces of proteins with unknown structure.

  11. Predictions of Alpha Heating in ITER L-mode and H-mode Plasmas

    Energy Technology Data Exchange (ETDEWEB)

    R.V. Budny

    2011-01-06

    Predictions of alpha heating in L-mode and H-mode DT plasmas in ITER are generated using the PTRANSP code. The baseline toroidal field of 5.3 T, plasma current ramped to 15 MA and a flat electron density profile ramped to Greenwald fraction 0.85 are assumed. Various combinations of external heating by negative ion neutral beam injection, ion cyclotron resonance, and electron cyclotron resonance are assumed to start half-way up the density ramp. The time evolution of plasma temperatures and, for some cases, toroidal rotation are predicted assuming GLF23 and boundary parameters. Significant toroidal rotation and flow-shearing rates are predicted by GLF23 even in the L-mode phase with low boundary temperatures, and the alpha heating power is predicted to be significant if the power threshold for the transition to H-mode is higher than the planned total heating power. The alpha heating is predicted to be 8-76 MW in L-mode at full density. External heating mixes with higher beam injection power have higher alpha heating power. Alternatively if the toroidal rotation is predicted assuming that the ratio of the momentum to thermal ion energy conductivity is 0.5, the flow-shearing rate is predicted to have insignificant effects on the GLF23- predicted temperatures, and alpha heating is predicted to be 8-20 MW. In H-mode plasmas the alpha heating is predicted to depend sensitively on the assumed pedestal temperatures. Cases with fusion gain greater than 10 are predicted to have alpha heating greater than 80 MW.

  12. Prediction of MHC class I binding peptides, using SVMHC

    Directory of Open Access Journals (Sweden)

    Elofsson Arne

    2002-09-01

    Full Text Available Abstract Background T-cells are key players in regulating a specific immune response. Activation of cytotoxic T-cells requires recognition of specific peptides bound to Major Histocompatibility Complex (MHC class I molecules. MHC-peptide complexes are potential tools for diagnosis and treatment of pathogens and cancer, as well as for the development of peptide vaccines. Only one in 100 to 200 potential binders actually binds to a certain MHC molecule, therefore a good prediction method for MHC class I binding peptides can reduce the number of candidate binders that need to be synthesized and tested. Results Here, we present a novel approach, SVMHC, based on support vector machines to predict the binding of peptides to MHC class I molecules. This method seems to perform slightly better than two profile based methods, SYFPEITHI and HLA_BIND. The implementation of SVMHC is quite simple and does not involve any manual steps, therefore as more data become available it is trivial to provide prediction for more MHC types. SVMHC currently contains prediction for 26 MHC class I types from the MHCPEP database or alternatively 6 MHC class I types from the higher quality SYFPEITHI database. The prediction models for these MHC types are implemented in a public web service available at http://www.sbc.su.se/svmhc/. Conclusions Prediction of MHC class I binding peptides using Support Vector Machines, shows high performance and is easy to apply to a large number of MHC class I types. As more peptide data are put into MHC databases, SVMHC can easily be updated to give prediction for additional MHC class I types. We suggest that the number of binding peptides needed for SVM training is at least 20 sequences.

  13. Predicting where small molecules bind at protein-protein interfaces.

    Directory of Open Access Journals (Sweden)

    Peter Walter

    Full Text Available Small molecules that bind at protein-protein interfaces may either block or stabilize protein-protein interactions in cells. Thus, some of these binding interfaces may turn into prospective targets for drug design. Here, we collected 175 pairs of protein-protein (PP complexes and protein-ligand (PL complexes with known three-dimensional structures for which (1 one protein from the PP complex shares at least 40% sequence identity with the protein from the PL complex, and (2 the interface regions of these proteins overlap at least partially with each other. We found that those residues of the interfaces that may bind the other protein as well as the small molecule are evolutionary more conserved on average, have a higher tendency of being located in pockets and expose a smaller fraction of their surface area to the solvent than the remaining protein-protein interface region. Based on these findings we derived a statistical classifier that predicts patches at binding interfaces that have a higher tendency to bind small molecules. We applied this new prediction method to more than 10,000 interfaces from the protein data bank. For several complexes related to apoptosis the predicted binding patches were in direct contact to co-crystallized small molecules.

  14. A systems biology approach to transcription factor binding site prediction.

    Directory of Open Access Journals (Sweden)

    Xiang Zhou

    Full Text Available BACKGROUND: The elucidation of mammalian transcriptional regulatory networks holds great promise for both basic and translational research and remains one the greatest challenges to systems biology. Recent reverse engineering methods deduce regulatory interactions from large-scale mRNA expression profiles and cross-species conserved regulatory regions in DNA. Technical challenges faced by these methods include distinguishing between direct and indirect interactions, associating transcription regulators with predicted transcription factor binding sites (TFBSs, identifying non-linearly conserved binding sites across species, and providing realistic accuracy estimates. METHODOLOGY/PRINCIPAL FINDINGS: We address these challenges by closely integrating proven methods for regulatory network reverse engineering from mRNA expression data, linearly and non-linearly conserved regulatory region discovery, and TFBS evaluation and discovery. Using an extensive test set of high-likelihood interactions, which we collected in order to provide realistic prediction-accuracy estimates, we show that a careful integration of these methods leads to significant improvements in prediction accuracy. To verify our methods, we biochemically validated TFBS predictions made for both transcription factors (TFs and co-factors; we validated binding site predictions made using a known E2F1 DNA-binding motif on E2F1 predicted promoter targets, known E2F1 and JUND motifs on JUND predicted promoter targets, and a de novo discovered motif for BCL6 on BCL6 predicted promoter targets. Finally, to demonstrate accuracy of prediction using an external dataset, we showed that sites matching predicted motifs for ZNF263 are significantly enriched in recent ZNF263 ChIP-seq data. CONCLUSIONS/SIGNIFICANCE: Using an integrative framework, we were able to address technical challenges faced by state of the art network reverse engineering methods, leading to significant improvement in direct

  15. Oxypred: Prediction and Classification of Oxygen-Binding Proteins

    Institute of Scientific and Technical Information of China (English)

    S.; Muthukrishnan; Aarti; Garg; G.P.S.; Raghava

    2007-01-01

    This study describes a method for predicting and classifying oxygen-binding pro- teins. Firstly, support vector machine (SVM) modules were developed using amino acid composition and dipeptide composition for predicting oxygen-binding pro- teins, and achieved maximum accuracy of 85.5% and 87.8%, respectively. Sec- ondly, an SVM module was developed based on amino acid composition, classify- ing the predicted oxygen-binding proteins into six classes with accuracy of 95.8%, 97.5%, 97.5%, 96.9%, 99.4%, and 96.0% for erythrocruorin, hemerythrin, hemo- cyanin, hemoglobin, leghemoglobin, and myoglobin proteins, respectively. Finally, an SVM module was developed using dipeptide composition for classifying the oxygen-binding proteins, and achieved maximum accuracy of 96.1%, 98.7%, 98.7%, 85.6%, 99.6%, and 93.3% for the above six classes, respectively. All modules were trained and tested by five-fold cross validation. Based on the above approach, a web server Oxypred was developed for predicting and classifying oxygen-binding proteins(available from http://www.imtech.res.in/raghava/oxypred/).

  16. Predicting Modes and Displacements of Seismic Rock Slope Failures

    Science.gov (United States)

    Gibson, M. D.; Wartman, J.; Keefer, D. K.; Maclaughlin, M.; Arnold, L.; Applegate, K. N.; Smith, S.; Adams, S.

    2013-12-01

    Seismically induced rock slope failures have resulted in billions of dollars of economic damage and enormous loss of life throughout the world. Accurate prediction of the triggering and run out of these failures is elusive for a variety of reasons, including knowledge of the physical modes of failure. Our research explores the potential failure modes of an idealized rigid rock block and expands the modes typically considered to include not only sliding but also toppling (pure forward rotation) and slumping (combined backward rotation and translation). The yield acceleration (or minimum inertial acceleration to cause block movement) for slumping, similar to toppling, is found to be lower than for pure translational sliding. These yield accelerations indicate the initial modes of rock block failure; however, they do not always predict the ultimate failure mode. To predict the final failure modes, the results of discrete element numerical analyses were compared to pseudo static yield acceleration to develop a seismic failure mode decision-making chart based on block geometry and interface friction. With regard to seismic displacement predictions, current simplified models predicting ultimate displacement of a mass under seismic conditions are limited to purely translating, sliding blocks (i.e. Newmark's sliding block method). Our modeling introduces additional simplified analyses to predict ultimate displacement in toppling and slumping modes as well. Important findings from these new methods are that the magnitude of seismically-induced displacement is dependent on the size of the block (or failure mass) and that as the yield acceleration decreases the seismically induced displacements increase. We plan to map these tools into analyses that evaluate rock slope systems with complex geology and geotechnical characteristics. It is envisioned that the decision chart, which predicts the initial and ultimate modes of failure based on block geometry and interface friction

  17. The binding cavity of mouse major urinary protein is optimised for a variety of ligand binding modes

    Energy Technology Data Exchange (ETDEWEB)

    Pertinhez, Thelma A.; Ferrari, Elena; Casali, Emanuela [Department of Experimental Medicine, University of Parma, Via Volturno, 39, 43100 Parma (Italy); Patel, Jital A. [Department of Chemistry, University of Oxford, Inorganic Chemistry Laboratory, South Parks Road, Oxford OX1 3QR (United Kingdom); Spisni, Alberto, E-mail: alberto.spisni@unipr.it [Department of Experimental Medicine, University of Parma, Via Volturno, 39, 43100 Parma (Italy); Smith, Lorna J., E-mail: lorna.smith@chem.ox.ac.uk [Department of Chemistry, University of Oxford, Inorganic Chemistry Laboratory, South Parks Road, Oxford OX1 3QR (United Kingdom)

    2009-12-25

    {sup 15}N and {sup 1}HN chemical shift data and {sup 15}N relaxation studies have been used to characterise the binding of N-phenyl-naphthylamine (NPN) to mouse major urinary protein (MUP). NPN binds in the {beta}-barrel cavity of MUP, hydrogen bonding to Tyr120 and making extensive non-bonded contacts with hydrophobic side chains. In contrast to the natural pheromone 2-sec-butyl-4,5-dihydrothiazole, NPN binding gives no change to the overall mobility of the protein backbone of MUP. Comparison with 11 different ligands that bind to MUP shows a range of binding modes involving 16 different residues in the {beta}-barrel cavity. These finding justify why MUP is able to adapt to allow for many successful binding partners.

  18. Novel intra prediction modes for VP10 codec

    Science.gov (United States)

    Shleifer, Ariel; Lanka, Chinmayi; Setia, Mohit; Agarwal, Shubham; Hadar, Ofer; Mukherjee, Debargha

    2016-09-01

    The demand for high quality video is permanently on the rise and with it the need for more effective compression. Compression scope can be further expanded due to increased spatial correlation of pixels within a high quality video frame. One basic feature that takes advantage of pixels' spatial correlation for video compression is Intra-Prediction, which determines the codec's compression efficiency. Intra-Prediction enables significant reduction of the Intra-frame (I-frame) size and, therefore, contributes to more efficient bandwidth exploitation. It has been observed that the intra frame coding efficiency of VP9 is not as good as that of H.265/MPEG-HEVC. One possible reason is that HEVC's Intra-prediction algorithm uses as many as 35 prediction directions, while VP9 uses only 9 directions including the TM prediction mode. Therefore, there is high motivation to improve the Intra-Prediction scheme with new, original and proprietary algorithms that will enhance the overall performance of Google's future codec and bring its performance closer to that of HEVC. In this work, instead of using different angles for predictions, we introduce four unconventional Intra-Prediction modes for the VP10 codec - Weighted CALIC (WCALIC), Intra-Prediction using System of Linear Equations (ISLE), Prediction of Discrete Cosine Transformations (PrDCT) Coefficients and Reverse Least Power of Three (RLPT). Employed on a selection eleven (11) typical images with a variety of spatial characteristics, by using Mean Square Error (MSE) evaluation criteria, we show that our proposed algorithms (modes) were preferred and thus selected around 57% of the blocks, resulting in a reduced average prediction error, i.e. the MSE of 26%. We believe that our proposed techniques will achieve higher compression without compromising video quality, thus improving the Rate-Distortion (RD) performances of the compressed video stream.

  19. NMR Studies of a New Binding Mode of the Amino Acid Esters by Porphyrinatozinc(Ⅱ)

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    The binding mode of the amino acid ethyl esters(guest) by 5-(2-carboxylphenyl)-10,15,20-triphenylporphyrinatozinc(Ⅱ)(host 1) was studied by means of 1H NMR spectra. The binding mode is the hydrogen-bonding between the amino group of the guest and the carboxyl group of host 1 plus the coordination between the zinc atom of porphyrinatozinc(Ⅱ) and the carbonyl group of the guest. This is a novel binding mode of the metalloporphyrin to amino acid derivatives.

  20. Substrate Binding Mode and Its Implication on Drug Design for Botulinum Neurotoxin A

    Science.gov (United States)

    2008-09-26

    Substrate Binding Mode and Its Implication on Drug Design for Botulinum Neurotoxin A Desigan Kumaran1, Richa Rawat1, S. Ashraf Ahmed2, Subramanyam...Swaminathan S (2008) Substrate Binding Mode and Its Implication on Drug Design for Botulinum Neurotoxin A. PLoS Pathog 4(9): e1000165. doi:10.1371/journal.ppat...COVERED - 4. TITLE AND SUBTITLE Substrate binding mode and its implication on drug design for botulinum neurotoxin A. PLoS Pathogen 4:e100165 5a

  1. Theory and Normal Mode Analysis of Change in Protein Vibrational Dynamics on Ligand Binding

    Energy Technology Data Exchange (ETDEWEB)

    Mortisugu, Kei [RIKEN, Japan; Njunda, Brigitte [Computational Molecular Biophysics, Interdisciplinary Center for Scientific Computing (IWR); Smith, Jeremy C [ORNL

    2009-12-01

    The change of protein vibrations on ligand binding is of functional and thermodynamic importance. Here, this process is characterized using a simple analytical 'ball-and-spring' model and all-atom normal-mode analysis (NMA) of the binding of the cancer drug, methotrexate (MTX) to its target, dihydrofolate reductase (DHFR). The analytical model predicts that the coupling between protein vibrations and ligand external motion generates entropy-rich, low-frequency vibrations in the complex. This is consistent with the atomistic NMA which reveals vibrational softening in forming the DHFR-MTX complex, a result also in qualitative agreement with neutron-scattering experiments. Energy minimization of the atomistic bound-state (B) structure while gradually decreasing the ligand interaction to zero allows the generation of a hypothetical 'intermediate' (I) state, without the ligand force field but with a structure similar to that of B. In going from I to B, it is found that the vibrational entropies of both the protein and MTX decrease while the complex structure becomes enthalpically stabilized. However, the relatively weak DHFR:MTX interaction energy results in the net entropy gain arising from coupling between the protein and MTX external motion being larger than the loss of vibrational entropy on complex formation. This, together with the I structure being more flexible than the unbound structure, results in the observed vibrational softening on ligand binding.

  2. PRBP: Prediction of RNA-Binding Proteins Using a Random Forest Algorithm Combined with an RNA-Binding Residue Predictor.

    Science.gov (United States)

    Ma, Xin; Guo, Jing; Xiao, Ke; Sun, Xiao

    2015-01-01

    The prediction of RNA-binding proteins is an incredibly challenging problem in computational biology. Although great progress has been made using various machine learning approaches with numerous features, the problem is still far from being solved. In this study, we attempt to predict RNA-binding proteins directly from amino acid sequences. A novel approach, PRBP predicts RNA-binding proteins using the information of predicted RNA-binding residues in conjunction with a random forest based method. For a given protein, we first predict its RNA-binding residues and then judge whether the protein binds RNA or not based on information from that prediction. If the protein cannot be identified by the information associated with its predicted RNA-binding residues, then a novel random forest predictor is used to determine if the query protein is a RNA-binding protein. We incorporated features of evolutionary information combined with physicochemical features (EIPP) and amino acid composition feature to establish the random forest predictor. Feature analysis showed that EIPP contributed the most to the prediction of RNA-binding proteins. The results also showed that the information from the RNA-binding residue prediction improved the overall performance of our RNA-binding protein prediction. It is anticipated that the PRBP method will become a useful tool for identifying RNA-binding proteins. A PRBP Web server implementation is freely available at http://www.cbi.seu.edu.cn/PRBP/.

  3. Probing ligand-binding modes and binding mechanisms of benzoxazole-based amide inhibitors with soluble epoxide hydrolase by molecular docking and molecular dynamics simulation.

    Science.gov (United States)

    Chen, Hang; Zhang, Ying; Li, Liang; Han, Ju-Guang

    2012-08-30

    Soluble epoxide hydrolase (sEH) has become a new therapeutic target for treating a variety of human diseases. The inhibition of human sEH hydrolase activity was studied by molecular docking and molecular dynamics (MD) simulation techniques. A set of six benzoxazole-based amide inhibitors binding to sEH has been studied through molecular docking, MD simulation, free energy calculations, and energy decomposition analysis. On the basis of molecular mechanics-generalized Born/surface area (MM-GB/SA) computation and normal-mode analysis (NMA), the obtained results indicate that the rank of calculated binding free energies (ΔΔGTOT) of these inhibitors is in excellent agreement with that of experimental bioactivity data (IC50). The correlation coefficient (r(2)) between the predicted ΔΔGTOT and IC50 is 0.88. van der Waals energies are the largest component of the total energies, and the entropy changes play an indispensable role in determining the ΔΔGTOT. Rational binding modes were discussed and determined by the docking results and binding free energies. The free energy decomposition of each residue reveals that the residue Trp334 dominates the most binding free energies among all residues and that the activities for these molecules to the sEH are not decided by hydrogen bonds or a certain residue but by the common effect of multiple side chains in the active site.

  4. An in silico analysis of the binding modes and binding affinities of small molecule modulators of PDZ-peptide interactions.

    Directory of Open Access Journals (Sweden)

    Garima Tiwari

    Full Text Available Inhibitors of PDZ-peptide interactions have important implications in a variety of biological processes including treatment of cancer and Parkinson's disease. Even though experimental studies have reported characterization of peptidomimetic inhibitors of PDZ-peptide interactions, the binding modes for most of them have not been characterized by structural studies. In this study we have attempted to understand the structural basis of the small molecule-PDZ interactions by in silico analysis of the binding modes and binding affinities of a set of 38 small molecules with known K(i or K(d values for PDZ2 and PDZ3 domains of PSD-95 protein. These two PDZ domains show differential selectivity for these compounds despite having a high degree of sequence similarity and almost identical peptide binding pockets. Optimum binding modes for these ligands for PDZ2 and PDZ3 domains were identified by using a novel combination of semi-flexible docking and explicit solvent molecular dynamics (MD simulations. Analysis of the binding modes revealed most of the peptidomimectic ligands which had high K(i or K(d moved away from the peptide binding pocket, while ligands with high binding affinities remained in the peptide binding pocket. The differential specificities of the PDZ2 and PDZ3 domains primarily arise from differences in the conformation of the loop connecting βB and βC strands, because this loop interacts with the N-terminal chemical moieties of the ligands. We have also computed the MM/PBSA binding free energy values for these 38 compounds with both the PDZ domains from multiple 5 ns MD trajectories on each complex i.e. a total of 228 MD trajectories of 5 ns length each. Interestingly, computational binding free energies show good agreement with experimental binding free energies with a correlation coefficient of approximately 0.6. Thus our study demonstrates that combined use of docking and MD simulations can help in identification of potent inhibitors

  5. Prediction of DNA-binding specificity in zinc finger proteins

    Indian Academy of Sciences (India)

    Sumedha Roy; Shayoni Dutta; Kanika Khanna; Shruti Singla; Durai Sundar

    2012-07-01

    Zinc finger proteins interact via their individual fingers to three base pair subsites on the target DNA. The four key residue positions −1, 2, 3 and 6 on the alpha-helix of the zinc fingers have hydrogen bond interactions with the DNA. Mutating these key residues enables generation of a plethora of combinatorial possibilities that can bind to any DNA stretch of interest. Exploiting the binding specificity and affinity of the interaction between the zinc fingers and the respective DNA can help to generate engineered zinc fingers for therapeutic purposes involving genome targeting. Exploring the structure–function relationships of the existing zinc finger–DNA complexes can aid in predicting the probable zinc fingers that could bind to any target DNA. Computational tools ease the prediction of such engineered zinc fingers by effectively utilizing information from the available experimental data. A study of literature reveals many approaches for predicting DNA-binding specificity in zinc finger proteins. However, an alternative approach that looks into the physico-chemical properties of these complexes would do away with the difficulties of designing unbiased zinc fingers with the desired affinity and specificity. We present a physico-chemical approach that exploits the relative strengths of hydrogen bonding between the target DNA and all combinatorially possible zinc fingers to select the most optimum zinc finger protein candidate.

  6. Predicting accurate absolute binding energies in aqueous solution

    DEFF Research Database (Denmark)

    Jensen, Jan Halborg

    2015-01-01

    Recent predictions of absolute binding free energies of host-guest complexes in aqueous solution using electronic structure theory have been encouraging for some systems, while other systems remain problematic. In this paper I summarize some of the many factors that could easily contribute 1-3 kcal......-represented by continuum models. While I focus on binding free energies in aqueous solution the approach also applies (with minor adjustments) to any free energy difference such as conformational or reaction free energy differences or activation free energies in any solvent....

  7. Prediction of chloride ingress and binding in cement paste

    DEFF Research Database (Denmark)

    Geiker, Mette Rica; Nielsen, Erik Pram; Herforth, Duncan

    2007-01-01

    This paper summarizes recent work on an analytical model for predicting the ingress rate of chlorides in cement-based materials. An integral part of this is a thermodynamic model for predicting the phase equilibria in hydrated Portland cement. The model’s ability to predict chloride binding...... in Portland cement pastes at any content of chloride, alkalis, sulfates and carbonate was verified experimentally and found to be equally valid when applied to other data in the literature. The thermodynamic model for predicting the phase equilibria in hydrated Portland cement was introduced into an existing...... Finite Difference Model for the ingress of chlorides into concrete which takes into account its multi-component nature. The “composite theory” was then used to predict the diffusivity of each ion based on the phase assemblage present in the hydrated Portland cement paste. Agreement was found between...

  8. Molecular level studies on binding modes of labeling molecules with polyalanine peptides

    Science.gov (United States)

    Mao, Xiaobo; Wang, Chenxuan; Ma, Xiaojing; Zhang, Min; Liu, Lei; Zhang, Lan; Niu, Lin; Zeng, Qindao; Yang, Yanlian; Wang, Chen

    2011-04-01

    In this work, the binding modes of typical labeling molecules (thioflavin T (ThT), Congo red (CR) and copper(ii) phthalocyanine tetrasulfonic acid tetrasodium salt (PcCu(SO3Na)4)) on pentaalanine, which is a model peptide segment of amyloidpeptides, have been resolved at the molecular level by using scanning tunneling microscopy (STM). In the STM images, ThT molecules are predominantly adsorbed parallel to the peptide strands and two binding modes could be identified. It was found that ThT molecules are preferentially binding on top of the peptide strand, and the mode of intercalated between neighboring peptides also exists. The parallel binding mode of CR molecules can be observed with pentaalaninepeptides. Besides the binding modes of labeling molecules, the CR and PcCu(SO3Na)4 display different adsorption affinity with the pentaalaninepeptides. The results could be beneficial for obtaining molecular level insight of the interactions between labeling molecules and peptides.In this work, the binding modes of typical labeling molecules (thioflavin T (ThT), Congo red (CR) and copper(ii) phthalocyanine tetrasulfonic acid tetrasodium salt (PcCu(SO3Na)4)) on pentaalanine, which is a model peptide segment of amyloidpeptides, have been resolved at the molecular level by using scanning tunneling microscopy (STM). In the STM images, ThT molecules are predominantly adsorbed parallel to the peptide strands and two binding modes could be identified. It was found that ThT molecules are preferentially binding on top of the peptide strand, and the mode of intercalated between neighboring peptides also exists. The parallel binding mode of CR molecules can be observed with pentaalaninepeptides. Besides the binding modes of labeling molecules, the CR and PcCu(SO3Na)4 display different adsorption affinity with the pentaalaninepeptides. The results could be beneficial for obtaining molecular level insight of the interactions between labeling molecules and peptides. Electronic

  9. QSAR Models for the Prediction of Plasma Protein Binding

    Directory of Open Access Journals (Sweden)

    Zeshan Amin

    2013-02-01

    Full Text Available Introduction: The prediction of plasma protein binding (ppb is of paramount importance in the pharmacokinetics characterization of drugs, as it causes significant changes in volume of distribution, clearance and drug half life. This study utilized Quantitative Structure – Activity Relationships (QSAR for the prediction of plasma protein binding. Methods: Protein binding values for 794 compounds were collated from literature. The data was partitioned into a training set of 662 compounds and an external validation set of 132 compounds. Physicochemical and molecular descriptors were calculated for each compound using ACD labs/logD, MOE (Chemical Computing Group and Symyx QSAR software packages. Several data mining tools were employed for the construction of models. These included stepwise regression analysis, Classification and Regression Trees (CART, Boosted trees and Random Forest. Results: Several predictive models were identified; however, one model in particular produced significantly superior prediction accuracy for the external validation set as measured using mean absolute error and correlation coefficient. The selected model was a boosted regression tree model which had the mean absolute error for training set of 13.25 and for validation set of 14.96. Conclusion: Plasma protein binding can be modeled using simple regression trees or multiple linear regressions with reasonable model accuracies. These interpretable models were able to identify the governing molecular factors for a high ppb that included hydrophobicity, van der Waals surface area parameters, and aromaticity. On the other hand, the more complicated ensemble method of boosted regression trees produced the most accurate ppb estimations for the external validation set.

  10. Automated benchmarking of peptide-MHC class I binding predictions

    DEFF Research Database (Denmark)

    Trolle, Thomas; Metushi, Imir G.; Greenbaum, Jason

    2015-01-01

    the public access to frequent, up-to-date performance evaluations of all participating tools. To overcome potential selection bias in the data included in the IEDB, a strategy was implemented that suggests a set of peptides for which different prediction methods give divergent predictions as to their binding...... educated selections between participating tools. Of the four participating servers, NetMHCpan performed the best, followed by ANN, SMM and finally ARB. Availability and implementation: Up-to-date performance evaluations of each server can be found online at http://tools.iedb.org/auto_bench/mhci/weekly. All...

  11. Imputation for transcription factor binding predictions based on deep learning

    Science.gov (United States)

    Qin, Qian

    2017-01-01

    Understanding the cell-specific binding patterns of transcription factors (TFs) is fundamental to studying gene regulatory networks in biological systems, for which ChIP-seq not only provides valuable data but is also considered as the gold standard. Despite tremendous efforts from the scientific community to conduct TF ChIP-seq experiments, the available data represent only a limited percentage of ChIP-seq experiments, considering all possible combinations of TFs and cell lines. In this study, we demonstrate a method for accurately predicting cell-specific TF binding for TF-cell line combinations based on only a small fraction (4%) of the combinations using available ChIP-seq data. The proposed model, termed TFImpute, is based on a deep neural network with a multi-task learning setting to borrow information across transcription factors and cell lines. Compared with existing methods, TFImpute achieves comparable accuracy on TF-cell line combinations with ChIP-seq data; moreover, TFImpute achieves better accuracy on TF-cell line combinations without ChIP-seq data. This approach can predict cell line specific enhancer activities in K562 and HepG2 cell lines, as measured by massively parallel reporter assays, and predicts the impact of SNPs on TF binding. PMID:28234893

  12. Study on the binding mode of Mg(Sal2trien) with DNA

    Institute of Scientific and Technical Information of China (English)

    XI Xiaoli; YANG Manman; ZHOU Chengyong; ZHAO Jing; YANG Pin

    2006-01-01

    In this study the complex Mg(Sal2trien) was synthesized for the first time, the binding mode of which with CT DNA was studied by the methods of UV spectra, fluorescence spectra, viscosity and CV (cyclic voltammetry). It was found that after the complex acted with CT DNA, the Abs of UV spectra rose obviously; the fluorescence intensity of EB-DNA was almost not changed; viscosity decreased. Determination of cyclic voltammetry showed that DNA made the MgL's formal potential negatively shift. Scatchard plot showed that the addition of the binding mode of the complex to EB was uncompetitive inhibition compared with EB to DNA. So the binding mode of the complex with CT DNA was stable-electricity binding. Then the interaction of the complex with pBR322 was studied by the method of gel electrophoresis. The result showed that the complex could cleave pBR322 DNA effectively.

  13. A Predictive Model for Wind Farms Using Dynamic Mode Decomposition

    Science.gov (United States)

    Thomas, Vaughan; Meneveau, Charles; Gayme, Dennice

    2016-11-01

    In this work we extend traditional dynamic mode decomposition (DMD) to develop a linear predictive model for the time evolution of the velocity field for a multiple-turbine wind farm. Traditional DMD identifies a set of DMD modes which can be used to produce a linear system that approximates the dynamics of the original system. Typically, these DMD modes consist of those that both grow and decay, but in order to develop a predictive model we need a system that evolves along a manifold that neither grows nor decays. Here we modify the DMD calculation to build such a model. We then apply this method to three dimensional large eddy simulations (LES) of a multi-turbine wind farm. Our predictive wind farm model is initialized with a small time series of data independent of the original data used to create the system. When initialized in this manner our DMD based model can reproduce the subsequent time evolution of the velocity field over ten inter-turbine convective timescales with a gradual falloff in performance. This work is supported by the National Science Foundation (Grants ECCS-1230788 and OISE-1243482, the WINDINSPIRE project).

  14. Pharmacophore-based virtual screening, biological evaluation and binding mode analysis of a novel protease-activated receptor 2 antagonist

    Science.gov (United States)

    Cho, Nam-Chul; Seo, Seoung-Hwan; Kim, Dohee; Shin, Ji-Sun; Ju, Jeongmin; Seong, Jihye; Seo, Seon Hee; Lee, Iiyoun; Lee, Kyung-Tae; Kim, Yun Kyung; No, Kyoung Tai; Pae, Ae Nim

    2016-08-01

    Protease-activated receptor 2 (PAR2) is a G protein-coupled receptor, mediating inflammation and pain signaling in neurons, thus it is considered to be a potential therapeutic target for inflammatory diseases. In this study, we performed a ligand-based virtual screening of 1.6 million compounds by employing a common-feature pharmacophore model and two-dimensional similarity search to identify a new PAR2 antagonist. The common-feature pharmacophore model was established based on the biological screening results of our in-house library. The initial virtual screening yielded a total number of 47 hits, and additional biological activity tests including PAR2 antagonism and anti-inflammatory effects resulted in a promising candidate, compound 43, which demonstrated an IC50 value of 8.22 µM against PAR2. In next step, a PAR2 homology model was constructed using the crystal structure of the PAR1 as a template to explore the binding mode of the identified ligands. A molecular docking method was optimized by comparing the binding modes of a known PAR2 agonist GB110 and antagonist GB83, and applied to predict the binding mode of our hit compound 43. In-depth docking analyses revealed that the hydrophobic interaction with Phe2435.39 is crucial for PAR2 ligands to exert antagonistic activity. MD simulation results supported the predicted docking poses that PAR2 antagonist blocked a conformational rearrangement of Na+ allosteric site in contrast to PAR2 agonist that showed Na+ relocation upon GPCR activation. In conclusion, we identified new a PAR2 antagonist together with its binding mode, which provides useful insights for the design and development of PAR2 ligands.

  15. Pharmacophore-based virtual screening, biological evaluation and binding mode analysis of a novel protease-activated receptor 2 antagonist.

    Science.gov (United States)

    Cho, Nam-Chul; Seo, Seoung-Hwan; Kim, Dohee; Shin, Ji-Sun; Ju, Jeongmin; Seong, Jihye; Seo, Seon Hee; Lee, Iiyoun; Lee, Kyung-Tae; Kim, Yun Kyung; No, Kyoung Tai; Pae, Ae Nim

    2016-08-01

    Protease-activated receptor 2 (PAR2) is a G protein-coupled receptor, mediating inflammation and pain signaling in neurons, thus it is considered to be a potential therapeutic target for inflammatory diseases. In this study, we performed a ligand-based virtual screening of 1.6 million compounds by employing a common-feature pharmacophore model and two-dimensional similarity search to identify a new PAR2 antagonist. The common-feature pharmacophore model was established based on the biological screening results of our in-house library. The initial virtual screening yielded a total number of 47 hits, and additional biological activity tests including PAR2 antagonism and anti-inflammatory effects resulted in a promising candidate, compound 43, which demonstrated an IC50 value of 8.22 µM against PAR2. In next step, a PAR2 homology model was constructed using the crystal structure of the PAR1 as a template to explore the binding mode of the identified ligands. A molecular docking method was optimized by comparing the binding modes of a known PAR2 agonist GB110 and antagonist GB83, and applied to predict the binding mode of our hit compound 43. In-depth docking analyses revealed that the hydrophobic interaction with Phe243(5.39) is crucial for PAR2 ligands to exert antagonistic activity. MD simulation results supported the predicted docking poses that PAR2 antagonist blocked a conformational rearrangement of Na(+) allosteric site in contrast to PAR2 agonist that showed Na(+) relocation upon GPCR activation. In conclusion, we identified new a PAR2 antagonist together with its binding mode, which provides useful insights for the design and development of PAR2 ligands.

  16. Binding Mode of Insulin Receptor and Agonist Peptide

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Insulin is a protein hormone secreted by pancreatic β cells. One of its main functions is to keep the balance of glucose inside the body by regulating the absorption and metabolism of glucose in the periphery tissue, as well as the production and storage of hepatic glycogen. The insulin receptor is a transmembrane glycoprotein in which two α subunits with a molecular weight of 135 kD and twoβ subunits with a molecular weight of 95 kD are joined by a disulfide bond to form a β-α-α-β structure. The extracellular α subunit, especially, its three domains near the N-terminal are partially responsible for signal transduction or ligand-binding, as indicated by the experiments. The extracellular α subunits are involved in binding the ligands. The experimental results indicate that the three domains of the N-terminal of the α subunits are the main determinative parts of the insulin receptor to bind the insulin or mimetic peptide.We employed the extracellular domain (PDBID: 1IGR) of the insulin-like growth factor-1 receptor (IGF-1 R ) as the template to simulate and optimize the spatial structures of the three domains in the extracellular domain of the insulin receptor, which includes 468 residues. The work was accomplished by making use of the homology program in the Insight Ⅱ package on an Origin3800 server. The docking calculations of the insulin receptor obtained by homology with hexapeptides were carried out by means of the program Affinity. The analysis indicated that there were hydrogen bonding, and electrostatic and hydrophobic effects in the docking complex of the insulin receptor with hexapeptides.Moreover, we described the spatial orientation of a mimetic peptide with agonist activity in the docking complex. We obtained a rough model of binding of DLAPSQ or STIVYS with the insulin receptor, which provides the powerful theoretical support for designing the minimal insulin mimetic peptide with agonist activity, making it possible to develop oral small

  17. Development of predictive models for predicting binding affinity of endocrine disrupting chemicals to fish sex hormone-binding globulin.

    Science.gov (United States)

    Liu, Huihui; Yang, Xianhai; Yin, Cen; Wei, Mengbi; He, Xiao

    2017-02-01

    Disturbing the transport process is a crucial pathway for endocrine disrupting chemicals (EDCs) exerting disrupting endocrine function. However, this mechanism has not received enough attention compared with that of hormones receptors and synthetase. Recently, we have explored the interaction between EDCs and sex hormone-binding globulin of human (hSHBG). In this study, interactions between EDCs and sex hormone-binding globulin of eight fish species (fSHBG) were investigated by employing classification methods and quantitative structure-activity relationships (QSAR). In the modeling, the relative binding affinity (RBA) of a chemical with 17β-estradiol binding to fSHBG was selected as the endpoint. Classification models were developed for two fish species, while QSAR models were established for the other six fish species. Statistical results indicated that the models had satisfactory goodness of fit, robustness and predictive ability, and that application domain covered a large number of endogenous and exogenous steroidal and non-steroidal chemicals. Additionally, by comparing the log RBA values, it was found that the same chemical may have different affinities for fSHBG from different fish species, thus species diversity should be taken into account. However, the affinity of fSHBG showed a high correlation for fishes within the same Order (i.e., Salmoniformes, Cypriniformes, Perciformes and Siluriformes), thus the fSHBG binding data for one fish species could be used to extrapolate other fish species in the same Order.

  18. Determination of the cationic amphiphilic drug-DNA binding mode and DNA-assisted fluorescence resonance energy transfer amplification.

    Science.gov (United States)

    Yaseen, Zahid; Banday, Abdul Rouf; Hussain, Mohammed Aamir; Tabish, Mohammad; Kabir-ud-Din

    2014-03-25

    Understanding the mechanism of drug-DNA binding is crucial for predicting the potential genotoxicity of drugs. Agarose gel electrophoresis, absorption, steady state fluorescence, and circular dichroism have been used in exploring the interaction of cationic amphiphilic drugs (CADs) such as amitriptyline hydrochloride (AMT), imipramine hydrochloride (IMP), and promethazine hydrochloride (PMT) with calf thymus or pUC19 DNA. Agarose gel electrophoresis assay, along with absorption and steady state fluorescence studies, reveal interaction between the CADs and DNA. A comparative study of the drugs with respect to the effect of urea, iodide induced quenching, and ethidium bromide (EB) exclusion assay reflects binding of CADs to the DNA primarily in an intercalative fashion. Circular dichroism data also support the intercalative mode of binding. Besides quenching, there is fluorescence exchange energy transfer (FRET) in between CADs and EB using DNA as a template.

  19. Active site binding modes of inhibitors of Staphylococcus aureus mevalonate diphosphate decarboxylase from docking and molecular dynamics simulations.

    Science.gov (United States)

    Addo, James K; Skaff, D Andrew; Miziorko, Henry M

    2016-01-01

    Bacterial mevalonate diphosphate decarboxylase (MDD) is an attractive therapeutic target for antibacterial drug development. In this work, we discuss a combined docking and molecular dynamics strategy toward inhibitor binding to bacterial MDD. The docking parameters utilized in this study were first validated with observations for the inhibitors 6-fluoromevalonate diphosphate (FMVAPP) and diphosphoglycolylproline (DPGP) using existing structures for the Staphylococcus epidermidis enzyme. The validated docking protocol was then used to predict structures of the inhibitors bound to Staphylococcus aureus MDD using the unliganded crystal structure of Staphylococcus aureus MDD. We also investigated a possible interactions improvement by combining this docking method with molecular dynamics simulations. Thus, the predicted docking structures were analyzed in a molecular dynamics trajectory to generate dynamic models and reinforce the predicted binding modes. FMVAPP is predicted to make more extensive contacts with S. aureus MDD, forming stable hydrogen bonds with Arg144, Arg193, Lys21, Ser107, and Tyr18, as well as making stable hydrophobic interactions with Tyr18, Trp19, and Met196. The differences in predicted binding are supported by experimentally determined Ki values of 0.23 ± 0.02 and 34 ± 8 μM, for FMVAPP and DPGP, respectively. The structural information coupled with the kinetic characterization obtained from this study should be useful in defining the requirements for inhibition as well as in guiding the selection of active compounds for inhibitor optimization.

  20. Predicting accurate absolute binding energies in aqueous solution

    DEFF Research Database (Denmark)

    Jensen, Jan Halborg

    2015-01-01

    Recent predictions of absolute binding free energies of host-guest complexes in aqueous solution using electronic structure theory have been encouraging for some systems, while other systems remain problematic. In this paper I summarize some of the many factors that could easily contribute 1-3 kcal...... mol(-1) errors at 298 K: three-body dispersion effects, molecular symmetry, anharmonicity, spurious imaginary frequencies, insufficient conformational sampling, wrong or changing ionization states, errors in the solvation free energy of ions, and explicit solvent (and ion) effects that are not well......-represented by continuum models. While I focus on binding free energies in aqueous solution the approach also applies (with minor adjustments) to any free energy difference such as conformational or reaction free energy differences or activation free energies in any solvent....

  1. Half-life predictions for decay modes of superheavy nuclei

    Energy Technology Data Exchange (ETDEWEB)

    Duarte, S.B.; Tavares, O.A.P. [Centro Brasileiro de Pesquisas Fisicas (CBPF), Rio de Janeiro, RJ (Brazil); Goncalves, M. [Instituto de Radioprotecao e Dosimetria (IRD), Rio de Janeiro, RJ (Brazil); Rodriguez, O.; Guzman, F. [Instituto Superior de Ciencias e Tecnologia Nucleares (InSTEC), La Habana (Cuba); Barbosa, T.N.; Garcia, F.; Dimarco, A. [Universidade Estadual de Santa Cruz, Ilheus, BA (Brazil). Dept. de Ciencias Exatas e Tecnologicas

    2004-09-01

    We applied the Effective Liquid Drop Model (ELDM) to predict the alpha-decay, cluster emission and cold fission half-life-values of nuclei in the region of Superheavy Elements (SHE). The present calculations have been made in the region of the ZN-plane defined by 155 <=N <=220 and 110<=Z<=135. Shell effects are included via the Q-value of the corresponding decay case. We report the results of a systematic calculation of the half-life for the three nuclear decay modes in a region of the ZN-plane where superheavy elements are expected to be found. Results have shown that, among the decay modes investigated here, the alpha decay is the dominant one. i.e, the decay mode of smallest half-lives. Half-life predictions for alpha decay, cluster emission and cold fission for the isotopic family of the most recent SHE detected of Z=115 and for the isotopic family of the already consolidated SHE of Z=111 are presented. (author)

  2. Prediction of Protein-DNA binding by Monte Carlo method

    Science.gov (United States)

    Deng, Yuefan; Eisenberg, Moises; Korobka, Alex

    1997-08-01

    We present an analysis and prediction of protein-DNA binding specificity based on the hydrogen bonding between DNA, protein, and auxillary clusters of water molecules. Zif268, glucocorticoid receptor, λ-repressor mutant, HIN-recombinase, and tramtrack protein-DNA complexes are studied. Hydrogen bonds are approximated by the Lennard-Jones potential with a cutoff distance between the hydrogen and the acceptor atoms set to 3.2 Åand an angular component based on a dipole-dipole interaction. We use a three-stage docking algorithm: geometric hashing that matches pairs of hydrogen bonding sites; (2) least-squares minimization of pairwise distances to filter out insignificant matches; and (3) Monte Carlo stochastic search to minimize the energy of the system. More information can be obtained from our first paper on this subject [Y.Deng et all, J.Computational Chemistry (1995)]. Results show that the biologically correct base pair is selected preferentially when there are two or more strong hydrogen bonds (with LJ potential lower than -0.20) that bind it to the protein. Predicted sequences are less stable in the case of weaker bonding sites. In general the inclusion of water bridges does increase the number of base pairs for which correct specificity is predicted.

  3. Predicting the whispering gallery mode spectra of microresonators

    CERN Document Server

    Hall, Jonathan M M; Henderson, Matthew R; Francois, Alexandre; Reynolds, Tess; Riesena, Nicolas; Monro, Tanya M

    2015-01-01

    The whispering gallery modes (WGMs) of optical resonators have prompted intensive research efforts due to their usefulness in the field of biological sensing, and their employment in nonlinear optics. While much information is available in the literature on numerical modeling of WGMs in microspheres, it remains a challenging task to be able to predict the emitted spectra of spherical microresonators. Here, we establish a customizable Finite- Difference Time-Domain (FDTD)-based approach to investigate the WGM spectrum of microspheres. The simulations are carried out in the vicinity of a dipole source rather than a typical plane-wave beam excitation, thus providing an effective analogue of the fluorescent dye or nanoparticle coatings used in experiment. The analysis of a single dipole source at different positions on the surface or inside a microsphere, serves to assess the relative efficiency of nearby radiating TE and TM modes, characterizing the profile of the spectrum. By varying the number, positions and a...

  4. Structure-Based Understanding of Binding Affinity and Mode of Estrogen Receptor α Agonists and Antagonists

    Science.gov (United States)

    Barron, Mace G.

    2017-01-01

    The flexible hydrophobic ligand binding pocket (LBP) of estrogen receptor α (ERα) allows the binding of a wide variety of endocrine disruptors. Upon ligand binding, the LBP reshapes around the contours of the ligand and stabilizes the complex by complementary hydrophobic interactions and specific hydrogen bonds with the ligand. Here we present a framework for quantitative analysis of the steric and electronic features of the human ERα-ligand complex using three dimensional (3D) protein-ligand interaction description combined with 3D-QSAR approach. An empirical hydrophobicity density field is applied to account for hydrophobic contacts of ligand within the LBP. The obtained 3D-QSAR model revealed that hydrophobic contacts primarily determine binding affinity and govern binding mode with hydrogen bonds. Several residues of the LBP appear to be quite flexible and adopt a spectrum of conformations in various ERα-ligand complexes, in particular His524. The 3D-QSAR was combined with molecular docking based on three receptor conformations to accommodate receptor flexibility. The model indicates that the dynamic character of the LBP allows accommodation and stable binding of structurally diverse ligands, and proper representation of the protein flexibility is critical for reasonable description of binding of the ligands. Our results provide a quantitative and mechanistic understanding of binding affinity and mode of ERα agonists and antagonists that may be applicable to other nuclear receptors. PMID:28061508

  5. Binding Mode Selection Determines the Action of Ecstasy Homologs at Monoamine Transporters.

    Science.gov (United States)

    Sandtner, Walter; Stockner, Thomas; Hasenhuetl, Peter S; Partilla, John S; Seddik, Amir; Zhang, Yuan-Wei; Cao, Jianjing; Holy, Marion; Steinkellner, Thomas; Rudnick, Gary; Baumann, Michael H; Ecker, Gerhard F; Newman, Amy Hauck; Sitte, Harald H

    2016-01-01

    Determining the structural elements that define substrates and inhibitors at the monoamine transporters is critical to elucidating the mechanisms underlying these disparate functions. In this study, we addressed this question directly by generating a series of N-substituted 3,4-methylenedioxyamphetamine analogs that differ only in the number of methyl substituents on the terminal amine group. Starting with 3,4-methylenedioxy-N-methylamphetamine, 3,4-methylenedioxy-N,N-dimethylamphetamine (MDDMA) and 3,4-methylenedioxy-N,N,N-trimethylamphetamine (MDTMA) were prepared. We evaluated the functional activities of the compounds at all three monoamine transporters in native brain tissue and cells expressing the transporters. In addition, we used ligand docking to generate models of the respective protein-ligand complexes, which allowed us to relate the experimental findings to available structural information. Our results suggest that the 3,4-methylenedioxyamphetamine analogs bind at the monoamine transporter orthosteric binding site by adopting one of two mutually exclusive binding modes. 3,4-methylenedioxyamphetamine and 3,4-methylenedioxy-N-methylamphetamine adopt a high-affinity binding mode consistent with a transportable substrate, whereas MDDMA and MDTMA adopt a low-affinity binding mode consistent with an inhibitor, in which the ligand orientation is inverted. Importantly, MDDMA can alternate between both binding modes, whereas MDTMA exclusively binds to the low-affinity mode. Our experimental results are consistent with the idea that the initial orientation of bound ligands is critical for subsequent interactions that lead to transporter conformational changes and substrate translocation.

  6. Structure-based drug design enables conversion of a DFG-in binding CSF-1R kinase inhibitor to a DFG-out binding mode.

    Science.gov (United States)

    Meyers, Marvin J; Pelc, Matthew; Kamtekar, Satwik; Day, Jacqueline; Poda, Gennadiy I; Hall, Molly K; Michener, Marshall L; Reitz, Beverly A; Mathis, Karl J; Pierce, Betsy S; Parikh, Mihir D; Mischke, Deborah A; Long, Scott A; Parlow, John J; Anderson, David R; Thorarensen, Atli

    2010-03-01

    The work described herein demonstrates the utility of structure-based drug design (SBDD) in shifting the binding mode of an HTS hit from a DFG-in to a DFG-out binding mode resulting in a class of novel potent CSF-1R kinase inhibitors suitable for lead development.

  7. Structure-based drug design enables conversion of a DFG-in binding CSF-1R kinase inhibitor to a DFG-out binding mode

    Energy Technology Data Exchange (ETDEWEB)

    Meyers, Marvin J.; Pelc, Matthew; Kamtekar, Satwik; Day, Jacqueline; Poda, Gennadiy I.; Hall, Molly K.; Michener, Marshall L.; Reitz, Beverly A.; Mathis, Karl J.; Pierce, Betsy S.; Parikh, Mihir D.; Mischke, Deborah A.; Long, Scott A.; Parlow, John J.; Anderson, David R.; Thorarensen, Atli (Pfizer)

    2010-08-11

    The work described herein demonstrates the utility of structure-based drug design (SBDD) in shifting the binding mode of an HTS hit from a DFG-in to a DFG-out binding mode resulting in a class of novel potent CSF-1R kinase inhibitors suitable for lead development.

  8. Predictions of H-mode performance in ITER

    Energy Technology Data Exchange (ETDEWEB)

    Budny, R. V.; Andre, R.; Bateman, G.; Halpern, F.; Kessel, C. E.; Kritz, A.; McCune, D.

    2008-03-03

    Time-dependent integrated predictive modeling is carried out using the PTRANSP code to predict fusion power and parameters such as alpha particle density and pressure in ITER H-mode plasmas. Auxiliary heating by negative ion neutral beam injection and ion cyclotron heating of He3 minority ions are modeled, and the GLF23 transport model is used in the prediction of the evolution of plasma temperature profiles. Effects of beam steering, beam torque, plasma rotation, beam current drive, pedestal temperatures, sawtooth oscillations, magnetic diffusion, and accumulation of He ash are treated self-consistently. Variations in assumptions associated with physics uncertainties for standard base-line DT H-mode plasmas (with Ip=15 MA, BTF=5.3 T, and Greenwald fraction=0.86) lead to a range of predictions for DT fusion power PDT and quasi-steady state fusion QDT (≡ PDT/Paux). Typical predictions assuming Paux = 50-53 MW yield PDT = 250- 720 MW and QDT = 5 - 14. In some cases where Paux is ramped down or shut off after initial flat-top conditions, quasi-steady QDT can be considerably higher, even infinite. Adverse physics assumptions such as existence of an inward pinch of the helium ash and an ash recycling coefficient approaching unity lead to very low values for PDT. Alternative scenarios with different heating and reduced performance regimes are also considered including plasmas with only H or D isotopes, DT plasmas with toroidal field reduced 10 or 20%, and discharges with reduced beam voltage. In full-performance D-only discharges, tritium burn-up is predicted to generate central tritium densities up to 1016/m3 and DT neutron rates up to 5×1016/s, compared with the DD neutron rates of 6×1017/s. Predictions with the toroidal field reduced 10 or 20% below the planned 5.3 T and keeping the same q98, Greenwald fraction, and Βη indicate that the fusion yield PDT and QDT will be lower by about a factor of two (scaling as B3.5).

  9. Binding Modes of Aromatic Ligands to Mammalian Heme Peroxidases with Associated Functional Implications

    Science.gov (United States)

    Singh, Amit K.; Singh, Nagendra; Sinha, Mau; Bhushan, Asha; Kaur, Punit; Srinivasan, Alagiri; Sharma, Sujata; Singh, Tej P.

    2009-01-01

    The binding and structural studies of bovine lactoperoxidase with three aromatic ligands, acetylsalicylic acid (ASA), salicylhydoxamic acid (SHA), and benzylhydroxamic acid (BHA) show that all the three compounds bind to lactoperoxidase at the substrate binding site on the distal heme side. The binding of ASA occurs without perturbing the position of conserved heme water molecule W-1, whereas both SHA and BHA displace it by the hydroxyl group of their hydroxamic acid moieties. The acetyl group carbonyl oxygen atom of ASA forms a hydrogen bond with W-1, which in turn makes three other hydrogen-bonds, one each with heme iron, His-109 Nϵ2, and Gln-105 Nϵ2. In contrast, in the complexes of SHA and BHA, the OH group of hydroxamic acid moiety in both complexes interacts with heme iron directly with Fe-OH distances of 3.0 and 3.2Å respectively. The OH is also hydrogen bonded to His-109 Nϵ2 and Gln-105Nϵ2. The plane of benzene ring of ASA is inclined at 70.7° from the plane of heme moiety, whereas the aromatic planes of SHA and BHA are nearly parallel to the heme plane with inclinations of 15.7 and 6.2°, respectively. The mode of ASA binding provides the information about the mechanism of action of aromatic substrates, whereas the binding characteristics of SHA and BHA indicate the mode of inhibitor binding. PMID:19465478

  10. The PIP2 binding mode of the C2 domains of rabphilin-3A.

    Science.gov (United States)

    Montaville, Pierre; Coudevylle, Nicolas; Radhakrishnan, Anand; Leonov, Andrei; Zweckstetter, Markus; Becker, Stefan

    2008-06-01

    Phosphatidylinositol-4,5-bisphosphate (PIP2) is a key player in the neurotransmitter release process. Rabphilin-3A is a neuronal C2 domain tandem containing protein that is involved in this process. Both its C2 domains (C2A and C2B) are able to bind PIP2. The investigation of the interactions of the two C2 domains with the PIP2 headgroup IP3 (inositol-1,4,5-trisphosphate) by NMR showed that a well-defined binding site can be described on the concave surface of each domain. The binding modes of the two domains are different. The binding of IP3 to the C2A domain is strongly enhanced by Ca(2+) and is characterized by a K(D) of 55 microM in the presence of a saturating concentration of Ca(2+) (5 mM). Reciprocally, the binding of IP3 increases the apparent Ca(2+)-binding affinity of the C2A domain in agreement with a Target-Activated Messenger Affinity (TAMA) mechanism. The C2B domain binds IP3 in a Ca(2+)-independent fashion with low affinity. These different PIP2 headgroup recognition modes suggest that PIP2 is a target of the C2A domain of rabphilin-3A while this phospholipid is an effector of the C2B domain.

  11. Evidence of DNA-Ligand Binding with Different Modes Studied by Spectroscopy

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    The binding behavior of several fluorescence dyes to calf thymus DNA has been studied by absorption, fluorescence and atomic force microscopy (AFM), which could provide direct evidence of formation modes and the corresponding nanostructural features of the ligand-DNA complexes.

  12. DNA interaction with DAPI fluorescent dye: Force spectroscopy decouples two different binding modes.

    Science.gov (United States)

    Reis, L A; Rocha, M S

    2017-05-01

    In this work, we use force spectroscopy to investigate the interaction between the DAPI fluorescent dye and the λ-DNA molecule under high (174 mM) and low (34 mM) ionic strengths. Firstly, we have measured the changes on the mechanical properties (persistence and contour lengths) of the DNA-DAPI complexes as a function of the dye concentration in the sample. Then, we use recently developed models in order to connect the behavior of both mechanical properties to the physical chemistry of the interaction. Such analysis has allowed us to identify and to decouple two main binding modes, determining the relevant physicochemical (binding) parameters for each of these modes: minor groove binding, which saturates at very low DAPI concentrations ( CT ∼ 0.50 μM) and presents equilibrium binding constants of the order of ∼10(7) M(-1) for the two ionic strengths studied; and intercalation, which starts to play a significant role only after the saturation of the first mode, presenting much smaller equilibrium binding constants (∼10(5) M(-1) ).

  13. The binding modes of carbazole derivatives with telomere G-quadruplex

    Science.gov (United States)

    Zhang, Xiu-feng; Zhang, Hui-juan; Xiang, Jun-feng; Li, Qian; Yang, Qian-fan; Shang, Qian; Zhang, Yan-xia; Tang, Ya-lin

    2010-10-01

    It is reported that carbazole derivatives can stabilize G-quadruplex DNA structure formed by human telomeric sequence, and therefore, they have the potential to serve as anti-cancer agents. In this present study, in order to further explore the binding mode between carbazole derivatives and G-quadruplex formed by human telomeric sequence, two carbazole iodides (BMVEC, MVEC) molecules were synthesized and used to investigate the interaction with the human telomeric parallel and antiparallel G-quadruplex structures by NMR, CD and molecular modeling study. Interestingly, it is the pivotal the cationic charge pendant groups of pyridinium rings of carbazole that plays an essential role in the stabilizing and binding mode of the human telomeric sequences G-quadruplex structure. It was found that BMVEC with two cationic charge pendant groups of pyridinium rings of 9-ethylcarbazole cannot only stabilize parallel G-quadruple of Hum6 by groove binding and G-tetrad stacking modes and antiparallel G-quadruplex of Hum22 by groove binding, but also induce the formation of mixed G-quadruplex of Hum22. While MVEC with one cationic charge pendant groups of pyridinium ring only can bind with the parallel G-quadruplex of Hum6 by the stacking onto the G4 G-tetrad and could not interact with the G-quadruplex of Hum22.

  14. Platelet serotonin transporter function predicts default-mode network activity.

    Directory of Open Access Journals (Sweden)

    Christian Scharinger

    Full Text Available The serotonin transporter (5-HTT is abundantly expressed in humans by the serotonin transporter gene SLC6A4 and removes serotonin (5-HT from extracellular space. A blood-brain relationship between platelet and synaptosomal 5-HT reuptake has been suggested, but it is unknown today, if platelet 5-HT uptake can predict neural activation of human brain networks that are known to be under serotonergic influence.A functional magnetic resonance study was performed in 48 healthy subjects and maximal 5-HT uptake velocity (Vmax was assessed in blood platelets. We used a mixed-effects multilevel analysis technique (MEMA to test for linear relationships between whole-brain, blood-oxygen-level dependent (BOLD activity and platelet Vmax.The present study demonstrates that increases in platelet Vmax significantly predict default-mode network (DMN suppression in healthy subjects independent of genetic variation within SLC6A4. Furthermore, functional connectivity analyses indicate that platelet Vmax is related to global DMN activation and not intrinsic DMN connectivity.This study provides evidence that platelet Vmax predicts global DMN activation changes in healthy subjects. Given previous reports on platelet-synaptosomal Vmax coupling, results further suggest an important role of neuronal 5-HT reuptake in DMN regulation.

  15. Ligand-induced conformational changes: Improved predictions of ligand binding conformations and affinities

    DEFF Research Database (Denmark)

    Frimurer, T.M.; Peters, Günther H.J.; Iversen, L.F.

    2003-01-01

    A computational docking strategy using multiple conformations of the target protein is discussed and evaluated. A series of low molecular weight, competitive, nonpeptide protein tyrosine phosphatase inhibitors are considered for which the x-ray crystallographic structures in complex with protein...... tyrosine phosphatase 1 B (PTP1B) are known. To obtain a quantitative measure of the impact of conformational changes induced by the inhibitors, these were docked to the active site region of various structures of PTP1B using the docking program FlexX. Firstly, the inhibitors were docked to a PTP1B crystal...... predicted binding energy and a correct docking mode. Thirdly, to improve the predictability of the docking procedure in the general case, where only a single target protein structure is known, we evaluate an approach which takes possible protein side-chain conformational changes into account. Here, side...

  16. Mechanisms of Intentional Binding and Sensory Attenuation: The Role of Temporal Prediction, Temporal Control, Identity Prediction, and Motor Prediction

    Science.gov (United States)

    Hughes, Gethin; Desantis, Andrea; Waszak, Florian

    2013-01-01

    Sensory processing of action effects has been shown to differ from that of externally triggered stimuli, with respect both to the perceived timing of their occurrence (intentional binding) and to their intensity (sensory attenuation). These phenomena are normally attributed to forward action models, such that when action prediction is consistent…

  17. Convolutional neural network architectures for predicting DNA–protein binding

    Science.gov (United States)

    Zeng, Haoyang; Edwards, Matthew D.; Liu, Ge; Gifford, David K.

    2016-01-01

    Motivation: Convolutional neural networks (CNN) have outperformed conventional methods in modeling the sequence specificity of DNA–protein binding. Yet inappropriate CNN architectures can yield poorer performance than simpler models. Thus an in-depth understanding of how to match CNN architecture to a given task is needed to fully harness the power of CNNs for computational biology applications. Results: We present a systematic exploration of CNN architectures for predicting DNA sequence binding using a large compendium of transcription factor datasets. We identify the best-performing architectures by varying CNN width, depth and pooling designs. We find that adding convolutional kernels to a network is important for motif-based tasks. We show the benefits of CNNs in learning rich higher-order sequence features, such as secondary motifs and local sequence context, by comparing network performance on multiple modeling tasks ranging in difficulty. We also demonstrate how careful construction of sequence benchmark datasets, using approaches that control potentially confounding effects like positional or motif strength bias, is critical in making fair comparisons between competing methods. We explore how to establish the sufficiency of training data for these learning tasks, and we have created a flexible cloud-based framework that permits the rapid exploration of alternative neural network architectures for problems in computational biology. Availability and Implementation: All the models analyzed are available at http://cnn.csail.mit.edu. Contact: gifford@mit.edu Supplementary information: Supplementary data are available at Bioinformatics online. PMID:27307608

  18. Absolute analytical prediction of photonic crystal guided mode resonance wavelengths

    DEFF Research Database (Denmark)

    Hermannsson, Pétur Gordon; Vannahme, Christoph; Smith, Cameron;

    2014-01-01

    A class of photonic crystal resonant reflectors known as guided mode resonant filters are optical structures that are widely used in the field of refractive index sensing, particularly in biosensing. For the purposes of understanding and design, their behavior has traditionally been modeled...... numerically with methods such as rigorous coupled wave analysis. Here it is demonstrated how the absolute resonance wavelengths of such structures can be predicted by analytically modeling them as slab waveguides in which the propagation constant is determined by a phase matching condition. The model...... into account. Furthermore, it is demonstrated that the model is valid beyond the limit of low grating modulation, for periodically discontinuous waveguide layers, high refractive index contrasts, and highly dispersive media....

  19. RNA tertiary structure prediction with ModeRNA.

    Science.gov (United States)

    Rother, Magdalena; Rother, Kristian; Puton, Tomasz; Bujnicki, Janusz M

    2011-11-01

    Noncoding RNAs perform important roles in the cell. As their function is tightly connected with structure, and as experimental methods are time-consuming and expensive, the field of RNA structure prediction is developing rapidly. Here, we present a detailed study on using the ModeRNA software. The tool uses the comparative modeling approach and can be applied when a structural template is available and an alignment of reasonable quality can be performed. We guide the reader through the entire process of modeling Escherichia coli tRNA(Thr) in a conformation corresponding to the complex with an aminoacyl-tRNA synthetase (aaRS). We describe the choice of a template structure, preparation of input files, and explore three possible modeling strategies. In the end, we evaluate the resulting models using six alternative benchmarks. The ModeRNA software can be freely downloaded from http://iimcb.genesilico.pl/moderna/ under the conditions of the General Public License. It runs under LINUX, Windows and Mac OS. It is also available as a server at http://iimcb.genesilico.pl/modernaserver/. The models and the script to reproduce the study from this article are available at http://www.genesilico.pl/moderna/examples/.

  20. Study on the Binding Mode of a Co(Ⅱ) Complex with DNA

    Institute of Scientific and Technical Information of China (English)

    ZHOU Qing-Hua; YANG Pin

    2005-01-01

    The mode of binding of CoLCl2, here L=bis(2-benzimidazolylmethyl)amine, with calf thymus DNA has been investigated by fluorescence measurements, equilibrium dialysis, viscosity experiments and gel electrophoresis. The complex was found to bind but weakly to DNA, with binding constant of 1.96× 104 L/mol determind at 20 ℃ in a solution containing 5 mmol/L Tris-HCl (pH 7.1) and 50 mmol/L NaCl. Polyelectrolyte theory was applied to analyse these values. Viscosity experiments show that binding did not alter the relative viscosity of DNA with any complexes to an appreciable extent. Electrophoresis test displayed that the compound could not cleave the DNA.These results show that the complex is essentially electrostatically bound to DNA.

  1. Prediction of nucleosome positioning based on transcription factor binding sites.

    Directory of Open Access Journals (Sweden)

    Xianfu Yi

    Full Text Available BACKGROUND: The DNA of all eukaryotic organisms is packaged into nucleosomes, the basic repeating units of chromatin. The nucleosome consists of a histone octamer around which a DNA core is wrapped and the linker histone H1, which is associated with linker DNA. By altering the accessibility of DNA sequences, the nucleosome has profound effects on all DNA-dependent processes. Understanding the factors that influence nucleosome positioning is of great importance for the study of genomic control mechanisms. Transcription factors (TFs have been suggested to play a role in nucleosome positioning in vivo. PRINCIPAL FINDINGS: Here, the minimum redundancy maximum relevance (mRMR feature selection algorithm, the nearest neighbor algorithm (NNA, and the incremental feature selection (IFS method were used to identify the most important TFs that either favor or inhibit nucleosome positioning by analyzing the numbers of transcription factor binding sites (TFBSs in 53,021 nucleosomal DNA sequences and 50,299 linker DNA sequences. A total of nine important families of TFs were extracted from 35 families, and the overall prediction accuracy was 87.4% as evaluated by the jackknife cross-validation test. CONCLUSIONS: Our results are consistent with the notion that TFs are more likely to bind linker DNA sequences than the sequences in the nucleosomes. In addition, our results imply that there may be some TFs that are important for nucleosome positioning but that play an insignificant role in discriminating nucleosome-forming DNA sequences from nucleosome-inhibiting DNA sequences. The hypothesis that TFs play a role in nucleosome positioning is, thus, confirmed by the results of this study.

  2. Schizosaccharomyces pombe protection of telomeres 1 utilizes alternate binding modes to accommodate different telomeric sequences.

    Science.gov (United States)

    Altschuler, Sarah E; Dickey, Thayne H; Wuttke, Deborah S

    2011-09-01

    The ends of eukaryotic chromosomes consist of long tracts of repetitive GT-rich DNA with variable sequence homogeneity between and within organisms. Telomeres terminate in a conserved 3'-ssDNA overhang that, regardless of sequence variability, is specifically and tightly bound by proteins of the telomere-end protection family. The high affinity ssDNA-binding activity of S. pombe Pot1 protein (SpPot1) is conferred by a DNA-binding domain consisting of two subdomains, Pot1pN and Pot1pC. Previous work has shown that Pot1pN binds a single repeat of the core telomere sequence (GGTTAC) with exquisite specificity, while Pot1pC binds an extended sequence of nine nucleotides (GGTTACGGT) with modest specificity requirements. We find that full-length SpPot1 binds the composite 15mer, (GGTTAC)(2)GGT, and a shorter two-repeat 12mer, (GGTTAC)(2), with equally high affinity (<3 pM), but with substantially different kinetic and thermodynamic properties. The binding mode of the SpPot1/15mer complex is more stable than that of the 12mer complex, with a 2-fold longer half-life and increased tolerance to nucleotide and amino acid substitutions. Our data suggest that SpPot1 protection of heterogeneous telomeres is mediated through 5'-sequence recognition and the use of alternate binding modes to maintain high affinity interaction with the G-strand, while simultaneously discriminating against the complementary strand.

  3. Deciphering the groove binding modes of tau-fluvalinate and flumethrin with calf thymus DNA

    Science.gov (United States)

    Tao, Mo; Zhang, Guowen; Pan, Junhui; Xiong, Chunhong

    2016-02-01

    Tau-fluvalinate (TFL) and flumethrin (FL), widely used in agriculture and a class of synthetic pyrethroid pesticides with a similar structure, may cause a potential security risk. Herein, the modes of binding in vitro of TFL and FL with calf thymus DNA (ctDNA) were characterized by fluorescence, UV-vis absorption, circular dichroism (CD) and Fourier transform infrared (FT-IR) spectroscopy with the aid of viscosity measurements, melting analyses and molecular docking studies. The fluorescence titration indicated that both TFL and FL bound to ctDNA forming complexes through hydrogen bonding and van der Waals forces. The binding constants of TFL and FL with ctDNA were in the range of 104 L mol- 1, and FL exhibited a higher binding propensity than TFL. The iodide quenching effect, single/double-stranded DNA effects, and ctDNA melting and viscosity measurements demonstrated that the binding of both TFL and FL to ctDNA was groove mode. The FT-IR analyses suggested the A-T region of the minor groove of ctDNA as the preferential binding for TFL and FL, which was confirmed by the displacement assays with Hoechst 33258 probe, and the molecular docking visualized the specific binding. The changes in CD spectra indicated that both FL and TFL induced the perturbation on the base stacking and helicity of B-DNA, but the disturbance caused by FL was more obvious. Gel electrophoresis analyses indicated that both TFL and FL did not cause significant DNA cleavage. This study provides novel insights into the binding properties of TFL/FL with ctDNA and its toxic mechanisms.

  4. Deciphering the groove binding modes of tau-fluvalinate and flumethrin with calf thymus DNA.

    Science.gov (United States)

    Tao, Mo; Zhang, Guowen; Pan, Junhui; Xiong, Chunhong

    2016-02-15

    Tau-fluvalinate (TFL) and flumethrin (FL), widely used in agriculture and a class of synthetic pyrethroid pesticides with a similar structure, may cause a potential security risk. Herein, the modes of binding in vitro of TFL and FL with calf thymus DNA (ctDNA) were characterized by fluorescence, UV-vis absorption, circular dichroism (CD) and Fourier transform infrared (FT-IR) spectroscopy with the aid of viscosity measurements, melting analyses and molecular docking studies. The fluorescence titration indicated that both TFL and FL bound to ctDNA forming complexes through hydrogen bonding and van der Waals forces. The binding constants of TFL and FL with ctDNA were in the range of 10(4)Lmol(-1), and FL exhibited a higher binding propensity than TFL. The iodide quenching effect, single/double-stranded DNA effects, and ctDNA melting and viscosity measurements demonstrated that the binding of both TFL and FL to ctDNA was groove mode. The FT-IR analyses suggested the A-T region of the minor groove of ctDNA as the preferential binding for TFL and FL, which was confirmed by the displacement assays with Hoechst 33258 probe, and the molecular docking visualized the specific binding. The changes in CD spectra indicated that both FL and TFL induced the perturbation on the base stacking and helicity of B-DNA, but the disturbance caused by FL was more obvious. Gel electrophoresis analyses indicated that both TFL and FL did not cause significant DNA cleavage. This study provides novel insights into the binding properties of TFL/FL with ctDNA and its toxic mechanisms.

  5. Computational determination of the binding mode of α-conotoxin to nicotinic acetylcholine receptor

    Science.gov (United States)

    Tabassum, Nargis; Yu, Rilei; Jiang, Tao

    2016-12-01

    Conotoxins belong to the large families of disulfide-rich peptide toxins from cone snail venom, and can act on a broad spectrum of ion channels and receptors. They are classified into different subtypes based on their targets. The α-conotoxins selectively inhibit the current of the nicotinic acetylcholine receptors. Because of their unique selectivity towards distinct nAChR subtypes, α-conotoxins become valuable tools in nAChR study. In addition to the X-ray structures of α-conotoxins in complex with acetylcholine-binding protein, a homolog of the nAChR ligand-binding domain, the high-resolution crystal structures of the extracellular domain of the α1 and α9 subunits are also obtained. Such structures not only revealed the details of the configuration of nAChR, but also provided higher sequence identity templates for modeling the binding modes of α-conotoxins to nAChR. This mini-review summarizes recent modeling studies for the determination of the binding modes of α-conotoxins to nAChR. As there are not crystal structures of the nAChR in complex with conotoxins, computational modeling in combination of mutagenesis data is expected to reveal the molecular recognition mechanisms that govern the interactions between α-conotoxins and nAChR at molecular level. An accurate determination of the binding modes of α-conotoxins on AChRs allows rational design of α-conotoxin analogues with improved potency or selectivity to nAChRs.

  6. Study on the drug resistance and the binding mode of HIV-1 integrase with LCA inhibitor

    Institute of Scientific and Technical Information of China (English)

    HU; JianPing; CHANG; Shan; CHEN; WeiZu; WANG; CunXin

    2007-01-01

    Human immunodeficiency virus type 1 (HIV-1) integrase (IN) is an essential enzyme in the lifecycle of this virus and also an important target for the study of anti-HIV drugs. The binding mode of the wild type IN core domain and its G140S mutant with L-Chicoric acid (LCA) inhibitor were investigated by using multiple conformation molecular docking and molecular dynamics (MD) simulation. Based on the binding modes, the drug resistance mechanism was explored for the G140S mutant of IN with LCA. The results indicate that the binding site of the G140S mutant of IN core domain with LCA is different from that of the core domain of the wild type IN, which leads to the partial loss of inhibition potency of LCA. The flexibility of the IN functional loop region and the interactions between Mg2+ ion and the three key residues (i.e., D64, D116, E152) stimulate the biological operation of IN. The drug resistance also lies in several other important effects, such as the repulsion between LCA and E152 in the G140S mutant core domain, the weakening of K159 binding with LCA and Y143 pointing to the pocket of the G140S mutant. All of the above simulation results agree well with experimental data, which provide us with some helpful information for designing the drug of anti-HIV based on the structure of IN.

  7. Interaction of coumarin with calf thymus DNA: deciphering the mode of binding by in vitro studies.

    Science.gov (United States)

    Sarwar, Tarique; Rehman, Sayeed Ur; Husain, Mohammed Amir; Ishqi, Hassan Mubarak; Tabish, Mohammad

    2015-02-01

    DNA is the major target for a wide range of therapeutic substances. Thus, there has been considerable interest in the binding studies of small molecules with DNA. Interaction between small molecules and DNA provides a structural guideline in rational drug designing and in the synthesis of new and improved drugs with enhanced selective activity and greater clinical efficacy. Plant derived polyphenolic compounds have a large number of biological and pharmacological properties. Coumarin is a polyphenolic compound which has been extensively studied for its diverse pharmacological properties. However, its mode of interaction with DNA has not been elucidated. In the present study, we have attempted to ascertain the mode of binding of coumarin with calf thymus DNA (Ct-DNA) through various biophysical techniques. Analysis of UV-visible absorbance spectra and fluorescence spectra indicates the formation of complex between coumarin and Ct-DNA. Several other experiments such as effect of ionic strength, iodide induced quenching, competitive binding assay with ethidium bromide, acridine orange and Hoechst 33258 reflected that coumarin possibly binds to the minor groove of the Ct-DNA. These observations were further supported by CD spectral analysis, viscosity measurements, DNA melting studies and in silico molecular docking.

  8. MHC class I epitope binding prediction trained on small data sets

    DEFF Research Database (Denmark)

    Lundegaard, Claus; Nielsen, Morten; Lamberth, K.;

    2004-01-01

    prediction methods exist only for alleles were the binding pattern have been deduced from peptide motifs. Using empirical knowledge of important anchor positions within the binding peptides dramatically reduces the number of peptides needed for reliable predictions. We here present a general method...... for predicting peptides binding to specific MHC class I alleles. The method combines advanced automatic scoring matrix generation with empirical position specific differential anchor weighting. The method leads to predictions with a comparable or higher accuracy than other established prediction servers, even...

  9. The Interplay of Chromatin Landscape and DNA-Binding Context Suggests Distinct Modes of EIN3 Regulation in Arabidopsis thaliana

    Science.gov (United States)

    Zemlyanskaya, Elena V.; Levitsky, Victor G.; Oshchepkov, Dmitry Y.; Grosse, Ivo; Mironova, Victoria V.

    2017-01-01

    The plant hormone ethylene regulates numerous developmental processes and stress responses. Ethylene signaling proceeds via a linear pathway, which activates transcription factor (TF) EIN3, a primary transcriptional regulator of ethylene response. EIN3 influences gene expression upon binding to a specific sequence in gene promoters. This interaction, however, might be considerably affected by additional co-factors. In this work, we perform whole genome bioinformatics study to identify the impact of epigenetic factors in EIN3 functioning. The analysis of publicly available ChIP-Seq data on EIN3 binding in Arabidopsis thaliana showed bimodality of distribution of EIN3 binding regions (EBRs) in gene promoters. Besides a sharp peak in close proximity to transcription start site, which is a common binding region for a wide variety of TFs, we found an additional extended peak in the distal promoter region. We characterized all EBRs with respect to the epigenetic status appealing to previously published genome-wide map of nine chromatin states in A. thaliana. We found that the implicit distal peak was associated with a specific chromatin state (referred to as chromatin state 4 in the primary source), which was just poorly represented in the pronounced proximal peak. Intriguingly, EBRs corresponding to this chromatin state 4 were significantly associated with ethylene response, unlike the others representing the overwhelming majority of EBRs related to the explicit proximal peak. Moreover, we found that specific EIN3 binding sequences predicted with previously described model were enriched in the EBRs mapped to the chromatin state 4, but not to the rest ones. These results allow us to conclude that the interplay of genetic and epigenetic factors might cause the distinct modes of EIN3 regulation. PMID:28119721

  10. Medial Temporal Lobe Activity Predicts Successful Relational Memory Binding

    Science.gov (United States)

    Hannula, Deborah E.; Ranganath, Charan

    2009-01-01

    Previous neuropsychological findings have implicated medial temporal lobe (MTL) structures in retaining object-location relations over the course of short delays, but MTL effects have not always been reported in neuroimaging investigations with similar short-term memory requirements. Here, we used event-related functional magnetic resonance imaging to test the hypothesis that the hippocampus and related MTL structures support accurate retention of relational memory representations, even across short delays. On every trial, four objects were presented, each in one of nine possible locations of a three-dimensional grid. Participants were to mentally rotate the grid and then maintain the rotated representation in anticipation of a test stimulus: a rendering of the grid, rotated 90° from the original viewpoint. The test stimulus was either a “match” display, in which object-location relations were intact, or a “mismatch” display, in which one object occupied a new, previously unfilled location (mismatch position), or two objects had swapped locations (mismatch swap). Encoding phase activation in anterior and posterior regions of the left hippocampus, and in bilateral perirhinal cortex, predicted subsequent accuracy on the short-term memory decision, as did bilateral posterior hippocampal activity after the test stimulus. Notably, activation in these posterior hippocampal regions was also sensitive to the degree to which object-location bindings were preserved in the test stimulus; activation was greatest for match displays, followed by mismatch-position displays, and finally mismatch-swap displays. These results indicate that the hippocampus and related MTL structures contribute to successful encoding and retrieval of relational information in visual short-term memory. PMID:18171929

  11. Late Pregnancy Thyroid-Binding Globulin Predicts Perinatal Depression

    Science.gov (United States)

    Pedersen, Cort; Leserman, Jane; Garcia, Nacire; Stansbury, Melissa; Meltzer-Brody, Samantha; Johnson, Jacqueline

    2016-01-01

    Previously we found that late pregnancy total and free thyroxine (TT4, FT4) concentrations were negatively related to greater pre and/or postpartum depressive symptoms. In a much larger cohort, the current study examined whether these thyroid indices measured earlier in the third trimester (31-33 weeks) predict subsequent perinatal depression and anxiety ratings as well as syndromal depression. Thyroid-binding globulin (TBG) concentrations increase markedly during pregnancy and may be an index of sensitivity to elevated estrogen levels. TBG was examined in this study because prior findings suggest that postpartum depression is related to sensitivity to mood destabilization by elevated sex hormone concentrations during pregnancy. Our cohort was 199 euthyroid women recruited from a public health obstetrics clinic (63.8% Hispanic, 21.6% Black). After screening and blood draws for hormone measures at pregnancy weeks 31-33, subjects were evaluated during home visits at pregnancy weeks 35-36 as well as postpartum weeks 6 and 12. Evaluations included psychiatric interviews for current and life-time DSM-IV psychiatric history (M.I.N.I.-Plus), subject self-ratings and interviewer ratings for depression and anxiety (Edinburgh Postnatal Depression Scale, Montgomery-Ǻsberg Depression Rating Scale; Spielberger State-Trait Anxiety Inventory, Hamilton Anxiety Inventory), as well as a standardized interview to obtain life-time trauma history. Numerous covariates were included in all regression analyses. Trauma and major depression history were robustly significant predictors of depression and anxiety ratings over the study period when these variables were analyzed individually or in a combined model including FT4 or TBG (pdepression and anxiety ratings (pdepression history, were significant individual predictors of syndromal depression during the study period (pdepression history, FT4 and TBG generally were not significantly predictive of depression or anxiety ratings, and FT4

  12. Mode of Binding of the Tuberculosis Prodrug Isoniazid to Heme Peroxidases

    Science.gov (United States)

    Singh, Amit K.; Kumar, Ramasamy P.; Pandey, Nisha; Singh, Nagendra; Sinha, Mau; Bhushan, Asha; Kaur, Punit; Sharma, Sujata; Singh, Tej P.

    2010-01-01

    Isoniazid (INH) is an anti-tuberculosis prodrug that is activated by mammalian lactoperoxidase and Mycobacterium tuberculosis catalase peroxidase (MtCP). We report here binding studies, an enzyme assay involving INH, and the crystal structure of the complex of bovine lactoperoxidase (LPO) with INH to illuminate binding properties and INH activation as well as the mode of diffusion and interactions together with a detailed structural and functional comparison with MtCP. The structure determination shows that isoniazid binds to LPO at the substrate binding site on the distal heme side. The substrate binding site is connected to the protein surface through a long hydrophobic channel. The acyl hydrazide moiety of isoniazid interacts with Phe422 O, Gln423 Oϵ1, and Phe254 O. In this arrangement, pyridinyl nitrogen forms a hydrogen bond with a water molecule, W-1, which in turn forms three hydrogen bonds with Fe3+, His109 Nϵ2, and Gln105 Nϵ2. The remaining two sides of isoniazid form hydrophobic interactions with the atoms of heme pyrrole ring A, Cβ and Cγ atoms of Glu258, and Cγ and Cδ atoms of Arg255. The binding studies indicate that INH binds to LPO with a value of 0.9 × 10−6 m for the dissociation constant. The nitro blue tetrazolium reduction assay shows that INH is activated by the reaction of LPO-H2O2 with INH. This suggests that LPO can be used for INH activation. It also indicates that the conversion of INH into isonicotinoyl radical by LPO may be the cause of INH toxicity. PMID:19907057

  13. Predictive model of cationic surfactant binding to humic substances

    NARCIS (Netherlands)

    Ishiguro, M.; Koopal, L.K.

    2011-01-01

    The humic substances (HS) have a high reactivity with other components in the natural environment. An important factor for the reactivity of HS is their negative charge. Cationic surfactants bind strongly to HS by electrostatic and specific interaction. Therefore, a surfactant binding model is devel

  14. BiPPred: Combined sequence- and structure-based prediction of peptide binding to the Hsp70 chaperone BiP.

    Science.gov (United States)

    Schneider, Markus; Rosam, Mathias; Glaser, Manuel; Patronov, Atanas; Shah, Harpreet; Back, Katrin Christiane; Daake, Marina Angelika; Buchner, Johannes; Antes, Iris

    2016-10-01

    Substrate binding to Hsp70 chaperones is involved in many biological processes, and the identification of potential substrates is important for a comprehensive understanding of these events. We present a multi-scale pipeline for an accurate, yet efficient prediction of peptides binding to the Hsp70 chaperone BiP by combining sequence-based prediction with molecular docking and MMPBSA calculations. First, we measured the binding of 15mer peptides from known substrate proteins of BiP by peptide array (PA) experiments and performed an accuracy assessment of the PA data by fluorescence anisotropy studies. Several sequence-based prediction models were fitted using this and other peptide binding data. A structure-based position-specific scoring matrix (SB-PSSM) derived solely from structural modeling data forms the core of all models. The matrix elements are based on a combination of binding energy estimations, molecular dynamics simulations, and analysis of the BiP binding site, which led to new insights into the peptide binding specificities of the chaperone. Using this SB-PSSM, peptide binders could be predicted with high selectivity even without training of the model on experimental data. Additional training further increased the prediction accuracies. Subsequent molecular docking (DynaDock) and MMGBSA/MMPBSA-based binding affinity estimations for predicted binders allowed the identification of the correct binding mode of the peptides as well as the calculation of nearly quantitative binding affinities. The general concept behind the developed multi-scale pipeline can readily be applied to other protein-peptide complexes with linearly bound peptides, for which sufficient experimental binding data for the training of classical sequence-based prediction models is not available. Proteins 2016; 84:1390-1407. © 2016 Wiley Periodicals, Inc.

  15. Distinct pose of discodermolide in taxol binding pocket drives a complementary mode of microtubule stabilization.

    Science.gov (United States)

    Khrapunovich-Baine, Marina; Menon, Vilas; Verdier-Pinard, Pascal; Smith, Amos B; Angeletti, Ruth Hogue; Fiser, Andras; Horwitz, Susan Band; Xiao, Hui

    2009-12-15

    The microtubule cytoskeleton has proven to be an effective target for cancer therapeutics. One class of drugs, known as microtubule stabilizing agents (MSAs), binds to microtubule polymers and stabilizes them against depolymerization. The prototype of this group of drugs, Taxol, is an effective chemotherapeutic agent used extensively in the treatment of human ovarian, breast, and lung carcinomas. Although electron crystallography and photoaffinity labeling experiments determined that the binding site for Taxol is in a hydrophobic pocket in beta-tubulin, little was known about the effects of this drug on the conformation of the entire microtubule. A recent study from our laboratory utilizing hydrogen-deuterium exchange (HDX) in concert with various mass spectrometry (MS) techniques has provided new information on the structure of microtubules upon Taxol binding. In the current study we apply this technique to determine the binding mode and the conformational effects on chicken erythrocyte tubulin (CET) of another MSA, discodermolide, whose synthetic analogues may have potential use in the clinic. We confirmed that, like Taxol, discodermolide binds to the taxane binding pocket in beta-tubulin. However, as opposed to Taxol, which has major interactions with the M-loop, discodermolide orients itself away from this loop and toward the N-terminal H1-S2 loop. Additionally, discodermolide stabilizes microtubules mainly via its effects on interdimer contacts, specifically on the alpha-tubulin side, and to a lesser extent on interprotofilament contacts between adjacent beta-tubulin subunits. Also, our results indicate complementary stabilizing effects of Taxol and discodermolide on the microtubules, which may explain the synergy observed between the two drugs in vivo.

  16. Exploring the DNA binding mode of transition metal based biologically active compounds

    Science.gov (United States)

    Raman, N.; Sobha, S.

    2012-01-01

    Few novel 4-aminoantipyrine derived Schiff bases and their metal complexes were synthesized and characterized. Their structural features and other properties were deduced from the elemental analysis, magnetic susceptibility and molar conductivity as well as from mass, IR, UV-vis, 1H NMR and EPR spectral studies. The binding of the complexes with CT-DNA was analyzed by electronic absorption spectroscopy, viscosity measurement, and cyclic voltammetry. The interaction of the metal complexes with DNA was also studied by molecular modeling with special reference to docking. The experimental and docking results revealed that the complexes have the ability of interaction with DNA of minor groove binding mode. The intrinsic binding constants ( Kb) of the complexes with CT-DNA were found out which show that they are minor groove binders. Gel electrophoresis assay demonstrated the ability of the complexes to cleave the pUC19 DNA in the presence of AH 2 (ascorbic acid). Moreover, the oxidative cleavage studies using distamycin revealed the minor groove binding for the newly synthesized 4-aminoantipyrine derived Schiff bases and their metal complexes. Evaluation of antibacterial activity of the complexes against Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Staphylococcus epidermidis, and Klebsiella pneumoniae exhibited that the complexes have potent biocidal activity than the free ligands.

  17. Prediction of the Fundamental Mode Lamb Wave Reflection from a Crack-Like Discontinuity Using Eigen-Mode Expansion

    Energy Technology Data Exchange (ETDEWEB)

    Park, Jae Seok [Doosan Heavy Industries and Construction, Changwon (Korea, Republic of); Jang, Chang Heui [Korea Advanced Institute of Science and Technology, Daejeon (Korea, Republic of); Lee, Jong Po [ANSCO Corp., Daejeon (Korea, Republic of)

    2010-06-15

    Based on the idea of eigen-mode expansion, a method to analyze the reflection of Lamb wave from a finite vertical discontinuity of plate is theoretically derived and verified by experiment. The theoretical prediction is in good agreement with the experimental result, and this strongly suggests that eigen-mode expansion method could be used for solution of inverse scattering problem for ultrasonic testing using Lamb wave

  18. Structure prediction and binding sites analysis of curcin protein of Jatropha curcas using computational approaches.

    Science.gov (United States)

    Srivastava, Mugdha; Gupta, Shishir K; Abhilash, P C; Singh, Nandita

    2012-07-01

    Ribosome inactivating proteins (RIPs) are defense proteins in a number of higher-plant species that are directly targeted toward herbivores. Jatropha curcas is one of the biodiesel plants having RIPs. The Jatropha seed meal, after extraction of oil, is rich in curcin, a highly toxic RIP similar to ricin, which makes it unsuitable for animal feed. Although the toxicity of curcin is well documented in the literature, the detailed toxic properties and the 3D structure of curcin has not been determined by X-ray crystallography, NMR spectroscopy or any in silico techniques to date. In this pursuit, the structure of curcin was modeled by a composite approach of 3D structure prediction using threading and ab initio modeling. Assessment of model quality was assessed by methods which include Ramachandran plot analysis and Qmean score estimation. Further, we applied the protein-ligand docking approach to identify the r-RNA binding residue of curcin. The present work provides the first structural insight into the binding mode of r-RNA adenine to the curcin protein and forms the basis for designing future inhibitors of curcin. Cloning of a future peptide inhibitor within J. curcas can produce non-toxic varieties of J. curcas, which would make the seed-cake suitable as animal feed without curcin detoxification.

  19. Distinct ETA receptor binding mode of macitentan as determined by site directed mutagenesis.

    Directory of Open Access Journals (Sweden)

    John Gatfield

    Full Text Available The competitive endothelin receptor antagonists (ERA bosentan and ambrisentan, which have long been approved for the treatment of pulmonary arterial hypertension, are characterized by very short (1 min occupancy half-lives at the ET(A receptor. The novel ERA macitentan, displays a 20-fold increased receptor occupancy half-life, causing insurmountable antagonism of ET-1-induced signaling in pulmonary arterial smooth muscle cells. We show here that the slow ET(A receptor dissociation rate of macitentan was shared with a set of structural analogs, whereas compounds structurally related to bosentan displayed fast dissociation kinetics. NMR analysis showed that macitentan adopts a compact structure in aqueous solution and molecular modeling suggests that this conformation tightly fits into a well-defined ET(A receptor binding pocket. In contrast the structurally different and negatively charged bosentan-type molecules only partially filled this pocket and expanded into an extended endothelin binding site. To further investigate these different ET(A receptor-antagonist interaction modes, we performed functional studies using ET(A receptor variants harboring amino acid point mutations in the presumed ERA interaction site. Three ET(A receptor residues significantly and differentially affected ERA activity: Mutation R326Q did not affect the antagonist activity of macitentan, however the potencies of bosentan and ambrisentan were significantly reduced; mutation L322A rendered macitentan less potent, whereas bosentan and ambrisentan were unaffected; mutation I355A significantly reduced bosentan potency, but not ambrisentan and macitentan potencies. This suggests that--in contrast to bosentan and ambrisentan--macitentan-ET(A receptor binding is not dependent on strong charge-charge interactions, but depends predominantly on hydrophobic interactions. This different binding mode could be the reason for macitentan's sustained target occupancy and

  20. Dynamics in the DNA recognition by DAPI: exploration of the various binding modes.

    Science.gov (United States)

    Banerjee, Debapriya; Pal, Samir Kumar

    2008-01-24

    Two distinct modes of interaction of the fluorescent probe 4',6-diamidino-2-phenylindole (DAPI), depending on the sequence of DNA, have been reported in the literature. In the present study, the dynamics of solvation has been utilized to explore the binding interaction of DAPI to DNA oligomers of different sequences. Picosecond-resolved fluorescence and polarization-gated anisotropy have been used to characterize the binding of DAPI to the different oligomers. In the double-stranded dodecamer of sequence CGCGAATTCGCG (oligo1), the solvation relaxation dynamics of the probe reveals time constants of 0.130 ns (75%) and 2.35 ns (25%). Independent exploration of the minor-groove environment of oligo1 using another well-known minor-groove binder Hoechst 33258 (H258) shows similar timescales, further confirming minor-groove binding of DAPI to oligo1. In the double-stranded dodecamer (oligo2) having the sequence GCGCGCGCGCGC, where intercalation has been reported in the literature, no solvation is observed in our experimental window. DAPI bound to oligo2 shows quenching of fluorescence compared to that of DAPI in a buffer. The quenching of fluorescence of DAPI intercalated in DNA is also borne out by the appearance of a fast component of 30 ps in the fluorescence lifetime, revealing electron transfer to DAPI from GC base pairs, between which it intercalates. In addition to this, the excited-state lifetime of the probe in the DAPI-DNA complex also shows a time constant similar to that of the dye in a buffer, indicating that the excited-state photoprocesses associated with the free dye is also operative in this binding mode, consistent with the binding geometry of the DAPI in the DNA. The dynamics of DAPI in calf thymus DNA having a random sequence of base pairs is similar to that associated with the DNA minor groove. Our studies clearly explore the structure-dynamics correlation of the DAPI-DNA complex in the two distinct modes of interaction of DAPI with DNA.

  1. A sequence-based dynamic ensemble learning system for protein ligand-binding site prediction

    KAUST Repository

    Chen, Peng

    2015-12-03

    Background: Proteins have the fundamental ability to selectively bind to other molecules and perform specific functions through such interactions, such as protein-ligand binding. Accurate prediction of protein residues that physically bind to ligands is important for drug design and protein docking studies. Most of the successful protein-ligand binding predictions were based on known structures. However, structural information is not largely available in practice due to the huge gap between the number of known protein sequences and that of experimentally solved structures

  2. Structural investigations into the binding mode of novel neolignans Cmp10 and Cmp19 microtubule stabilizers by in silico molecular docking, molecular dynamics, and binding free energy calculations.

    Science.gov (United States)

    Tripathi, Shubhandra; Kumar, Akhil; Kumar, B Sathish; Negi, Arvind S; Sharma, Ashok

    2016-06-01

    Microtubule stabilizers provide an important mode of treatment via mitotic cell arrest of cancer cells. Recently, we reported two novel neolignans derivatives Cmp10 and Cmp19 showing anticancer activity and working as microtubule stabilizers at micromolar concentrations. In this study, we have explored the binding site, mode of binding, and stabilization by two novel microtubule stabilizers Cmp10 and Cmp19 using in silico molecular docking, molecular dynamics (MD) simulation, and binding free energy calculations. Molecular docking studies were performed to explore the β-tubulin binding site of Cmp10 and Cmp19. Further, MD simulations were used to probe the β-tubulin stabilization mechanism by Cmp10 and Cmp19. Binding affinity was also compared for Cmp10 and Cmp19 using binding free energy calculations. Our docking results revealed that both the compounds bind at Ptxl binding site in β-tubulin. MD simulation studies showed that Cmp10 and Cmp19 binding stabilizes M-loop (Phe272-Val288) residues of β-tubulin and prevent its dynamics, leading to a better packing between α and β subunits from adjacent tubulin dimers. In addition, His229, Ser280 and Gln281, and Arg278, Thr276, and Ser232 were found to be the key amino acid residues forming H-bonds with Cmp10 and Cmp19, respectively. Consequently, binding free energy calculations indicated that Cmp10 (-113.655 kJ/mol) had better binding compared to Cmp19 (-95.216 kJ/mol). This study provides useful insight for better understanding of the binding mechanism of Cmp10 and Cmp19 and will be helpful in designing novel microtubule stabilizers.

  3. High-throughput prediction of RNA, DNA and protein binding regions mediated by intrinsic disorder.

    Science.gov (United States)

    Peng, Zhenling; Kurgan, Lukasz

    2015-10-15

    Intrinsically disordered proteins and regions (IDPs and IDRs) lack stable 3D structure under physiological conditions in-vitro, are common in eukaryotes, and facilitate interactions with RNA, DNA and proteins. Current methods for prediction of IDPs and IDRs do not provide insights into their functions, except for a handful of methods that address predictions of protein-binding regions. We report first-of-its-kind computational method DisoRDPbind for high-throughput prediction of RNA, DNA and protein binding residues located in IDRs from protein sequences. DisoRDPbind is implemented using a runtime-efficient multi-layered design that utilizes information extracted from physiochemical properties of amino acids, sequence complexity, putative secondary structure and disorder and sequence alignment. Empirical tests demonstrate that it provides accurate predictions that are competitive with other predictors of disorder-mediated protein binding regions and complementary to the methods that predict RNA- and DNA-binding residues annotated based on crystal structures. Application in Homo sapiens, Mus musculus, Caenorhabditis elegans and Drosophila melanogaster proteomes reveals that RNA- and DNA-binding proteins predicted by DisoRDPbind complement and overlap with the corresponding known binding proteins collected from several sources. Also, the number of the putative protein-binding regions predicted with DisoRDPbind correlates with the promiscuity of proteins in the corresponding protein-protein interaction networks. Webserver: http://biomine.ece.ualberta.ca/DisoRDPbind/.

  4. Prediction of calcium-binding sites by combining loop-modeling with machine learning

    Directory of Open Access Journals (Sweden)

    Altman Russ B

    2009-12-01

    Full Text Available Abstract Background Protein ligand-binding sites in the apo state exhibit structural flexibility. This flexibility often frustrates methods for structure-based recognition of these sites because it leads to the absence of electron density for these critical regions, particularly when they are in surface loops. Methods for recognizing functional sites in these missing loops would be useful for recovering additional functional information. Results We report a hybrid approach for recognizing calcium-binding sites in disordered regions. Our approach combines loop modeling with a machine learning method (FEATURE for structure-based site recognition. For validation, we compared the performance of our method on known calcium-binding sites for which there are both holo and apo structures. When loops in the apo structures are rebuilt using modeling methods, FEATURE identifies 14 out of 20 crystallographically proven calcium-binding sites. It only recognizes 7 out of 20 calcium-binding sites in the initial apo crystal structures. We applied our method to unstructured loops in proteins from SCOP families known to bind calcium in order to discover potential cryptic calcium binding sites. We built 2745 missing loops and evaluated them for potential calcium binding. We made 102 predictions of calcium-binding sites. Ten predictions are consistent with independent experimental verifications. We found indirect experimental evidence for 14 other predictions. The remaining 78 predictions are novel predictions, some with intriguing potential biological significance. In particular, we see an enrichment of beta-sheet folds with predicted calcium binding sites in the connecting loops on the surface that may be important for calcium-mediated function switches. Conclusion Protein crystal structures are a potentially rich source of functional information. When loops are missing in these structures, we may be losing important information about binding sites and active

  5. Prediction of the binding affinities of peptides to class II MHC using a regularized thermodynamic model

    Directory of Open Access Journals (Sweden)

    Mittelmann Hans D

    2010-01-01

    Full Text Available Abstract Background The binding of peptide fragments of extracellular peptides to class II MHC is a crucial event in the adaptive immune response. Each MHC allotype generally binds a distinct subset of peptides and the enormous number of possible peptide epitopes prevents their complete experimental characterization. Computational methods can utilize the limited experimental data to predict the binding affinities of peptides to class II MHC. Results We have developed the Regularized Thermodynamic Average, or RTA, method for predicting the affinities of peptides binding to class II MHC. RTA accounts for all possible peptide binding conformations using a thermodynamic average and includes a parameter constraint for regularization to improve accuracy on novel data. RTA was shown to achieve higher accuracy, as measured by AUC, than SMM-align on the same data for all 17 MHC allotypes examined. RTA also gave the highest accuracy on all but three allotypes when compared with results from 9 different prediction methods applied to the same data. In addition, the method correctly predicted the peptide binding register of 17 out of 18 peptide-MHC complexes. Finally, we found that suboptimal peptide binding registers, which are often ignored in other prediction methods, made significant contributions of at least 50% of the total binding energy for approximately 20% of the peptides. Conclusions The RTA method accurately predicts peptide binding affinities to class II MHC and accounts for multiple peptide binding registers while reducing overfitting through regularization. The method has potential applications in vaccine design and in understanding autoimmune disorders. A web server implementing the RTA prediction method is available at http://bordnerlab.org/RTA/.

  6. Studies of the binding mode of TXNHCH2COOH with calf thymus DNA by spectroscopic methods

    Science.gov (United States)

    Ataci, Nese; Arsu, Nergis

    2016-12-01

    In this study, a thioxanthone derivative named 2-(9-oxo-9H-thioxanthen-2ylamino) acetic acid (TX-NHCH2COOH) was used to investigate small molecule and DNA binding interactions. Absorption and fluorescence emission spectroscopy were used and melting studies were used to explain the binding mode of TXNHCH2COOH-DNA. Intrinsic binding constant Kb TXNHCH2COOH was found 6 × 105 M- 1from UV-Vis absorption spectroscopy. Fluorescence emmision intensity increased by adding ct-DNA to the TXNHCH2COOH and KI quenching experiments resulted with low Ksv value. Additionally, 3.7 °C increase for Tm was observed. The observed quenching of EB and ct-DNA complex and increase viscosity values of ct-DNA by addition of TXNHCH2COOH was determined. All those results indicate that TXNHCH2COOH can intercalate into DNA base pairs. Fluorescence microscopy helped to display imaging of the TXNHCH2COOH-DNA solution.

  7. An Overview of the Prediction of Protein DNA-Binding Sites

    Directory of Open Access Journals (Sweden)

    Jingna Si

    2015-03-01

    Full Text Available Interactions between proteins and DNA play an important role in many essential biological processes such as DNA replication, transcription, splicing, and repair. The identification of amino acid residues involved in DNA-binding sites is critical for understanding the mechanism of these biological activities. In the last decade, numerous computational approaches have been developed to predict protein DNA-binding sites based on protein sequence and/or structural information, which play an important role in complementing experimental strategies. At this time, approaches can be divided into three categories: sequence-based DNA-binding site prediction, structure-based DNA-binding site prediction, and homology modeling and threading. In this article, we review existing research on computational methods to predict protein DNA-binding sites, which includes data sets, various residue sequence/structural features, machine learning methods for comparison and selection, evaluation methods, performance comparison of different tools, and future directions in protein DNA-binding site prediction. In particular, we detail the meta-analysis of protein DNA-binding sites. We also propose specific implications that are likely to result in novel prediction methods, increased performance, or practical applications.

  8. Identification of a potent synthetic FXR agonist with an unexpected mode of binding and activation

    Energy Technology Data Exchange (ETDEWEB)

    Soisson, Stephen M.; Parthasarathy, Gopalakrishnan; Adams, Alan D.; Sahoo, Soumya; Sitlani, Ayesha; Sparrow, Carl; Cui, Jisong; Becker, Joseph W. (Merck)

    2008-07-08

    The farnesoid X receptor (FXR), a member of the nuclear hormone receptor family, plays important roles in the regulation of bile acid and cholesterol homeostasis, glucose metabolism, and insulin sensitivity. There is intense interest in understanding the mechanisms of FXR regulation and in developing pharmaceutically suitable synthetic FXR ligands that might be used to treat metabolic syndrome. We report here the identification of a potent FXR agonist (MFA-1) and the elucidation of the structure of this ligand in ternary complex with the human receptor and a coactivator peptide fragment using x-ray crystallography at 1.9-{angstrom} resolution. The steroid ring system of MFA-1 binds with its D ring-facing helix 12 (AF-2) in a manner reminiscent of hormone binding to classical steroid hormone receptors and the reverse of the pose adopted by naturally occurring bile acids when bound to FXR. This binding mode appears to be driven by the presence of a carboxylate on MFA-1 that is situated to make a salt-bridge interaction with an arginine residue in the FXR-binding pocket that is normally used to neutralize bound bile acids. Receptor activation by MFA-1 differs from that by bile acids in that it relies on direct interactions between the ligand and residues in helices 11 and 12 and only indirectly involves a protonated histidine that is part of the activation trigger. The structure of the FXR:MFA-1 complex differs significantly from that of the complex with a structurally distinct agonist, fexaramine, highlighting the inherent plasticity of the receptor.

  9. Edge Feature Based Fast Mode Decision Algorithm for H.264 Intra Prediction

    Institute of Scientific and Technical Information of China (English)

    GAO Wei; LI Hua; ZHANG Shufang; HOU Ling; ZHANG Shujun

    2006-01-01

    A fast intra mode decision algorithm is proposed in this paper to reduce the complexity of H. 264 encoder. The proposed algorithm adopted the pre-processing method based on edge feature in pictures to filter out some impossible prediction modes. Context information and pre-computed threshold are used to determine whether it is necessary to check the DC mode. This method is able to get rid of most of candidate modes so that only 66-150 modes are left for the final mode decision, instead of 592 modes in the case of full search(FS)method of H. 264. Simulation results demonstrate that the coding time of the proposed algorithm falls down 71.7% compared with FS method, while the performance loss is trivial compared with FS mode decision scheme.

  10. Combining transcription factor binding affinities with open-chromatin data for accurate gene expression prediction

    Science.gov (United States)

    Schmidt, Florian; Gasparoni, Nina; Gasparoni, Gilles; Gianmoena, Kathrin; Cadenas, Cristina; Polansky, Julia K.; Ebert, Peter; Nordström, Karl; Barann, Matthias; Sinha, Anupam; Fröhler, Sebastian; Xiong, Jieyi; Dehghani Amirabad, Azim; Behjati Ardakani, Fatemeh; Hutter, Barbara; Zipprich, Gideon; Felder, Bärbel; Eils, Jürgen; Brors, Benedikt; Chen, Wei; Hengstler, Jan G.; Hamann, Alf; Lengauer, Thomas; Rosenstiel, Philip; Walter, Jörn; Schulz, Marcel H.

    2017-01-01

    The binding and contribution of transcription factors (TF) to cell specific gene expression is often deduced from open-chromatin measurements to avoid costly TF ChIP-seq assays. Thus, it is important to develop computational methods for accurate TF binding prediction in open-chromatin regions (OCRs). Here, we report a novel segmentation-based method, TEPIC, to predict TF binding by combining sets of OCRs with position weight matrices. TEPIC can be applied to various open-chromatin data, e.g. DNaseI-seq and NOMe-seq. Additionally, Histone-Marks (HMs) can be used to identify candidate TF binding sites. TEPIC computes TF affinities and uses open-chromatin/HM signal intensity as quantitative measures of TF binding strength. Using machine learning, we find low affinity binding sites to improve our ability to explain gene expression variability compared to the standard presence/absence classification of binding sites. Further, we show that both footprints and peaks capture essential TF binding events and lead to a good prediction performance. In our application, gene-based scores computed by TEPIC with one open-chromatin assay nearly reach the quality of several TF ChIP-seq data sets. Finally, these scores correctly predict known transcriptional regulators as illustrated by the application to novel DNaseI-seq and NOMe-seq data for primary human hepatocytes and CD4+ T-cells, respectively. PMID:27899623

  11. Combining transcription factor binding affinities with open-chromatin data for accurate gene expression prediction.

    Science.gov (United States)

    Schmidt, Florian; Gasparoni, Nina; Gasparoni, Gilles; Gianmoena, Kathrin; Cadenas, Cristina; Polansky, Julia K; Ebert, Peter; Nordström, Karl; Barann, Matthias; Sinha, Anupam; Fröhler, Sebastian; Xiong, Jieyi; Dehghani Amirabad, Azim; Behjati Ardakani, Fatemeh; Hutter, Barbara; Zipprich, Gideon; Felder, Bärbel; Eils, Jürgen; Brors, Benedikt; Chen, Wei; Hengstler, Jan G; Hamann, Alf; Lengauer, Thomas; Rosenstiel, Philip; Walter, Jörn; Schulz, Marcel H

    2017-01-09

    The binding and contribution of transcription factors (TF) to cell specific gene expression is often deduced from open-chromatin measurements to avoid costly TF ChIP-seq assays. Thus, it is important to develop computational methods for accurate TF binding prediction in open-chromatin regions (OCRs). Here, we report a novel segmentation-based method, TEPIC, to predict TF binding by combining sets of OCRs with position weight matrices. TEPIC can be applied to various open-chromatin data, e.g. DNaseI-seq and NOMe-seq. Additionally, Histone-Marks (HMs) can be used to identify candidate TF binding sites. TEPIC computes TF affinities and uses open-chromatin/HM signal intensity as quantitative measures of TF binding strength. Using machine learning, we find low affinity binding sites to improve our ability to explain gene expression variability compared to the standard presence/absence classification of binding sites. Further, we show that both footprints and peaks capture essential TF binding events and lead to a good prediction performance. In our application, gene-based scores computed by TEPIC with one open-chromatin assay nearly reach the quality of several TF ChIP-seq data sets. Finally, these scores correctly predict known transcriptional regulators as illustrated by the application to novel DNaseI-seq and NOMe-seq data for primary human hepatocytes and CD4+ T-cells, respectively.

  12. Benzimidazole inhibitors of the protein kinase CHK2: Clarification of the binding mode by flexible side chain docking and protein–ligand crystallography

    Science.gov (United States)

    Matijssen, Cornelis; Silva-Santisteban, M. Cris; Westwood, Isaac M.; Siddique, Samerene; Choi, Vanessa; Sheldrake, Peter; van Montfort, Rob L.M.; Blagg, Julian

    2012-01-01

    Two closely related binding modes have previously been proposed for the ATP-competitive benzimidazole class of checkpoint kinase 2 (CHK2) inhibitors; however, neither binding mode is entirely consistent with the reported SAR. Unconstrained rigid docking of benzimidazole ligands into representative CHK2 protein crystal structures reveals an alternative binding mode involving a water-mediated interaction with the hinge region; docking which incorporates protein side chain flexibility for selected residues in the ATP binding site resulted in a refinement of the water-mediated hinge binding mode that is consistent with observed SAR. The flexible docking results are in good agreement with the crystal structures of four exemplar benzimidazole ligands bound to CHK2 which unambiguously confirmed the binding mode of these inhibitors, including the water-mediated interaction with the hinge region, and which is significantly different from binding modes previously postulated in the literature. PMID:23058106

  13. Predicting DNA-binding sites of proteins based on sequential and 3D structural information.

    Science.gov (United States)

    Li, Bi-Qing; Feng, Kai-Yan; Ding, Juan; Cai, Yu-Dong

    2014-06-01

    Protein-DNA interactions play important roles in many biological processes. To understand the molecular mechanisms of protein-DNA interaction, it is necessary to identify the DNA-binding sites in DNA-binding proteins. In the last decade, computational approaches have been developed to predict protein-DNA-binding sites based solely on protein sequences. In this study, we developed a novel predictor based on support vector machine algorithm coupled with the maximum relevance minimum redundancy method followed by incremental feature selection. We incorporated not only features of physicochemical/biochemical properties, sequence conservation, residual disorder, secondary structure, solvent accessibility, but also five three-dimensional (3D) structural features calculated from PDB data to predict the protein-DNA interaction sites. Feature analysis showed that 3D structural features indeed contributed to the prediction of DNA-binding site and it was demonstrated that the prediction performance was better with 3D structural features than without them. It was also shown via analysis of features from each site that the features of DNA-binding site itself contribute the most to the prediction. Our prediction method may become a useful tool for identifying the DNA-binding sites and the feature analysis described in this paper may provide useful insights for in-depth investigations into the mechanisms of protein-DNA interaction.

  14. Genome-wide prediction, display and refinement of binding sites with information theory-based models

    Directory of Open Access Journals (Sweden)

    Leeder J Steven

    2003-09-01

    Full Text Available Abstract Background We present Delila-genome, a software system for identification, visualization and analysis of protein binding sites in complete genome sequences. Binding sites are predicted by scanning genomic sequences with information theory-based (or user-defined weight matrices. Matrices are refined by adding experimentally-defined binding sites to published binding sites. Delila-Genome was used to examine the accuracy of individual information contents of binding sites detected with refined matrices as a measure of the strengths of the corresponding protein-nucleic acid interactions. The software can then be used to predict novel sites by rescanning the genome with the refined matrices. Results Parameters for genome scans are entered using a Java-based GUI interface and backend scripts in Perl. Multi-processor CPU load-sharing minimized the average response time for scans of different chromosomes. Scans of human genome assemblies required 4–6 hours for transcription factor binding sites and 10–19 hours for splice sites, respectively, on 24- and 3-node Mosix and Beowulf clusters. Individual binding sites are displayed either as high-resolution sequence walkers or in low-resolution custom tracks in the UCSC genome browser. For large datasets, we applied a data reduction strategy that limited displays of binding sites exceeding a threshold information content to specific chromosomal regions within or adjacent to genes. An HTML document is produced listing binding sites ranked by binding site strength or chromosomal location hyperlinked to the UCSC custom track, other annotation databases and binding site sequences. Post-genome scan tools parse binding site annotations of selected chromosome intervals and compare the results of genome scans using different weight matrices. Comparisons of multiple genome scans can display binding sites that are unique to each scan and identify sites with significantly altered binding strengths

  15. Mode of bindings of zinc oxide nanoparticles to myoglobin and horseradish peroxidase: A spectroscopic investigations

    Science.gov (United States)

    Mandal, Gopa; Bhattacharya, Sudeshna; Ganguly, Tapan

    2011-07-01

    The interactions between two heme proteins myoglobin (HMb) and horseradish peroxidase (HRP) with zinc oxide (ZnO) nanoparticles are investigated by using UV-vis absorption, steady state fluorescence, synchronous fluorescence, time-resolved fluorescence, FT-IR, atomic force microscopy (AFM) and circular dichroism (CD) techniques under physiological condition of pH˜7.4. The presence of mainly static mode in fluorescence quenching mechanism of HMb and HRP by ZnO nanoparticle indicates the possibility of formation of ground state complex. The processes of bindings of ZnO nanoparticles with the two proteins are spontaneous molecular interaction procedures. In both cases hydrogen bonding plays a major role. The circular dichroism (CD) spectra reveal that a helicity of the proteins is reduced by increasing ZnO nanoparticle concentration although the α-helical structures of HMb and HRP retain their identity. On binding to the ZnO nanoparticles the secondary structure of HRP molecules (or HMb molecules) remains unchanged while there is a substantial change in the environment of the tyrosin active site in case of HRP molecules and tryptophan active site in case of HMb molecules. Tapping mode atomic force microscopy (AFM) was applied for the investigation the structure of HRP adsorbed in the environment of nanoparticles on the silicon and on the bare silicon. HRP molecules adsorb and aggregate on the mica with ZnO nanoparticle. The aggregation indicates an attractive interaction among the adsorbed molecules. The molecules are randomly distributed on the bare silicon wafer. The adsorption of HRP in the environment of ZnO nanoparticle changes drastically the domains due to a strong interaction between HRP and ZnO nanoparticles. Similar situation is observed in case of HMb molecules. These findings demonstrate the efficacy of biomedical applications of ZnO nanoparticles as well as in elucidating their mechanisms of action as drugs in both human and plant systems.

  16. Spatial distribution of predicted transcription factor binding sites in Drosophila ChIP peaks.

    Science.gov (United States)

    Pettie, Kade P; Dresch, Jacqueline M; Drewell, Robert A

    2016-08-01

    In the development of the Drosophila embryo, gene expression is directed by the sequence-specific interactions of a large network of protein transcription factors (TFs) and DNA cis-regulatory binding sites. Once the identity of the typically 8-10bp binding sites for any given TF has been determined by one of several experimental procedures, the sequences can be represented in a position weight matrix (PWM) and used to predict the location of additional TF binding sites elsewhere in the genome. Often, alignments of large (>200bp) genomic fragments that have been experimentally determined to bind the TF of interest in Chromatin Immunoprecipitation (ChIP) studies are trimmed under the assumption that the majority of the binding sites are located near the center of all the aligned fragments. In this study, ChIP/chip datasets are analyzed using the corresponding PWMs for the well-studied TFs; CAUDAL, HUNCHBACK, KNIRPS and KRUPPEL, to determine the distribution of predicted binding sites. All four TFs are critical regulators of gene expression along the anterio-posterior axis in early Drosophila development. For all four TFs, the ChIP peaks contain multiple binding sites that are broadly distributed across the genomic region represented by the peak, regardless of the prediction stringency criteria used. This result suggests that ChIP peak trimming may exclude functional binding sites from subsequent analyses.

  17. Using TESS to predict transcription factor binding sites in DNA sequence.

    Science.gov (United States)

    Schug, Jonathan

    2008-03-01

    This unit describes how to use the Transcription Element Search System (TESS). This Web site predicts transcription factor binding sites (TFBS) in DNA sequence using two different kinds of models of sites, strings and positional weight matrices. The binding of transcription factors to DNA is a major part of the control of gene expression. Transcription factors exhibit sequence-specific binding; they form stronger bonds to some DNA sequences than to others. Identification of a good binding site in the promoter for a gene suggests the possibility that the corresponding factor may play a role in the regulation of that gene. However, the sequences transcription factors recognize are typically short and allow for some amount of mismatch. Because of this, binding sites for a factor can typically be found at random every few hundred to a thousand base pairs. TESS has features to help sort through and evaluate the significance of predicted sites.

  18. Prediction of peptide binding to a major histocompatibility complex class I molecule based on docking simulation.

    Science.gov (United States)

    Ishikawa, Takeshi

    2016-10-01

    Binding between major histocompatibility complex (MHC) class I molecules and immunogenic epitopes is one of the most important processes for cell-mediated immunity. Consequently, computational prediction of amino acid sequences of MHC class I binding peptides from a given sequence may lead to important biomedical advances. In this study, an efficient structure-based method for predicting peptide binding to MHC class I molecules was developed, in which the binding free energy of the peptide was evaluated by two individual docking simulations. An original penalty function and restriction of degrees of freedom were determined by analysis of 361 published X-ray structures of the complex and were then introduced into the docking simulations. To validate the method, calculations using a 50-amino acid sequence as a prediction target were performed. In 27 calculations, the binding free energy of the known peptide was within the top 5 of 166 peptides generated from the 50-amino acid sequence. Finally, demonstrative calculations using a whole sequence of a protein as a prediction target were performed. These data clearly demonstrate high potential of this method for predicting peptide binding to MHC class I molecules.

  19. A Prediction Method of Binding Free Energy of Protein and Ligand

    Science.gov (United States)

    Yang, Kun; Wang, Xicheng

    2010-05-01

    Predicting the binding free energy is an important problem in bimolecular simulation. Such prediction would be great benefit in understanding protein functions, and may be useful for computational prediction of ligand binding strengths, e.g., in discovering pharmaceutical drugs. Free energy perturbation (FEP)/thermodynamics integration (TI) is a classical method to explicitly predict free energy. However, this method need plenty of time to collect datum, and that attempts to deal with some simple systems and small changes of molecular structures. Another one for estimating ligand binding affinities is linear interaction energy (LIE) method. This method employs averages of interaction potential energy terms from molecular dynamics simulations or other thermal conformational sampling techniques. Incorporation of systematic deviations from electrostatic linear response, derived from free energy perturbation studies, into the absolute binding free energy expression significantly enhances the accuracy of the approach. However, it also is time-consuming work. In this paper, a new prediction method based on steered molecular dynamics (SMD) with direction optimization is developed to compute binding free energy. Jarzynski's equality is used to derive the PMF or free-energy. The results for two numerical examples are presented, showing that the method has good accuracy and efficiency. The novel method can also simulate whole binding proceeding and give some important structural information about development of new drugs.

  20. Prediction of small molecule binding property of protein domains with Bayesian classifiers based on Markov chains.

    Science.gov (United States)

    Bulashevska, Alla; Stein, Martin; Jackson, David; Eils, Roland

    2009-12-01

    Accurate computational methods that can help to predict biological function of a protein from its sequence are of great interest to research biologists and pharmaceutical companies. One approach to assume the function of proteins is to predict the interactions between proteins and other molecules. In this work, we propose a machine learning method that uses a primary sequence of a domain to predict its propensity for interaction with small molecules. By curating the Pfam database with respect to the small molecule binding ability of its component domains, we have constructed a dataset of small molecule binding and non-binding domains. This dataset was then used as training set to learn a Bayesian classifier, which should distinguish members of each class. The domain sequences of both classes are modelled with Markov chains. In a Jack-knife test, our classification procedure achieved the predictive accuracies of 77.2% and 66.7% for binding and non-binding classes respectively. We demonstrate the applicability of our classifier by using it to identify previously unknown small molecule binding domains. Our predictions are available as supplementary material and can provide very useful information to drug discovery specialists. Given the ubiquitous and essential role small molecules play in biological processes, our method is important for identifying pharmaceutically relevant components of complete proteomes. The software is available from the author upon request.

  1. A Bayesian network model for predicting aquatic toxicity mode ...

    Science.gov (United States)

    The mode of toxic action (MoA) has been recognized as a key determinant of chemical toxicity but MoA classification in aquatic toxicology has been limited. We developed a Bayesian network model to classify aquatic toxicity mode of action using a recently published dataset containing over one thousand chemicals with MoA assignments for aquatic animal toxicity. Two dimensional theoretical chemical descriptors were generated for each chemical using the Toxicity Estimation Software Tool. The model was developed through augmented Markov blanket discovery from the data set with the MoA broad classifications as a target node. From cross validation, the overall precision for the model was 80.2% with a R2 of 0.959. The best precision was for the AChEI MoA (93.5%) where 257 chemicals out of 275 were correctly classified. Model precision was poorest for the reactivity MoA (48.5%) where 48 out of 99 reactive chemicals were correctly classified. Narcosis represented the largest class within the MoA dataset and had a precision and reliability of 80.0%, reflecting the global precision across all of the MoAs. False negatives for narcosis most often fell into electron transport inhibition, neurotoxicity or reactivity MoAs. False negatives for all other MoAs were most often narcosis. A probabilistic sensitivity analysis was undertaken for each MoA to examine the sensitivity to individual and multiple descriptor findings. The results show that the Markov blanket of a structurally

  2. Prediction of primary climate variability modes at the Beijing Climate Center

    Science.gov (United States)

    Ren, Hong-Li; Jin, Fei-Fei; Song, Lianchun; Lu, Bo; Tian, Ben; Zuo, Jinqing; Liu, Ying; Wu, Jie; Zhao, Chongbo; Nie, Yu; Zhang, Peiqun; Ba, Jin; Wu, Yujie; Wan, Jianghua; Yan, Yuping; Zhou, Fang

    2017-02-01

    Climate variability modes, usually known as primary climate phenomena, are well recognized as the most important predictability sources in subseasonal-interannual climate prediction. This paper begins by reviewing the research and development carried out, and the recent progress made, at the Beijing Climate Center (BCC) in predicting some primary climate variability modes. These include the El Niño-Southern Oscillation (ENSO), Madden-Julian Oscillation (MJO), and Arctic Oscillation (AO), on global scales, as well as the sea surface temperature (SST) modes in the Indian Ocean and North Atlantic, western Pacific subtropical high (WPSH), and the East Asian winter and summer monsoons (EAWM and EASM, respectively), on regional scales. Based on its latest climate and statistical models, the BCC has established a climate phenomenon prediction system (CPPS) and completed a hindcast experiment for the period 1991-2014. The performance of the CPPS in predicting such climate variability modes is systematically evaluated. The results show that skillful predictions have been made for ENSO, MJO, the Indian Ocean basin mode, the WPSH, and partly for the EASM, whereas less skillful predictions were made for the Indian Ocean Dipole (IOD) and North Atlantic SST Tripole, and no clear skill at all for the AO, subtropical IOD, and EAWM. Improvements in the prediction of these climate variability modes with low skill need to be achieved by improving the BCC's climate models, developing physically based statistical models as well as correction methods for model predictions. Some of the monitoring/prediction products of the BCC-CPPS are also introduced in this paper.

  3. Major histocompatibility complex class I binding predictions as a tool in epitope discovery

    DEFF Research Database (Denmark)

    Lundegaard, Claus; Lund, Ole; Buus, Søren;

    2010-01-01

    Over the last decade, in silico models of the major histocompatibility complex (MHC) class I pathway have developed significantly. Before, peptide binding could only be reliably modelled for a few major human or mouse histocompatibility molecules; now, high-accuracy predictions are available...... for any human leucocyte antigen (HLA) -A or -B molecule with known protein sequence. Furthermore, peptide binding to MHC molecules from several non-human primates, mouse strains and other mammals can now be predicted. In this review, a number of different prediction methods are briefly explained...

  4. In vivo detection of molybdate-binding proteins using a competition assay with ModE in Escherichia coli.

    Science.gov (United States)

    Kuper, Jochen; Meyer zu Berstenhorst, Sonja; Vödisch, Bernd; Mendel, Ralf R; Schwarz, Günter; Boxer, David H

    2003-01-21

    Molybdenum is an important trace element as it forms the essential part of the active site in all molybdenum-containing enzymes. We have designed an assay for the in vivo detection of molybdate binding to proteins in Escherichia coli. The assay is based on (i). the molybdate-dependent transcriptional regulation of the moa operon by the ModE protein, and (ii). the competition for molybdate between ModE and other molybdate-binding proteins in the cytoplasm of E. coli. We were able to verify in vivo molybdate binding to three different bacterial proteins that are known to bind molybdate. This sensitive in vivo system allows the testing of different proteins for molybdate binding under in vivo conditions and will facilitate the identification of other cellular factors needed for molybdate binding. As a first example, we examined the eukaryotic protein Cnx1 that is involved in the last step of molybdenum cofactor biosynthesis in plants, and show that it is able to compete with ModE for molybdate in a molybdopterin-dependent fashion.

  5. A community resource benchmarking predictions of peptide binding to MHC-I molecules.

    Directory of Open Access Journals (Sweden)

    Bjoern Peters

    2006-06-01

    Full Text Available Recognition of peptides bound to major histocompatibility complex (MHC class I molecules by T lymphocytes is an essential part of immune surveillance. Each MHC allele has a characteristic peptide binding preference, which can be captured in prediction algorithms, allowing for the rapid scan of entire pathogen proteomes for peptide likely to bind MHC. Here we make public a large set of 48,828 quantitative peptide-binding affinity measurements relating to 48 different mouse, human, macaque, and chimpanzee MHC class I alleles. We use this data to establish a set of benchmark predictions with one neural network method and two matrix-based prediction methods extensively utilized in our groups. In general, the neural network outperforms the matrix-based predictions mainly due to its ability to generalize even on a small amount of data. We also retrieved predictions from tools publicly available on the internet. While differences in the data used to generate these predictions hamper direct comparisons, we do conclude that tools based on combinatorial peptide libraries perform remarkably well. The transparent prediction evaluation on this dataset provides tool developers with a benchmark for comparison of newly developed prediction methods. In addition, to generate and evaluate our own prediction methods, we have established an easily extensible web-based prediction framework that allows automated side-by-side comparisons of prediction methods implemented by experts. This is an advance over the current practice of tool developers having to generate reference predictions themselves, which can lead to underestimating the performance of prediction methods they are not as familiar with as their own. The overall goal of this effort is to provide a transparent prediction evaluation allowing bioinformaticians to identify promising features of prediction methods and providing guidance to immunologists regarding the reliability of prediction tools.

  6. A strong diffusive ion mode in dense ionized matter predicted by Langevin dynamics.

    Science.gov (United States)

    Mabey, P; Richardson, S; White, T G; Fletcher, L B; Glenzer, S H; Hartley, N J; Vorberger, J; Gericke, D O; Gregori, G

    2017-01-30

    The state and evolution of planets, brown dwarfs and neutron star crusts is determined by the properties of dense and compressed matter. Due to the inherent difficulties in modelling strongly coupled plasmas, however, current predictions of transport coefficients differ by orders of magnitude. Collective modes are a prominent feature, whose spectra may serve as an important tool to validate theoretical predictions for dense matter. With recent advances in free electron laser technology, X-rays with small enough bandwidth have become available, allowing the investigation of the low-frequency ion modes in dense matter. Here, we present numerical predictions for these ion modes and demonstrate significant changes to their strength and dispersion if dissipative processes are included by Langevin dynamics. Notably, a strong diffusive mode around zero frequency arises, which is not present, or much weaker, in standard simulations. Our results have profound consequences in the interpretation of transport coefficients in dense plasmas.

  7. SABinder: A Web Service for Predicting Streptavidin-Binding Peptides.

    Science.gov (United States)

    He, Bifang; Kang, Juanjuan; Ru, Beibei; Ding, Hui; Zhou, Peng; Huang, Jian

    2016-01-01

    Streptavidin is sometimes used as the intended target to screen phage-displayed combinatorial peptide libraries for streptavidin-binding peptides (SBPs). More often in the biopanning system, however, streptavidin is just a commonly used anchoring molecule that can efficiently capture the biotinylated target. In this case, SBPs creeping into the biopanning results are not desired binders but target-unrelated peptides (TUP). Taking them as intended binders may mislead subsequent studies. Therefore, it is important to find if a peptide is likely to be an SBP when streptavidin is either the intended target or just the anchoring molecule. In this paper, we describe an SVM-based ensemble predictor called SABinder. It is the first predictor for SBP. The model was built with the feature of optimized dipeptide composition. It was observed that 89.20% (MCC = 0.78; AUC = 0.93; permutation test, p web server, SABinder is freely accessible. The tool provides a highly efficient way to exclude potential SBP when they are TUP or to facilitate identification of possibly new SBP when they are the desired binders. In either case, it will be helpful and can benefit related scientific community.

  8. Predicting peptides binding to MHC class II molecules using multi-objective evolutionary algorithms

    Directory of Open Access Journals (Sweden)

    Feng Lin

    2007-11-01

    Full Text Available Abstract Background Peptides binding to Major Histocompatibility Complex (MHC class II molecules are crucial for initiation and regulation of immune responses. Predicting peptides that bind to a specific MHC molecule plays an important role in determining potential candidates for vaccines. The binding groove in class II MHC is open at both ends, allowing peptides longer than 9-mer to bind. Finding the consensus motif facilitating the binding of peptides to a MHC class II molecule is difficult because of different lengths of binding peptides and varying location of 9-mer binding core. The level of difficulty increases when the molecule is promiscuous and binds to a large number of low affinity peptides. In this paper, we propose two approaches using multi-objective evolutionary algorithms (MOEA for predicting peptides binding to MHC class II molecules. One uses the information from both binders and non-binders for self-discovery of motifs. The other, in addition, uses information from experimentally determined motifs for guided-discovery of motifs. Results The proposed methods are intended for finding peptides binding to MHC class II I-Ag7 molecule – a promiscuous binder to a large number of low affinity peptides. Cross-validation results across experiments on two motifs derived for I-Ag7 datasets demonstrate better generalization abilities and accuracies of the present method over earlier approaches. Further, the proposed method was validated and compared on two publicly available benchmark datasets: (1 an ensemble of qualitative HLA-DRB1*0401 peptide data obtained from five different sources, and (2 quantitative peptide data obtained for sixteen different alleles comprising of three mouse alleles and thirteen HLA alleles. The proposed method outperformed earlier methods on most datasets, indicating that it is well suited for finding peptides binding to MHC class II molecules. Conclusion We present two MOEA-based algorithms for finding motifs

  9. Adaboost Ensemble with Simple Genetic Algorithm for Student Prediction Mode

    Directory of Open Access Journals (Sweden)

    AhmedSharaf ElDen

    2013-05-01

    Full Text Available Predicting the student performance is a great concern to the higher education managements.Thisprediction helps to identify and to improve students' performance.Several factors may improve thisperformance.In the present study, we employ the data mining processes, particularly classification, toenhance the quality of the higher educational system. Recently, a new direction is used for the improvementof the classification accuracy by combining classifiers.In thispaper, we design and evaluate a fastlearningalgorithm using AdaBoost ensemble with a simple genetic algorithmcalled “Ada-GA” where the geneticalgorithm is demonstrated to successfully improve the accuracy of the combined classifier performance.The Ada-GA algorithm proved to be of considerable usefulness in identifying the students at risk early,especially in very large classes. This early prediction allows the instructor to provide appropriate advisingto those students. The Ada/GA algorithm is implemented and tested on ASSISTments dataset, the resultsshowed that this algorithm hassuccessfully improved the detection accuracy as well as it reduces thecomplexity of computation.

  10. A computational analysis of the binding mode of closantel as inhibitor of the Onchocerca volvulus chitinase: insights on macrofilaricidal drug design

    Science.gov (United States)

    Segura-Cabrera, Aldo; Bocanegra-García, Virgilio; Lizarazo-Ortega, Cristian; Guo, Xianwu; Correa-Basurto, José; Rodríguez-Pérez, Mario A.

    2011-12-01

    Onchocerciasis is a leading cause of blindness with at least 37 million people infected and more than 120 million people at risk of contracting the disease; most (99%) of this population, threatened by infection, live in Africa. The drug of choice for mass treatment is the microfilaricidal Mectizan® (ivermectin); it does not kill the adult stages of the parasite at the standard dose which is a single annual dose aimed at disease control. However, multiple treatments a year with ivermectin have effects on adult worms. The discovery of new therapeutic targets and drugs directed towards the killing of the adult parasites are thus urgently needed. The chitinase of filarial nematodes is a new drug target due to its essential function in the metabolism and molting of the parasite. Closantel is a potent and specific inhibitor of chitinase of Onchocerca volvulus (OvCHT1) and other filarial chitinases. However, the binding mode and specificity of closantel towards OvCHT1 remain unknown. In the absence of a crystallographic structure of OvCHT1, we developed a homology model of OvCHT1 using the currently available X-ray structures of human chitinases as templates. Energy minimization and molecular dynamics (MD) simulation of the model led to a high quality of 3D structure of OvCHIT1. A flexible docking study using closantel as the ligand on the binding site of OvCHIT1 and human chitinases was performed and demonstrated the differences in the closantel binding mode between OvCHIT1 and human chitinase. Furthermore, molecular dynamics simulations and free-energy calculation were employed to determine and compare the detailed binding mode of closantel with OvCHT1 and the structure of human chitinase. This comparative study allowed identification of structural features and properties responsible for differences in the computationally predicted closantel binding modes. The homology model and the closantel binding mode reported herein might help guide the rational development of

  11. Predicting Modes of the Unsteady Vorticity Field near the Trailing Edge of a Blade

    Science.gov (United States)

    Devenport, William J.; Spitz, Nicolas; Envia, Edmane (Technical Monitor)

    2003-01-01

    Progress on predicting modes of the unsteady velocity/vorticity field of a turbulent boundary layer from Reynolds stress statistics is described. Prediction of these modes, that provide the source terms for trailing edge noise predictions in aircraft engine fans and other configurations, will allow for the first time detailed viscous flow effects to be included in such noise calculations. The key accomplishments of this work in FY02 are: (1) The development of a Matlab code for the prediction of modes in two- and three-dimensional boundary layers, previously applied to plane wakes; (2) Predictions with the code using a constant lengthscale formulation in a fully developed turbulence channel flow. Comparison of these boundary layer predictions with available DNS simulation results; and (3) Formulation of an improved model using a variable lengthscale proportional to mixing length. Turbulent channel flow predictions and comparison with DNS results. This work is being carried out in continuous communication and collaboration with the Glegg research group at Florida Atlantic University, which will be incorporating mode predictions into engine noise calculations.

  12. Computational protocol for predicting the binding affinities of zinc containing metalloprotein-ligand complexes.

    Science.gov (United States)

    Jain, Tarun; Jayaram, B

    2007-06-01

    Zinc is one of the most important metal ions found in proteins performing specific functions associated with life processes. Coordination geometry of the zinc ion in the active site of the metalloprotein-ligand complexes poses a challenge in determining ligand binding affinities accurately in structure-based drug design. We report here an all atom force field based computational protocol for estimating rapidly the binding affinities of zinc containing metalloprotein-ligand complexes, considering electrostatics, van der Waals, hydrophobicity, and loss in conformational entropy of protein side chains upon ligand binding along with a nonbonded approach to model the interactions of the zinc ion with all the other atoms of the complex. We examined the sensitivity of the binding affinity predictions to the choice of Lennard-Jones parameters, partial atomic charges, and dielectric treatments adopted for system preparation and scoring. The highest correlation obtained was R2 = 0.77 (r = 0.88) for the predicted binding affinity against the experiment on a heterogenous dataset of 90 zinc containing metalloprotein-ligand complexes consisting of five unique protein targets. Model validation and parameter analysis studies underscore the robustness and predictive ability of the scoring function. The high correlation obtained suggests the potential applicability of the methodology in designing novel ligands for zinc-metalloproteins. The scoring function has been web enabled for free access at www.scfbio-iitd.res.in/software/drugdesign/bapplz.jsp as BAPPL-Z server (Binding Affinity Prediction of Protein-Ligand complexes containing Zinc metal ions).

  13. MBSTAR: multiple instance learning for predicting specific functional binding sites in microRNA targets

    Science.gov (United States)

    Bandyopadhyay, Sanghamitra; Ghosh, Dip; Mitra, Ramkrishna; Zhao, Zhongming

    2015-01-01

    MicroRNA (miRNA) regulates gene expression by binding to specific sites in the 3'untranslated regions of its target genes. Machine learning based miRNA target prediction algorithms first extract a set of features from potential binding sites (PBSs) in the mRNA and then train a classifier to distinguish targets from non-targets. However, they do not consider whether the PBSs are functional or not, and consequently result in high false positive rates. This substantially affects the follow up functional validation by experiments. We present a novel machine learning based approach, MBSTAR (Multiple instance learning of Binding Sites of miRNA TARgets), for accurate prediction of true or functional miRNA binding sites. Multiple instance learning framework is adopted to handle the lack of information about the actual binding sites in the target mRNAs. Biologically validated 9531 interacting and 973 non-interacting miRNA-mRNA pairs are identified from Tarbase 6.0 and confirmed with PAR-CLIP dataset. It is found that MBSTAR achieves the highest number of binding sites overlapping with PAR-CLIP with maximum F-Score of 0.337. Compared to the other methods, MBSTAR also predicts target mRNAs with highest accuracy. The tool and genome wide predictions are available at http://www.isical.ac.in/~bioinfo_miu/MBStar30.htm.

  14. Predicting the mode of flow in pneumatic conveying systems-A review

    Institute of Scientific and Technical Information of China (English)

    Mark G.Jones; Kenneth C.Williams

    2008-01-01

    An initial prediction of the particulate mode of flow in pneumatic conveying systems is beneficial as this knowledge can provide clearer direction to the pneumatic conveying design process.There are three general categories of modes of flow,two dense flows:fluidised dense phase and plug flow,and dilute phase only.Detailed in this paper is a review of the commonly used and available techniques for predicting mode of flow.Two types of predictive charts were defined:basic particle parameter based (e.g.particle size and density) and air-particle parameter based (e.g.permeability and de-aeration).The basic particle techniques were found to have strong and weak areas of predictive ability,on the basis of a comparison with data from materials with known mode of flow capability.It was found that there was only slight improvement in predictive ability when the particle density was replaced by loose-poured bulk density in the basic parameter techniques.The air-particle-parameter-based techniques also showed well-defined regions for mode of flow prediction though the data set used was smaller than that for the basic techniques.Also,it was found to be difficult to utilise de-aeration values from different researchers and subsequently,an air-particle-based technique was developed which does not require any de-aeration parameter in its assessment.

  15. Variable structure control with sliding mode prediction for discrete-time nonlinear systems

    Institute of Scientific and Technical Information of China (English)

    Lingfei XIAO; Hongye SU; Xiaoyu ZHANG; Jian CHU

    2006-01-01

    A new variable structure control algorithm based on sliding mode prediction for a class of discrete-time nonlinear systems is presented. By employing a special model to predict future sliding mode value, and combining feedback correction and receding horizon optimization methods which are extensively applied on predictive control strategy, a discrete-time variable structure control law is constructed. The closed-loop systems are proved to have robustness to uncertainties with unspecified boundaries. Numerical simulation and pendulum experiment results illustrate that the closed-loop systems possess desired performance, such as strong robustness, fast convergence and chattering elimination.

  16. Nonspecific recognition is achieved in Pot1pC through the use of multiple binding modes.

    Science.gov (United States)

    Dickey, Thayne H; McKercher, Marissa A; Wuttke, Deborah S

    2013-01-01

    Pot1 is the protein responsible for binding to and protecting the 3' single-stranded DNA (ssDNA) overhang at most eukaryotic telomeres. Here, we present the crystal structure of one of the two oligonucleotide/oligosaccharide-binding folds (Pot1pC) that make up the ssDNA-binding domain in S. pombe Pot1. Comparison with the homologous human domain reveals unexpected structural divergence in the mode of ligand binding that explains the differing ligand requirements between species. Despite the presence of apparently base-specific hydrogen bonds, Pot1pC is able to bind a wide range of ssDNA sequences with thermodynamic equivalence. To address how Pot1pC binds ssDNA with little to no specificity, multiple structures of Pot1pC bound to noncognate ssDNA ligands were solved. These structures reveal that this promiscuity is implemented through new binding modes that thermodynamically compensate for base-substitutions through alternate stacking interactions and new H-bonding networks.

  17. Prediction of Coronary Artery Disease by B-Mode Sonography

    Directory of Open Access Journals (Sweden)

    J Kheirkhah

    2010-09-01

    Full Text Available Background: Although coronary angiography is gold standard for diagnosis of coronary artery disease, it is nevertheless an invasive and potentially hazardous procedure. The aim of this study was to investigate the predictive value of carotid and femoral artery Intima-Media Thickness (IMT for detection of coronary artery disease.Methods: The present study comprised 100 consecutive patients referred for coronary angiography due to symptoms of ischemic heart disease. Ultrasound assessment of common carotid and common femoral artery were performed with an ultrasound device equipped with a high-resolution transducer. IMT was measured in the common carotid and common femoral artery (10 mm proximal to the deep femoral artery origin. Results: There were 25 cases in each of single (S, double (D and triple (T vessel disease and 25 in significant left main diseases groups of patients. In regard to common carotid artery IMT was 0.78 mm in S, 0.84 mm in D, 0.97 mm in T and 1.05 mm in left main disease groups. There was a significant correlation between IMT measured in the carotid artery and severity of coronary artery disease (P = 0.0001. With respect to common femoral artery IMT was 0.66 mm in S group, 0.73 mm in D group, 0.84 mm in T groups and 0.85 mm in patients with left main disease.. There is a significant correlation between IMT (measured in the common femoral artery and severity of coronary artery disease (P = 0.0001.Conclusion: Our results indicated that early atherosclerosis in both carotid and femoral arteries were highly predictive of coronary involvement and IMT being associated with the number of coronary vessels disorder.

  18. SAAMBE: Webserver to Predict the Charge of Binding Free Energy Caused by Amino Acids Mutations.

    Science.gov (United States)

    Petukh, Marharyta; Dai, Luogeng; Alexov, Emil

    2016-04-12

    Predicting the effect of amino acid substitutions on protein-protein affinity (typically evaluated via the change of protein binding free energy) is important for both understanding the disease-causing mechanism of missense mutations and guiding protein engineering. In addition, researchers are also interested in understanding which energy components are mostly affected by the mutation and how the mutation affects the overall structure of the corresponding protein. Here we report a webserver, the Single Amino Acid Mutation based change in Binding free Energy (SAAMBE) webserver, which addresses the demand for tools for predicting the change of protein binding free energy. SAAMBE is an easy to use webserver, which only requires that a coordinate file be inputted and the user is provided with various, but easy to navigate, options. The user specifies the mutation position, wild type residue and type of mutation to be made. The server predicts the binding free energy change, the changes of the corresponding energy components and provides the energy minimized 3D structure of the wild type and mutant proteins for download. The SAAMBE protocol performance was tested by benchmarking the predictions against over 1300 experimentally determined changes of binding free energy and a Pearson correlation coefficient of 0.62 was obtained. How the predictions can be used for discriminating disease-causing from harmless mutations is discussed. The webserver can be accessed via http://compbio.clemson.edu/saambe_webserver/.

  19. Modeling Nonlinear Adsorption with a Single Chemical Parameter: Predicting Chemical Median Langmuir Binding Constants.

    Science.gov (United States)

    Davis, Craig Warren; Di Toro, Dominic M

    2015-07-07

    Procedures for accurately predicting linear partition coefficients onto various sorbents (e.g., organic carbon, soils, clay) are reliable and well established. However, similar procedures for the prediction of sorption parameters of nonlinear isotherm models are not. The purpose of this paper is to present a procedure for predicting nonlinear isotherm parameters, specifically the median Langmuir binding constants, K̃L, obtained utilizing the single-chemical parameter log-normal Langmuir isotherm developed in the accompanying work. A reduced poly parameter linear free energy relationship (pp-LFER) is able to predict median Langmuir binding constants for graphite, charcoal, and Darco granular activated carbon (GAC) adsorption data. For the larger F400 GAC data set, a single pp-LFER model was insufficient, as a plateau is observed for the median Langmuir binding constants of larger molecular volume sorbates. This volumetric cutoff occurs in proximity to the median pore diameter for F400 GAC. A log-linear relationship exists between the aqueous solubility of these large compounds and their median Langmuir binding constants. Using this relationship for the chemicals above the volumetric cutoff and the pp-LFER below the cutoff, the median Langmuir binding constants can be predicted with a root-mean square error for graphite (n = 13), charcoal (n = 11), Darco GAC (n = 14), and F400 GAC (n = 44) of 0.129, 0.307, 0.407, and 0.424, respectively.

  20. New insight into the binding modes of TNP-AMP to human liver fructose-1,6-bisphosphatase

    Science.gov (United States)

    Han, Xinya; Huang, Yunyuan; Zhang, Rui; Xiao, San; Zhu, Shuaihuan; Qin, Nian; Hong, Zongqin; Wei, Lin; Feng, Jiangtao; Ren, Yanliang; Feng, Lingling; Wan, Jian

    2016-08-01

    Human liver fructose-1,6-bisphosphatase (FBPase) contains two binding sites, a substrate fructose-1,6-bisphosphate (FBP) active site and an adenosine monophosphate (AMP) allosteric site. The FBP active site works by stabilizing the FBPase, and the allosteric site impairs the activity of FBPase through its binding of a nonsubstrate molecule. The fluorescent AMP analogue, 2‧,3‧-O-(2,4,6-trinitrophenyl)adenosine 5‧-monophosphate (TNP-AMP) has been used as a fluorescent probe as it is able to competitively inhibit AMP binding to the AMP allosteric site and, therefore, could be used for exploring the binding modes of inhibitors targeted on the allosteric site. In this study, we have re-examined the binding modes of TNP-AMP to FBPase. However, our present enzyme kinetic assays show that AMP and FBP both can reduce the fluorescence from the bound TNP-AMP through competition for FBPase, suggesting that TNP-AMP binds not only to the AMP allosteric site but also to the FBP active site. Mutagenesis assays of K274L (located in the FBP active site) show that the residue K274 is very important for TNP-AMP to bind to the active site of FBPase. The results further prove that TNP-AMP is able to bind individually to the both sites. Our present study provides a new insight into the binding mechanism of TNP-AMP to the FBPase. The TNP-AMP fluorescent probe can be used to exam the binding site of an inhibitor (the active site or the allosteric site) using FBPase saturated by AMP and FBP, respectively, or the K247L mutant FBPase.

  1. Structural Dynamics Investigation of Human Family 1 & 2 Cystatin-Cathepsin L1 Interaction: A Comparison of Binding Modes

    Science.gov (United States)

    Nandy, Suman Kumar; Seal, Alpana

    2016-01-01

    Cystatin superfamily is a large group of evolutionarily related proteins involved in numerous physiological activities through their inhibitory activity towards cysteine proteases. Despite sharing the same cystatin fold, and inhibiting cysteine proteases through the same tripartite edge involving highly conserved N-terminal region, L1 and L2 loop; cystatins differ widely in their inhibitory affinity towards C1 family of cysteine proteases and molecular details of these interactions are still elusive. In this study, inhibitory interactions of human family 1 & 2 cystatins with cathepsin L1 are predicted and their stability and viability are verified through protein docking & comparative molecular dynamics. An overall stabilization effect is observed in all cystatins on complex formation. Complexes are mostly dominated by van der Waals interaction but the relative participation of the conserved regions varied extensively. While van der Waals contacts prevail in L1 and L2 loop, N-terminal segment chiefly acts as electrostatic interaction site. In fact the comparative dynamics study points towards the instrumental role of L1 loop in directing the total interaction profile of the complex either towards electrostatic or van der Waals contacts. The key amino acid residues surfaced via interaction energy, hydrogen bonding and solvent accessible surface area analysis for each cystatin-cathepsin L1 complex influence the mode of binding and thus control the diverse inhibitory affinity of cystatins towards cysteine proteases. PMID:27764212

  2. Structural Dynamics Investigation of Human Family 1 & 2 Cystatin-Cathepsin L1 Interaction: A Comparison of Binding Modes.

    Science.gov (United States)

    Nandy, Suman Kumar; Seal, Alpana

    2016-01-01

    Cystatin superfamily is a large group of evolutionarily related proteins involved in numerous physiological activities through their inhibitory activity towards cysteine proteases. Despite sharing the same cystatin fold, and inhibiting cysteine proteases through the same tripartite edge involving highly conserved N-terminal region, L1 and L2 loop; cystatins differ widely in their inhibitory affinity towards C1 family of cysteine proteases and molecular details of these interactions are still elusive. In this study, inhibitory interactions of human family 1 & 2 cystatins with cathepsin L1 are predicted and their stability and viability are verified through protein docking & comparative molecular dynamics. An overall stabilization effect is observed in all cystatins on complex formation. Complexes are mostly dominated by van der Waals interaction but the relative participation of the conserved regions varied extensively. While van der Waals contacts prevail in L1 and L2 loop, N-terminal segment chiefly acts as electrostatic interaction site. In fact the comparative dynamics study points towards the instrumental role of L1 loop in directing the total interaction profile of the complex either towards electrostatic or van der Waals contacts. The key amino acid residues surfaced via interaction energy, hydrogen bonding and solvent accessible surface area analysis for each cystatin-cathepsin L1 complex influence the mode of binding and thus control the diverse inhibitory affinity of cystatins towards cysteine proteases.

  3. Initial value predictability of intrinsic oceanic modes and implications for decadal prediction over North America

    Energy Technology Data Exchange (ETDEWEB)

    Branstator, Grant [National Center for Atmospheric Research, Boulder, CO (United States)

    2014-12-09

    The overall aim of our project was to quantify and characterize predictability of the climate as it pertains to decadal time scale predictions. By predictability we mean the degree to which a climate forecast can be distinguished from the climate that exists at initial forecast time, taking into consideration the growth of uncertainty that occurs as a result of the climate system being chaotic. In our project we were especially interested in predictability that arises from initializing forecasts from some specific state though we also contrast this predictability with predictability arising from forecasting the reaction of the system to external forcing – for example changes in greenhouse gas concentration. Also, we put special emphasis on the predictability of prominent intrinsic patterns of the system because they often dominate system behavior. Highlights from this work include: • Development of novel methods for estimating the predictability of climate forecast models. • Quantification of the initial value predictability limits of ocean heat content and the overturning circulation in the Atlantic as they are represented in various state of the art climate models. These limits varied substantially from model to model but on average were about a decade with North Atlantic heat content tending to be more predictable than North Pacific heat content. • Comparison of predictability resulting from knowledge of the current state of the climate system with predictability resulting from estimates of how the climate system will react to changes in greenhouse gas concentrations. It turned out that knowledge of the initial state produces a larger impact on forecasts for the first 5 to 10 years of projections. • Estimation of the predictability of dominant patterns of ocean variability including well-known patterns of variability in the North Pacific and North Atlantic. For the most part these patterns were predictable for 5 to 10 years. • Determination of

  4. A knowledge-guided strategy for improving the accuracy of scoring functions in binding affinity prediction

    Directory of Open Access Journals (Sweden)

    Wang Renxiao

    2010-04-01

    Full Text Available Abstract Background Current scoring functions are not very successful in protein-ligand binding affinity prediction albeit their popularity in structure-based drug designs. Here, we propose a general knowledge-guided scoring (KGS strategy to tackle this problem. Our KGS strategy computes the binding constant of a given protein-ligand complex based on the known binding constant of an appropriate reference complex. A good training set that includes a sufficient number of protein-ligand complexes with known binding data needs to be supplied for finding the reference complex. The reference complex is required to share a similar pattern of key protein-ligand interactions to that of the complex of interest. Thus, some uncertain factors in protein-ligand binding may cancel out, resulting in a more accurate prediction of absolute binding constants. Results In our study, an automatic algorithm was developed for summarizing key protein-ligand interactions as a pharmacophore model and identifying the reference complex with a maximal similarity to the query complex. Our KGS strategy was evaluated in combination with two scoring functions (X-Score and PLP on three test sets, containing 112 HIV protease complexes, 44 carbonic anhydrase complexes, and 73 trypsin complexes, respectively. Our results obtained on crystal structures as well as computer-generated docking poses indicated that application of the KGS strategy produced more accurate predictions especially when X-Score or PLP alone did not perform well. Conclusions Compared to other targeted scoring functions, our KGS strategy does not require any re-parameterization or modification on current scoring methods, and its application is not tied to certain systems. The effectiveness of our KGS strategy is in theory proportional to the ever-increasing knowledge of experimental protein-ligand binding data. Our KGS strategy may serve as a more practical remedy for current scoring functions to improve their

  5. The telomeric protein Pot1 from Schizosaccharomyces pombe binds ssDNA in two modes with differing 3' end availability.

    Science.gov (United States)

    Dickey, Thayne H; Wuttke, Deborah S

    2014-09-01

    Telomere protection and length regulation are important processes for aging, cancer and several other diseases. At the heart of these processes lies the single-stranded DNA (ssDNA)-binding protein Pot1, a component of the telomere maintenance complex shelterin, which is present in species ranging from fission yeast to humans. Pot1 contains a dual OB-fold DNA-binding domain (DBD) that fully confers its high affinity for telomeric ssDNA. Studies of S. pombe Pot1-DBD and its individual OB-fold domains revealed a complex non-additive behavior of the two OB-folds in the context of the complete Pot1 protein. This behavior includes the use of multiple distinct binding modes and an ability to form higher order complexes. Here we use NMR and biochemical techniques to investigate the structural features of the complete Pot1-DBD. These experiments reveal one binding mode characterized by only subtle alternations to the individual OB-fold subdomain structures, resulting in an inaccessible 3' end of the ssDNA. The second binding mode, which has equivalent affinity, interacts differently with the 3' end, rendering it available for interaction with other proteins. These findings suggest a structural switch that contributes to telomere end-protection and length regulation.

  6. A Large-Scale Assessment of Nucleic Acids Binding Site Prediction Programs.

    Directory of Open Access Journals (Sweden)

    Zhichao Miao

    2015-12-01

    Full Text Available Computational prediction of nucleic acid binding sites in proteins are necessary to disentangle functional mechanisms in most biological processes and to explore the binding mechanisms. Several strategies have been proposed, but the state-of-the-art approaches display a great diversity in i the definition of nucleic acid binding sites; ii the training and test datasets; iii the algorithmic methods for the prediction strategies; iv the performance measures and v the distribution and availability of the prediction programs. Here we report a large-scale assessment of 19 web servers and 3 stand-alone programs on 41 datasets including more than 5000 proteins derived from 3D structures of protein-nucleic acid complexes. Well-defined binary assessment criteria (specificity, sensitivity, precision, accuracy… are applied. We found that i the tools have been greatly improved over the years; ii some of the approaches suffer from theoretical defects and there is still room for sorting out the essential mechanisms of binding; iii RNA binding and DNA binding appear to follow similar driving forces and iv dataset bias may exist in some methods.

  7. Non-specific recognition is achieved in Pot1pC through the use of multiple binding modes

    Science.gov (United States)

    Dickey, Thayne H.; McKercher, Marissa A.; Wuttke, Deborah S.

    2012-01-01

    Summary Pot1 is the protein responsible for binding to and protecting the 3’ single-stranded DNA (ssDNA) overhang at most eukaryotic telomeres. Here we present the crystal structure of one of the two OB-folds (Pot1pC) that make up the ssDNA-binding domain in S. pombe Pot1. Comparison with the homologous human domain reveals unexpected structural divergence in the mode of ligand binding that explains the differing ligand requirements between species. Despite the presence of apparently base-specific hydrogen bonds, Pot1pC is able to bind a wide range of ssDNA sequences with thermodynamic equivalence. To address how Pot1pC binds ssDNA with little to no specificity, multiple structures of Pot1pC bound to non-cognate ssDNA ligands were solved. These structures reveal that this promiscuity is implemented through new binding modes that thermodynamically compensate for base-substitutions through alternate stacking interactions and new H-bonding networks. PMID:23201273

  8. From intercalation to groove binding: switching the DNA-binding mode of isostructural transition-metal complexes.

    Science.gov (United States)

    Ahmad, Haslina; Wragg, Ashley; Cullen, Will; Wombwell, Claire; Meijer, Anthony J H M; Thomas, Jim A

    2014-03-10

    The interaction with duplex DNA of a small library of structurally related complexes that all contain a d6-metal ion coordinated to either the 2,2′:4,4′′:4′,4′′′-quaterpyridyl ligand or its methylated derivative are reported. This library is made up of a mixture of newly synthesised and previously reported systems. Despite their structural similarities the complexes display an almost 20-fold variation in binding affinities. Although effects due to the overall charge of the complexes are apparent, the differences in binding characteristics are deeper than this; indeed, in a number of cases, changes in overall charge have little effect on binding affinity. Intriguingly, despite interacting with DNA through unfused ring systems, although two of the complexes studied are groove binders, the majority are non-classical intercalators. A rationale for these effects has been obtained through a combination of experimental and computational studies.

  9. Crystal structure and RNA-binding properties of an Hfq homolog from the deep-branching Aquificae: conservation of the lateral RNA-binding mode.

    Science.gov (United States)

    Stanek, Kimberly A; Patterson-West, Jennifer; Randolph, Peter S; Mura, Cameron

    2017-04-01

    The host factor Hfq, as the bacterial branch of the Sm family, is an RNA-binding protein involved in the post-transcriptional regulation of mRNA expression and turnover. Hfq facilitates pairing between small regulatory RNAs (sRNAs) and their corresponding mRNA targets by binding both RNAs and bringing them into close proximity. Hfq homologs self-assemble into homo-hexameric rings with at least two distinct surfaces that bind RNA. Recently, another binding site, dubbed the `lateral rim', has been implicated in sRNA·mRNA annealing; the RNA-binding properties of this site appear to be rather subtle, and its degree of evolutionary conservation is unknown. An Hfq homolog has been identified in the phylogenetically deep-branching thermophile Aquifex aeolicus (Aae), but little is known about the structure and function of Hfq from basal bacterial lineages such as the Aquificae. Therefore, Aae Hfq was cloned, overexpressed, purified, crystallized and biochemically characterized. Structures of Aae Hfq were determined in space groups P1 and P6, both to 1.5 Å resolution, and nanomolar-scale binding affinities for uridine- and adenosine-rich RNAs were discovered. Co-crystallization with U6 RNA reveals that the outer rim of the Aae Hfq hexamer features a well defined binding pocket that is selective for uracil. This Aae Hfq structure, combined with biochemical and biophysical characterization of the homolog, reveals deep evolutionary conservation of the lateral RNA-binding mode, and lays a foundation for further studies of Hfq-associated RNA biology in ancient bacterial phyla.

  10. An alternate mode of binding of the polyphenol quercetin with serum albumins when complexed with Cu(II)

    Energy Technology Data Exchange (ETDEWEB)

    Singha Roy, Atanu; Tripathy, Debi Ranjan; Ghosh, Arup Kumar [Department of Chemistry, Indian Institute of Technology, Kharagpur 721302 (India); Dasgupta, Swagata, E-mail: swagata@chem.iitkgp.ernet.in [Department of Chemistry, Indian Institute of Technology, Kharagpur 721302 (India)

    2012-11-15

    Polyphenols find wide use as antioxidants, cancer chemopreventive agents and metal chelators. The latter activity has proved interesting in many aspects. We have probed the binding characteristics of the polyphenol quercetin-Cu(II) complex with human serum albumin (HSA) and bovine serum albumin (BSA). Fluorescence studies reveal that the quercetin-Cu(II) complex can quench the fluorescence of the serum albumins. The binding constant (K{sub b}) values are of the order of 10{sup 5} M{sup -1} which increased with rise in temperature in case of HSA and BSA interacting with the quercetin-Cu(II) complex. Displacement studies reveal that both the ligands bind to site 1 (subdomain IIA) of the serum albumins. However, thermodynamic parameters calculated from temperature dependent studies indicated that the mode of interaction of the complexes with the proteins differs. Both {Delta}H Degree-Sign and {Delta}S Degree-Sign were positive for the interaction of the quercetin-Cu(II) complex with both proteins but the value of {Delta}H Degree-Sign was negative in case of the interaction of quercetin with the proteins. This implies that after chelation with metal ions, the polyphenol alters its mode of interaction which could have varying implications on its other physicochemical activities. - Research Highlights: Black-Right-Pointing-Pointer Mode of binding of quercetin with SAs is altered after complexation with Cu(II). Black-Right-Pointing-Pointer Hydrophobic forces play a key role in the binding of the copper complex with SAs. Black-Right-Pointing-Pointer Negative {Delta}G Degree-Sign values indicate the spontaneity of the binding processes. Black-Right-Pointing-Pointer Quercetin and its copper complex bind at the same site of the SAs.

  11. Development of a protein-ligand-binding site prediction method based on interaction energy and sequence conservation.

    Science.gov (United States)

    Tsujikawa, Hiroto; Sato, Kenta; Wei, Cao; Saad, Gul; Sumikoshi, Kazuya; Nakamura, Shugo; Terada, Tohru; Shimizu, Kentaro

    2016-09-01

    We present a new method for predicting protein-ligand-binding sites based on protein three-dimensional structure and amino acid conservation. This method involves calculation of the van der Waals interaction energy between a protein and many probes placed on the protein surface and subsequent clustering of the probes with low interaction energies to identify the most energetically favorable locus. In addition, it uses amino acid conservation among homologous proteins. Ligand-binding sites were predicted by combining the interaction energy and the amino acid conservation score. The performance of our prediction method was evaluated using a non-redundant dataset of 348 ligand-bound and ligand-unbound protein structure pairs, constructed by filtering entries in a ligand-binding site structure database, LigASite. Ligand-bound structure prediction (bound prediction) indicated that 74.0 % of predicted ligand-binding sites overlapped with real ligand-binding sites by over 25 % of their volume. Ligand-unbound structure prediction (unbound prediction) indicated that 73.9 % of predicted ligand-binding residues overlapped with real ligand-binding residues. The amino acid conservation score improved the average prediction accuracy by 17.0 and 17.6 points for the bound and unbound predictions, respectively. These results demonstrate the effectiveness of the combined use of the interaction energy and amino acid conservation in the ligand-binding site prediction.

  12. Predicting the binding free energy of the inclusion process of 2-hydroxypropyl-β-cyclodextrin and small molecules by means of the MM/3D-RISM method

    Science.gov (United States)

    Sugita, Masatake; Hirata, Fumio

    2016-09-01

    A protocol to calculate the binding free energy of a host-guest system is proposed based on the MM/3D-RISM method, taking cyclodextrin derivatives and their ligands as model systems. The protocol involves the procedure to identify the most probable binding mode (MPBM) of receptors and ligands by means of the umbrella sampling method. The binding free energies calculated by the MM/3D-RISM method for the complexes of the seven ligands with the MPBM of the cyclodextrin, and with the fluctuated structures around it, are in agreement with the corresponding experimental data in a semi-quantitative manner. It suggests that the protocol proposed here is promising for predicting the binding affinity of a small ligand to a relatively rigid receptor such as cyclodextrin.

  13. The predicted 3D structure of the human D2 dopamine receptor and the binding site and binding affinities for agonists and antagonists

    Science.gov (United States)

    Kalani, M. Yashar S.; Vaidehi, Nagarajan; Hall, Spencer E.; Trabanino, Rene J.; Freddolino, Peter L.; Kalani, Maziyar A.; Floriano, Wely B.; Tak Kam, Victor Wai; Goddard, William A., III

    2004-03-01

    Dopamine neurotransmitter and its receptors play a critical role in the cell signaling process responsible for information transfer in neurons functioning in the nervous system. Development of improved therapeutics for such disorders as Parkinson's disease and schizophrenia would be significantly enhanced with the availability of the 3D structure for the dopamine receptors and of the binding site for dopamine and other agonists and antagonists. We report here the 3D structure of the long isoform of the human D2 dopamine receptor, predicted from primary sequence using first-principles theoretical and computational techniques (i.e., we did not use bioinformatic or experimental 3D structural information in predicting structures). The predicted 3D structure is validated by comparison of the predicted binding site and the relative binding affinities of dopamine, three known dopamine agonists (antiparkinsonian), and seven known antagonists (antipsychotic) in the D2 receptor to experimentally determined values. These structures correctly predict the critical residues for binding dopamine and several antagonists, identified by mutation studies, and give relative binding affinities that correlate well with experiments. The predicted binding site for dopamine and agonists is located between transmembrane (TM) helices 3, 4, 5, and 6, whereas the best antagonists bind to a site involving TM helices 2, 3, 4, 6, and 7 with minimal contacts to TM helix 5. We identify characteristic differences between the binding sites of agonists and antagonists.

  14. Cell-type specificity of ChIP-predicted transcription factor binding sites

    Directory of Open Access Journals (Sweden)

    Håndstad Tony

    2012-08-01

    Full Text Available Abstract Background Context-dependent transcription factor (TF binding is one reason for differences in gene expression patterns between different cellular states. Chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq identifies genome-wide TF binding sites for one particular context—the cells used in the experiment. But can such ChIP-seq data predict TF binding in other cellular contexts and is it possible to distinguish context-dependent from ubiquitous TF binding? Results We compared ChIP-seq data on TF binding for multiple TFs in two different cell types and found that on average only a third of ChIP-seq peak regions are common to both cell types. Expectedly, common peaks occur more frequently in certain genomic contexts, such as CpG-rich promoters, whereas chromatin differences characterize cell-type specific TF binding. We also find, however, that genotype differences between the cell types can explain differences in binding. Moreover, ChIP-seq signal intensity and peak clustering are the strongest predictors of common peaks. Compared with strong peaks located in regions containing peaks for multiple transcription factors, weak and isolated peaks are less common between the cell types and are less associated with data that indicate regulatory activity. Conclusions Together, the results suggest that experimental noise is prevalent among weak peaks, whereas strong and clustered peaks represent high-confidence binding events that often occur in other cellular contexts. Nevertheless, 30-40% of the strongest and most clustered peaks show context-dependent regulation. We show that by combining signal intensity with additional data—ranging from context independent information such as binding site conservation and position weight matrix scores to context dependent chromatin structure—we can predict whether a ChIP-seq peak is likely to be present in other cellular contexts.

  15. Micromechanical model of cross-over fibre bridging - Prediction of mixed mode bridging laws

    DEFF Research Database (Denmark)

    Sørensen, Bent F.; Gamstedt, E.K.; Østergaard, Rasmus Christian;

    2008-01-01

    on the observed bridging mechanism, a micromechanical model is developed for the prediction of macroscopic mixed mode bridging laws (stress-opening laws). The model predicts a high normal stress for very small openings, decreasing rapidly with increasing normal and tangential crack opening displacements......The fracture resistance of fibre composites can be greatly enhanced by crack bridging. In situ observations of mixed mode crack growth in a unidirectional carbon-fibre/epoxy composite reveal crack bridging by single fibres and by beam-like ligaments consisting of several fibres. Based...

  16. Predicting protein ligand binding sites by combining evolutionary sequence conservation and 3D structure.

    Directory of Open Access Journals (Sweden)

    John A Capra

    2009-12-01

    Full Text Available Identifying a protein's functional sites is an important step towards characterizing its molecular function. Numerous structure- and sequence-based methods have been developed for this problem. Here we introduce ConCavity, a small molecule binding site prediction algorithm that integrates evolutionary sequence conservation estimates with structure-based methods for identifying protein surface cavities. In large-scale testing on a diverse set of single- and multi-chain protein structures, we show that ConCavity substantially outperforms existing methods for identifying both 3D ligand binding pockets and individual ligand binding residues. As part of our testing, we perform one of the first direct comparisons of conservation-based and structure-based methods. We find that the two approaches provide largely complementary information, which can be combined to improve upon either approach alone. We also demonstrate that ConCavity has state-of-the-art performance in predicting catalytic sites and drug binding pockets. Overall, the algorithms and analysis presented here significantly improve our ability to identify ligand binding sites and further advance our understanding of the relationship between evolutionary sequence conservation and structural and functional attributes of proteins. Data, source code, and prediction visualizations are available on the ConCavity web site (http://compbio.cs.princeton.edu/concavity/.

  17. Predicting protein ligand binding sites by combining evolutionary sequence conservation and 3D structure.

    Science.gov (United States)

    Capra, John A; Laskowski, Roman A; Thornton, Janet M; Singh, Mona; Funkhouser, Thomas A

    2009-12-01

    Identifying a protein's functional sites is an important step towards characterizing its molecular function. Numerous structure- and sequence-based methods have been developed for this problem. Here we introduce ConCavity, a small molecule binding site prediction algorithm that integrates evolutionary sequence conservation estimates with structure-based methods for identifying protein surface cavities. In large-scale testing on a diverse set of single- and multi-chain protein structures, we show that ConCavity substantially outperforms existing methods for identifying both 3D ligand binding pockets and individual ligand binding residues. As part of our testing, we perform one of the first direct comparisons of conservation-based and structure-based methods. We find that the two approaches provide largely complementary information, which can be combined to improve upon either approach alone. We also demonstrate that ConCavity has state-of-the-art performance in predicting catalytic sites and drug binding pockets. Overall, the algorithms and analysis presented here significantly improve our ability to identify ligand binding sites and further advance our understanding of the relationship between evolutionary sequence conservation and structural and functional attributes of proteins. Data, source code, and prediction visualizations are available on the ConCavity web site (http://compbio.cs.princeton.edu/concavity/).

  18. Calciomics:prediction and analysis of EF-hand calcium binding proteins by protein engineering

    Institute of Scientific and Technical Information of China (English)

    YANG; Jenny; Jie

    2010-01-01

    Ca2+ plays a pivotal role in the physiology and biochemistry of prokaryotic and mammalian organisms.Viruses also utilize the universal Ca2+ signal to create a specific cellular environment to achieve coexistence with the host,and to propagate.In this paper we first describe our development of a grafting approach to understand site-specific Ca2+ binding properties of EF-hand proteins with a helix-loop-helix Ca2+ binding motif,then summarize our prediction and identification of EF-hand Ca2+ binding sites on a genome-wide scale in bacteria and virus,and next report the application of the grafting approach to probe the metal binding capability of predicted EF-hand motifs within the streptococcal hemoprotein receptor(Shr) of Streptococcus pyrogenes and the nonstructural protein 1(nsP1) of Sindbis virus.When methods such as the grafting approach are developed in conjunction with prediction algorithms we are better able to probe continuous Ca2+-binding sites that have been previously underrepresented due to the limitation of conventional methodology.

  19. TEPITOPEpan: extending TEPITOPE for peptide binding prediction covering over 700 HLA-DR molecules.

    Directory of Open Access Journals (Sweden)

    Lianming Zhang

    Full Text Available MOTIVATION: Accurate identification of peptides binding to specific Major Histocompatibility Complex Class II (MHC-II molecules is of great importance for elucidating the underlying mechanism of immune recognition, as well as for developing effective epitope-based vaccines and promising immunotherapies for many severe diseases. Due to extreme polymorphism of MHC-II alleles and the high cost of biochemical experiments, the development of computational methods for accurate prediction of binding peptides of MHC-II molecules, particularly for the ones with few or no experimental data, has become a topic of increasing interest. TEPITOPE is a well-used computational approach because of its good interpretability and relatively high performance. However, TEPITOPE can be applied to only 51 out of over 700 known HLA DR molecules. METHOD: We have developed a new method, called TEPITOPEpan, by extrapolating from the binding specificities of HLA DR molecules characterized by TEPITOPE to those uncharacterized. First, each HLA-DR binding pocket is represented by amino acid residues that have close contact with the corresponding peptide binding core residues. Then the pocket similarity between two HLA-DR molecules is calculated as the sequence similarity of the residues. Finally, for an uncharacterized HLA-DR molecule, the binding specificity of each pocket is computed as a weighted average in pocket binding specificities over HLA-DR molecules characterized by TEPITOPE. RESULT: The performance of TEPITOPEpan has been extensively evaluated using various data sets from different viewpoints: predicting MHC binding peptides, identifying HLA ligands and T-cell epitopes and recognizing binding cores. Among the four state-of-the-art competing pan-specific methods, for predicting binding specificities of unknown HLA-DR molecules, TEPITOPEpan was roughly the second best method next to NETMHCIIpan-2.0. Additionally, TEPITOPEpan achieved the best performance in

  20. Mode of binding of the tuberculosis prodrug isoniazid to heme peroxidases: binding studies and crystal structure of bovine lactoperoxidase with isoniazid at 2.7 A resolution.

    Science.gov (United States)

    Singh, Amit K; Kumar, Ramasamy P; Pandey, Nisha; Singh, Nagendra; Sinha, Mau; Bhushan, Asha; Kaur, Punit; Sharma, Sujata; Singh, Tej P

    2010-01-01

    Isoniazid (INH) is an anti-tuberculosis prodrug that is activated by mammalian lactoperoxidase and Mycobacterium tuberculosis catalase peroxidase (MtCP). We report here binding studies, an enzyme assay involving INH, and the crystal structure of the complex of bovine lactoperoxidase (LPO) with INH to illuminate binding properties and INH activation as well as the mode of diffusion and interactions together with a detailed structural and functional comparison with MtCP. The structure determination shows that isoniazid binds to LPO at the substrate binding site on the distal heme side. The substrate binding site is connected to the protein surface through a long hydrophobic channel. The acyl hydrazide moiety of isoniazid interacts with Phe(422) O, Gln(423) O(epsilon1), and Phe(254) O. In this arrangement, pyridinyl nitrogen forms a hydrogen bond with a water molecule, W-1, which in turn forms three hydrogen bonds with Fe(3+), His(109) N(epsilon2), and Gln(105) N(epsilon2). The remaining two sides of isoniazid form hydrophobic interactions with the atoms of heme pyrrole ring A, C(beta) and C(gamma) atoms of Glu(258), and C(gamma) and C(delta) atoms of Arg(255). The binding studies indicate that INH binds to LPO with a value of 0.9 x 10(-6) m for the dissociation constant. The nitro blue tetrazolium reduction assay shows that INH is activated by the reaction of LPO-H(2)O(2) with INH. This suggests that LPO can be used for INH activation. It also indicates that the conversion of INH into isonicotinoyl radical by LPO may be the cause of INH toxicity.

  1. NetMHCpan, a method for MHC class I binding prediction beyond humans

    DEFF Research Database (Denmark)

    Hoof, Ilka; Peters, B; Sidney, J;

    2009-01-01

    .0, a method that generates quantitative predictions of the affinity of any peptide-MHC class I interaction. NetMHCpan-2.0 has been trained on the hitherto largest set of quantitative MHC binding data available, covering HLA-A and HLA-B, as well as chimpanzee, rhesus macaque, gorilla, and mouse MHC class I...

  2. STarMir Tools for Prediction of microRNA binding sites

    Science.gov (United States)

    Kanoria, Shaveta; Rennie, William; Liu, Chaochun; Carmack, C. Steven; Lu, Jun; Ding, Ye

    2017-01-01

    MicroRNAs (miRNAs) are a class of endogenous short non-coding RNAs that regulate gene expression by targeting messenger RNAs (mRNAs), which results in translational repression and/or mRNA degradation. As regulatory molecules, miRNAs are involved in many mammalian biological processes and also in the manifestation of certain human diseases. As miRNAs play central role in the regulation of gene expression, understanding miRNA-binding patterns is essential to gain an insight of miRNA mediated gene regulation and also holds promise for therapeutic applications. Computational prediction of miRNA binding sites on target mRNAs facilitates experimental investigation of miRNA functions. This chapter provides protocols for using the STarMir web server for improved predictions of miRNA binding sites on a target mRNA. As an application module of the Sfold RNA package, the current version of STarMir is an implementation of logistic prediction models developed with high throughput miRNA binding data from crosslinking immuno-precipitation (CLIP) studies. The models incorporated comprehensive thermodynamic, structural and sequence features, and were found to make improved predictions of both seed and seedless sites, in comparison to the established algorithms [1]. Their broad applicability was indicated by their good performance in cross-species validation. STarMir is freely available at http://sfold.wadsworth.org/starmir.html PMID:27665594

  3. Description and prediction of peptide-MHC binding: the 'human MHC project'

    DEFF Research Database (Denmark)

    Buus, S

    1999-01-01

    MHC molecules are crucially involved in controlling the specific immune system. They are highly polymorphic receptors sampling peptides from the cellular environment and presenting these peptides for scrutiny by immune cells. Recent advances in combinatorial peptide chemistry have improved the de...... the description and prediction of peptide-MHC binding. It is envisioned that a complete mapping of human immune reactivities will be possible....

  4. Computational Studies of Difference in Binding Modes of Peptide and Non-Peptide Inhibitors to MDM2/MDMX Based on Molecular Dynamics Simulations

    Directory of Open Access Journals (Sweden)

    Yuxin Zhang

    2012-02-01

    Full Text Available Inhibition of p53-MDM2/MDMX interaction is considered to be a promising strategy for anticancer drug design to activate wild-type p53 in tumors. We carry out molecular dynamics (MD simulations to study the binding mechanisms of peptide and non-peptide inhibitors to MDM2/MDMX. The rank of binding free energies calculated by molecular mechanics generalized Born surface area (MM-GBSA method agrees with one of the experimental values. The results suggest that van der Waals energy drives two kinds of inhibitors to MDM2/MDMX. We also find that the peptide inhibitors can produce more interaction contacts with MDM2/MDMX than the non-peptide inhibitors. Binding mode predictions based on the inhibitor-residue interactions show that the π–π, CH–π and CH–CH interactions dominated by shape complimentarity, govern the binding of the inhibitors in the hydrophobic cleft of MDM2/MDMX. Our studies confirm the residue Tyr99 in MDMX can generate a steric clash with the inhibitors due to energy and structure. This finding may theoretically provide help to develop potent dual-specific or MDMX inhibitors.

  5. Electrostatics, structure prediction, and the energy landscapes for protein folding and binding.

    Science.gov (United States)

    Tsai, Min-Yeh; Zheng, Weihua; Balamurugan, D; Schafer, Nicholas P; Kim, Bobby L; Cheung, Margaret S; Wolynes, Peter G

    2016-01-01

    While being long in range and therefore weakly specific, electrostatic interactions are able to modulate the stability and folding landscapes of some proteins. The relevance of electrostatic forces for steering the docking of proteins to each other is widely acknowledged, however, the role of electrostatics in establishing specifically funneled landscapes and their relevance for protein structure prediction are still not clear. By introducing Debye-Hückel potentials that mimic long-range electrostatic forces into the Associative memory, Water mediated, Structure, and Energy Model (AWSEM), a transferable protein model capable of predicting tertiary structures, we assess the effects of electrostatics on the landscapes of thirteen monomeric proteins and four dimers. For the monomers, we find that adding electrostatic interactions does not improve structure prediction. Simulations of ribosomal protein S6 show, however, that folding stability depends monotonically on electrostatic strength. The trend in predicted melting temperatures of the S6 variants agrees with experimental observations. Electrostatic effects can play a range of roles in binding. The binding of the protein complex KIX-pKID is largely assisted by electrostatic interactions, which provide direct charge-charge stabilization of the native state and contribute to the funneling of the binding landscape. In contrast, for several other proteins, including the DNA-binding protein FIS, electrostatics causes frustration in the DNA-binding region, which favors its binding with DNA but not with its protein partner. This study highlights the importance of long-range electrostatics in functional responses to problems where proteins interact with their charged partners, such as DNA, RNA, as well as membranes.

  6. Dataset size and composition impact the reliability of performance benchmarks for peptide-MHC binding predictions

    DEFF Research Database (Denmark)

    Kim, Yohan; Sidney, John; Buus, Søren;

    2014-01-01

    Background: It is important to accurately determine the performance of peptide: MHC binding predictions, as this enables users to compare and choose between different prediction methods and provides estimates of the expected error rate. Two common approaches to determine prediction performance...... are cross-validation, in which all available data are iteratively split into training and testing data, and the use of blind sets generated separately from the data used to construct the predictive method. In the present study, we have compared cross-validated prediction performances generated on our last...... benchmark dataset from 2009 with prediction performances generated on data subsequently added to the Immune Epitope Database (IEDB) which served as a blind set. Results: We found that cross-validated performances systematically overestimated performance on the blind set. This was found not to be due...

  7. High resolution crystal structures of unliganded and liganded human liver ACBP reveal a new mode of binding for the acyl-CoA ligand

    DEFF Research Database (Denmark)

    Taskinen, Jukka P; van Aalten, Daan M; Knudsen, Jens;

    2007-01-01

    The acyl-CoA binding protein (ACBP) is essential for the fatty acid metabolism, membrane structure, membrane fusion, and ceramide synthesis. Here high resolution crystal structures of human cytosolic liver ACBP, unliganded and liganded with a physiological ligand, myristoyl-CoA are described....... The binding of the acyl-CoA molecule induces only few structural differences near the binding pocket. The crystal form of the liganded ACBP, which has two ACBP molecules in the asymmetric unit, shows that in human ACBP the same acyl-CoA binding pocket is present as previously described for the bovine...... and Plasmodium falciparum ACBP and the mode of binding of the 3'-phosphate-AMP moiety is conserved. Unexpectedly, in one of the acyl-CoA binding pockets the acyl moiety is bound in a reversed mode as compared with the bovine and P. falciparum structures. In this binding mode, the myristoyl-CoA molecule is fully...

  8. String Theory Based Predictions for Novel Collective Modes in Strongly Interacting Fermi Gases

    CERN Document Server

    Bantilan, H; Ishii, T; Lewis, W E; Romatschke, P

    2016-01-01

    Very different strongly interacting quantum systems such as Fermi gases, quark-gluon plasmas formed in high energy ion collisions and black holes studied theoretically in string theory are known to exhibit quantitatively similar damping of hydrodynamic modes. It is not known if such similarities extend beyond the hydrodynamic limit. Do non-hydrodynamic collective modes in Fermi gases with strong interactions also match those from string theory calculations? In order to answer this question, we use calculations based on string theory to make predictions for novel types of modes outside the hydrodynamic regime in trapped Fermi gases. These predictions are amenable to direct testing with current state-of-the-art cold atom experiments.

  9. MOAtox: A Comprehensive Mode of Action and Acute Aquatic Toxicity Database for Predictive Model Development

    Science.gov (United States)

    tThe mode of toxic action (MOA) has been recognized as a key determinant of chemical toxicity andas an alternative to chemical class-based predictive toxicity modeling. However, the development ofquantitative structure activity relationship (QSAR) and other models has been limite...

  10. A new instability index for unstable mode selection in squeal prediction by complex eigenvalue analysis

    Science.gov (United States)

    Brunetti, J.; Massi, F.; D`Ambrogio, W.; Berthier, Y.

    2016-09-01

    During these last decades the modal instability of systems, generated by frictional contact forces, has been the subject of a huge amount of works in friction induced vibration literature. Linear and nonlinear numerical analyses have been largely investigated to predict and reproduce squeal vibrations. While nonlinear transient analysis needs large computational efforts, results of Complex Eigenvalue Analysis (CEA) suffer from an over-prediction issue and it is not able to predict correctly the mode that will become effectively unstable in case of several unstable eigenvalues. Because the CEA has been adopted as an efficient tool for brake design, a more reliable index is here proposed, from the CEA outputs and energetic considerations, to identify the mode that will become effectively unstable. A modular lumped model is developed to reproduce friction induced vibrations. The use of the eigenvalue real part, as discriminant of the system instability, is here combined with information coming from the eigenvectors, projected on the equilibrium position, to account for the energy flows involved in the squeal phenomena. This approach allows to define a Modal Absorption Index (MAI). The MAI allows for comparing unstable modes of the same system and is applied in this paper to predict, by CEA outputs, the unstable mode that will effectively result in squeal vibrations.

  11. Improving the prediction of protein binding sites by combining heterogeneous data and Voronoi diagrams

    Directory of Open Access Journals (Sweden)

    Fernandez-Fuentes Narcis

    2011-08-01

    Full Text Available Abstract Background Protein binding site prediction by computational means can yield valuable information that complements and guides experimental approaches to determine the structure of protein complexes. Predictions become even more relevant and timely given the current resolution of protein interaction maps, where there is a very large and still expanding gap between the available information on: (i which proteins interact and (ii how proteins interact. Proteins interact through exposed residues that present differential physicochemical properties, and these can be exploited to identify protein interfaces. Results Here we present VORFFIP, a novel method for protein binding site prediction. The method makes use of broad set of heterogeneous data and defined of residue environment, by means of Voronoi Diagrams that are integrated by a two-steps Random Forest ensemble classifier. Four sets of residue features (structural, energy terms, sequence conservation, and crystallographic B-factors used in different combinations together with three definitions of residue environment (Voronoi Diagrams, sequence sliding window, and Euclidian distance have been analyzed in order to maximize the performance of the method. Conclusions The integration of different forms information such as structural features, energy term, evolutionary conservation and crystallographic B-factors, improves the performance of binding site prediction. Including the information of neighbouring residues also improves the prediction of protein interfaces. Among the different approaches that can be used to define the environment of exposed residues, Voronoi Diagrams provide the most accurate description. Finally, VORFFIP compares favourably to other methods reported in the recent literature.

  12. Proteins and Their Interacting Partners: An Introduction to Protein-Ligand Binding Site Prediction Methods.

    Science.gov (United States)

    Roche, Daniel Barry; Brackenridge, Danielle Allison; McGuffin, Liam James

    2015-12-15

    Elucidating the biological and biochemical roles of proteins, and subsequently determining their interacting partners, can be difficult and time consuming using in vitro and/or in vivo methods, and consequently the majority of newly sequenced proteins will have unknown structures and functions. However, in silico methods for predicting protein-ligand binding sites and protein biochemical functions offer an alternative practical solution. The characterisation of protein-ligand binding sites is essential for investigating new functional roles, which can impact the major biological research spheres of health, food, and energy security. In this review we discuss the role in silico methods play in 3D modelling of protein-ligand binding sites, along with their role in predicting biochemical functionality. In addition, we describe in detail some of the key alternative in silico prediction approaches that are available, as well as discussing the Critical Assessment of Techniques for Protein Structure Prediction (CASP) and the Continuous Automated Model EvaluatiOn (CAMEO) projects, and their impact on developments in the field. Furthermore, we discuss the importance of protein function prediction methods for tackling 21st century problems.

  13. Prediction of Carbohydrate-Binding Proteins from Sequences Using Support Vector Machines

    Directory of Open Access Journals (Sweden)

    Seizi Someya

    2010-01-01

    Full Text Available Carbohydrate-binding proteins are proteins that can interact with sugar chains but do not modify them. They are involved in many physiological functions, and we have developed a method for predicting them from their amino acid sequences. Our method is based on support vector machines (SVMs. We first clarified the definition of carbohydrate-binding proteins and then constructed positive and negative datasets with which the SVMs were trained. By applying the leave-one-out test to these datasets, our method delivered 0.92 of the area under the receiver operating characteristic (ROC curve. We also examined two amino acid grouping methods that enable effective learning of sequence patterns and evaluated the performance of these methods. When we applied our method in combination with the homology-based prediction method to the annotated human genome database, H-invDB, we found that the true positive rate of prediction was improved.

  14. Synthesis and structural characterization of a calcium coordination polymer based on a 3-bridging tetradentate binding mode of glycine

    Indian Academy of Sciences (India)

    Subramanian Natarajan; Bikshandarkoil R Srinivasan; J Kalyana Sundar; K Ravikumar; R V Krishnakumar; J Suresh

    2012-07-01

    A new coordination polymer namely [[Ca6(H-gly)12(H2O)18]Cl12·6H2O] (1) (H-gly = glycine) has been isolated from the calcium chloride-glycine-water system and structurally characterized. Each Ca(II) in 1 is eight-coordinated and is bonded to eight oxygen atoms three of which are from terminal water molecules and five oxygen atoms from four symmetry related zwitterionic glycine ligands. The H-gly ligands exhibit two different binding modes viz. a monodentate carboxylate ligation and a 3-tetradentate bridging carboxylate binding mode, which results in the formation of a one-dimensional coordination polymer. In the infinite chain the Ca(II) atoms are organized in a zigzag fashion. A comparative study reveals a rich and diverse structural chemistry of calcium halide-glycine compounds.

  15. Structure, mechanics, and binding mode heterogeneity of LEDGF/p75-DNA nucleoprotein complexes revealed by scanning force microscopy

    Science.gov (United States)

    Vanderlinden, Willem; Lipfert, Jan; Demeulemeester, Jonas; Debyser, Zeger; de Feyter, Steven

    2014-04-01

    LEDGF/p75 is a transcriptional coactivator implicated in the pathogenesis of AIDS and leukemia. In these contexts, LEDGF/p75 acts as a cofactor by tethering protein cargo to transcriptionally active regions in the human genome. Our study - based on scanning force microscopy (SFM) imaging - is the first to provide structural information on the interaction of LEDGF/p75 with DNA. Two novel approaches that allow obtaining insights into the DNA conformation inside nucleoprotein complexes revealed (1) that LEDGF/p75 can bind at least in three different binding modes, (2) how DNA topology and protein dimerization affect these binding modes, and (3) geometrical and mechanical aspects of the nucleoprotein complexes. These structural and mechanical details will help us to better understand the cellular mechanisms of LEDGF/p75 as a transcriptional coactivator and as a cofactor in disease.LEDGF/p75 is a transcriptional coactivator implicated in the pathogenesis of AIDS and leukemia. In these contexts, LEDGF/p75 acts as a cofactor by tethering protein cargo to transcriptionally active regions in the human genome. Our study - based on scanning force microscopy (SFM) imaging - is the first to provide structural information on the interaction of LEDGF/p75 with DNA. Two novel approaches that allow obtaining insights into the DNA conformation inside nucleoprotein complexes revealed (1) that LEDGF/p75 can bind at least in three different binding modes, (2) how DNA topology and protein dimerization affect these binding modes, and (3) geometrical and mechanical aspects of the nucleoprotein complexes. These structural and mechanical details will help us to better understand the cellular mechanisms of LEDGF/p75 as a transcriptional coactivator and as a cofactor in disease. Electronic supplementary information (ESI) available: SFM topographs of phage lambda DNA in situ, in the absence and presence of LEDGF/p75; model-independent tests for DNA chain equilibration in 2D; SFM topographs of

  16. DEPTH: a web server to compute depth and predict small-molecule binding cavities in proteins.

    Science.gov (United States)

    Tan, Kuan Pern; Varadarajan, Raghavan; Madhusudhan, M S

    2011-07-01

    Depth measures the extent of atom/residue burial within a protein. It correlates with properties such as protein stability, hydrogen exchange rate, protein-protein interaction hot spots, post-translational modification sites and sequence variability. Our server, DEPTH, accurately computes depth and solvent-accessible surface area (SASA) values. We show that depth can be used to predict small molecule ligand binding cavities in proteins. Often, some of the residues lining a ligand binding cavity are both deep and solvent exposed. Using the depth-SASA pair values for a residue, its likelihood to form part of a small molecule binding cavity is estimated. The parameters of the method were calibrated over a training set of 900 high-resolution X-ray crystal structures of single-domain proteins bound to small molecules (molecular weight structures. Users have the option of tuning several parameters to detect cavities of different sizes, for example, geometrically flat binding sites. The input to the server is a protein 3D structure in PDB format. The users have the option of tuning the values of four parameters associated with the computation of residue depth and the prediction of binding cavities. The computed depths, SASA and binding cavity predictions are displayed in 2D plots and mapped onto 3D representations of the protein structure using Jmol. Links are provided to download the outputs. Our server is useful for all structural analysis based on residue depth and SASA, such as guiding site-directed mutagenesis experiments and small molecule docking exercises, in the context of protein functional annotation and drug discovery.

  17. Theoretical and experimental studies on binding mode of 3,5-pyrazoledicarboxylic acid in its new La(III) complex

    Science.gov (United States)

    Peica, Niculina; Kostova, Irena; Kiefer, Wolfgang

    2006-06-01

    A new La(III) complex with 3,5-pyrazoledicarboxylic acid (HPy) was synthesized and characterized with elemental analysis, IR, and Raman spectroscopies. Significant differences in the IR and Raman spectra of the complex were observed as compared to the spectra of the ligand. The metal-ligand binding mode was studied on the basis of theoretical and experimental data. B3PW91 and B3LYP methods with 6-311++G ∗∗ and LANL2DZ basis sets were successfully applied to study the molecular and vibrational structures as well as the conformational behavior of the neutral ligand and its new La(III) complex. The theoretical calculations of HPy suggested bidentate binding mode through the carboxylic oxygens. Detailed vibrational analysis of HPy and La(III)-Py systems based on both the calculated and experimental spectra confirmed the suggested metal-ligand binding mode. The density functional theory (DFT) calculated geometries, harmonic vibrational wavenumbers including IR and Raman scattering activities for the ligand and its La(III) complex were in good agreement with the experimental data, a complete vibrational assignment being proposed.

  18. Predicting the relative binding affinity of mineralocorticoid receptor antagonists by density functional methods

    Science.gov (United States)

    Roos, Katarina; Hogner, Anders; Ogg, Derek; Packer, Martin J.; Hansson, Eva; Granberg, Kenneth L.; Evertsson, Emma; Nordqvist, Anneli

    2015-12-01

    In drug discovery, prediction of binding affinity ahead of synthesis to aid compound prioritization is still hampered by the low throughput of the more accurate methods and the lack of general pertinence of one method that fits all systems. Here we show the applicability of a method based on density functional theory using core fragments and a protein model with only the first shell residues surrounding the core, to predict relative binding affinity of a matched series of mineralocorticoid receptor (MR) antagonists. Antagonists of MR are used for treatment of chronic heart failure and hypertension. Marketed MR antagonists, spironolactone and eplerenone, are also believed to be highly efficacious in treatment of chronic kidney disease in diabetes patients, but is contra-indicated due to the increased risk for hyperkalemia. These findings and a significant unmet medical need among patients with chronic kidney disease continues to stimulate efforts in the discovery of new MR antagonist with maintained efficacy but low or no risk for hyperkalemia. Applied on a matched series of MR antagonists the quantum mechanical based method gave an R2 = 0.76 for the experimental lipophilic ligand efficiency versus relative predicted binding affinity calculated with the M06-2X functional in gas phase and an R2 = 0.64 for experimental binding affinity versus relative predicted binding affinity calculated with the M06-2X functional including an implicit solvation model. The quantum mechanical approach using core fragments was compared to free energy perturbation calculations using the full sized compound structures.

  19. Predicting Polymerase Ⅱ Core Promoters by Cooperating Transcription Factor Binding Sites in Eukaryotic Genes

    Institute of Scientific and Technical Information of China (English)

    Xiao-Tu MA; Min-Ping QIAN; Hai-Xu TANG

    2004-01-01

    Several discriminate functions for predicting core promoters that based on the potential cooperation between transcription factor binding sites (TFBSs) are discussed. It is demonstrated that the promoter predicting accuracy is improved when the cooperation among TFBSs is taken into consideration.The core promoter region of a newly discovered gene CKLFSF1 is predicted to locate more than 1.5 kb far away from the 5′ end of the transcript and in the last intron of its upstream gene, which is experimentally confirmed later. The core promoters of 3402 human RefSeq sequences, obtained by extending the mRNAs in human genome sequences, are predicted by our algorithm, and there are about 60% of the predicted core promoters locating within the ± 500 bp region relative to the annotated transcription start site.

  20. The IntFOLD server: an integrated web resource for protein fold recognition, 3D model quality assessment, intrinsic disorder prediction, domain prediction and ligand binding site prediction.

    Science.gov (United States)

    Roche, Daniel B; Buenavista, Maria T; Tetchner, Stuart J; McGuffin, Liam J

    2011-07-01

    The IntFOLD server is a novel independent server that integrates several cutting edge methods for the prediction of structure and function from sequence. Our guiding principles behind the server development were as follows: (i) to provide a simple unified resource that makes our prediction software accessible to all and (ii) to produce integrated output for predictions that can be easily interpreted. The output for predictions is presented as a simple table that summarizes all results graphically via plots and annotated 3D models. The raw machine readable data files for each set of predictions are also provided for developers, which comply with the Critical Assessment of Methods for Protein Structure Prediction (CASP) data standards. The server comprises an integrated suite of five novel methods: nFOLD4, for tertiary structure prediction; ModFOLD 3.0, for model quality assessment; DISOclust 2.0, for disorder prediction; DomFOLD 2.0 for domain prediction; and FunFOLD 1.0, for ligand binding site prediction. Predictions from the IntFOLD server were found to be competitive in several categories in the recent CASP9 experiment. The IntFOLD server is available at the following web site: http://www.reading.ac.uk/bioinf/IntFOLD/.

  1. Structure prediction of LDLR-HNP1 complex based on docking enhanced by LDLR binding 3D motif.

    Science.gov (United States)

    Esmaielbeiki, Reyhaneh; Naughton, Declan P; Nebel, Jean-Christophe

    2012-04-01

    Human antimicrobial peptides (AMPs), including defensins, have come under intense scrutiny owing to their key multiple roles as antimicrobial agents. Not only do they display direct action on microbes, but also recently they have been shown to interact with the immune system to increase antimicrobial activity. Unfortunately, since mechanisms involved in the binding of AMPs to mammalian cells are largely unknown, their potential as novel anti-infective agents cannot be exploited yet. Following the reported interaction of Human Neutrophil Peptide 1 dimer (HNP1) with a low density lipoprotein receptor (LDLR), a computational study was conducted to discover their putative mode of interaction. State-of-the-art docking software produced a set of LDLR-HNP1 complex 3D models. Creation of a 3D motif capturing atomic interactions of the LDLR binding interface allowed selection of the most plausible configurations. Eventually, only two models were in agreement with the literature. Binding energy estimations revealed that only one of them is particularly stable, but also interaction with LDLR weakens significantly bonds within the HNP1 dimer. This may be significant since it suggests a mechanism for internalisation of HNP1 in mammalian cells. In addition to a novel approach for complex structure prediction, this study proposes a 3D model of the LDLR-HNP1 complex which highlights the key residues which are involved in the interactions. The putative identification of the receptor binding mechanism should inform the future design of synthetic HNPs to afford maximum internalisation, which could lead to novel anti-infective drugs.

  2. Conserved inhibitory mechanism and competent ATP binding mode for adenylyltransferases with Fic fold.

    Directory of Open Access Journals (Sweden)

    Arnaud Goepfert

    Full Text Available The ubiquitous FIC domain is evolutionarily conserved from bacteria to human and has been shown to catalyze AMP transfer onto protein side-chain hydroxyl groups. Recently, it was predicted that most catalytically competent Fic proteins are inhibited by the presence of an inhibitory helix αinh that is provided by a cognate anti-toxin (class I, or is part of the N- or C-terminal part of the Fic protein itself (classes II and III. In vitro, inhibition is relieved by mutation of a conserved glutamate of αinh to glycine. For the class III bacterial Fic protein NmFic from Neisseria meningitidis, the inhibitory mechanism has been elucidated. Here, we extend above study by including bacterial class I and II Fic proteins VbhT from Bartonella schoenbuchensis and SoFic from Shewanella oneidensis, respectively, and the respective E->G mutants. Comparative enzymatic and crystallographic analyses show that, in all three classes, the ATP substrate binds to the wild-type FIC domains, but with the α-phosphate in disparate and non-competent orientations. In the E->G mutants, however, the tri-phosphate moiety is found reorganized to the same tightly bound structure through a unique set of hydrogen bonds with Fic signature motif residues. The γ-phosphate adopts the location that is taken by the inhibitory glutamate in wild-type resulting in an α-phosphate orientation that can be attacked in-line by a target side-chain hydroxyl group. The latter is properly registered to the Fic active center by main-chain β-interactions with the β-hairpin flap. These data indicate that the active site motif and the exposed edge of the flap are both required to form an adenylylation-competent Fic protein.

  3. Prediction of Instability Separation Modes and Its Application in Practical Dynamic Security Region

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    The transient critical boundary of dynamic security region (DSR) can be approximated by a few hyper planes correlated with instability separation modes. A method to fast predict instability separation modes is proposed for DSR calculation in power injection space. The method identifies coherent generation groups by the developed K-medoids algorithm, taking a similarity matrix derived from the reachability Grammian as the index. As an experimental result, reachability Grammian matrices under local injections are approximately invariant. It indicates that the generator coherency identifications are nearly consistent for different injections. Then instability separation modes can be predicted at the normal operating point, while average initial acceleration is considered as the measure of the critical generator group to amend the error. Moreover, based on these predicted instability separation modes, a critical point search strategy for DSR calculation is illustrated in the reduced injection space of the critical generators. The proposed method was evaluated using New England Test System, and the computation accuracy and speed in determining the practical DSR were improve.

  4. Seasonality and Predictability of the Indian Ocean Dipole Mode: ENSO Forcing and Internal Variability

    Science.gov (United States)

    Yang, Y.

    2015-12-01

    This study evaluates the relative contributions to the Indian Ocean Dipole (IOD) mode of interannual variability from the El Niño-Southern Oscillation (ENSO) forcing and ocean-atmosphere feedbacks internal to the Indian Ocean. The ENSO forcing and internal variability is extracted by conducting a 10-member coupled simulation for 1950-2012 where sea surface temperature (SST) is restored to the observed anomalies over the tropical Pacific but interactive with the atmosphere over the rest of the world ocean. In these experiments, the ensemble mean is due to ENSO forcing and the inter-member difference arises from internal variability of the climate system independent of ENSO. These elements contribute one third and two thirds of the total IOD variance, respectively. Both types of IOD variability develop into an east-west dipole pattern due to Bjerknes feedback and peak in September-November. The ENSO forced and internal IOD modes differ in several important ways. The forced IOD mode develops in August with a broad meridional pattern, and eventually evolves into the Indian Ocean Basin mode; while the internal IOD mode grows earlier in June, is more confined to the equator and decays rapidly after October. The internal IOD mode is more skewed than the ENSO forced response. The destructive interference of ENSO forcing and internal variability can explain early-terminating IOD events, referred to IOD-like perturbations that fail to grow during boreal summer. Our results have implications for predictability. Internal variability, as represented by pre-season sea surface height anomalies off Sumatra, contributes to predictability considerably. Including this indicator of internal variability, together with ENSO, improves the predictability of IOD.

  5. Computational prediction of cAMP receptor protein (CRP binding sites in cyanobacterial genomes

    Directory of Open Access Journals (Sweden)

    Su Zhengchang

    2009-01-01

    Full Text Available Abstract Background Cyclic AMP receptor protein (CRP, also known as catabolite gene activator protein (CAP, is an important transcriptional regulator widely distributed in many bacteria. The biological processes under the regulation of CRP are highly diverse among different groups of bacterial species. Elucidation of CRP regulons in cyanobacteria will further our understanding of the physiology and ecology of this important group of microorganisms. Previously, CRP has been experimentally studied in only two cyanobacterial strains: Synechocystis sp. PCC 6803 and Anabaena sp. PCC 7120; therefore, a systematic genome-scale study of the potential CRP target genes and binding sites in cyanobacterial genomes is urgently needed. Results We have predicted and analyzed the CRP binding sites and regulons in 12 sequenced cyanobacterial genomes using a highly effective cis-regulatory binding site scanning algorithm. Our results show that cyanobacterial CRP binding sites are very similar to those in E. coli; however, the regulons are very different from that of E. coli. Furthermore, CRP regulons in different cyanobacterial species/ecotypes are also highly diversified, ranging from photosynthesis, carbon fixation and nitrogen assimilation, to chemotaxis and signal transduction. In addition, our prediction indicates that crp genes in modern cyanobacteria are likely inherited from a common ancestral gene in their last common ancestor, and have adapted various cellular functions in different environments, while some cyanobacteria lost their crp genes as well as CRP binding sites during the course of evolution. Conclusion The CRP regulons in cyanobacteria are highly diversified, probably as a result of divergent evolution to adapt to various ecological niches. Cyanobacterial CRPs may function as lineage-specific regulators participating in various cellular processes, and are important in some lineages. However, they are dispensable in some other lineages. The

  6. Nonlinear scoring functions for similarity-based ligand docking and binding affinity prediction.

    Science.gov (United States)

    Brylinski, Michal

    2013-11-25

    A common strategy for virtual screening considers a systematic docking of a large library of organic compounds into the target sites in protein receptors with promising leads selected based on favorable intermolecular interactions. Despite a continuous progress in the modeling of protein-ligand interactions for pharmaceutical design, important challenges still remain, thus the development of novel techniques is required. In this communication, we describe eSimDock, a new approach to ligand docking and binding affinity prediction. eSimDock employs nonlinear machine learning-based scoring functions to improve the accuracy of ligand ranking and similarity-based binding pose prediction, and to increase the tolerance to structural imperfections in the target structures. In large-scale benchmarking using the Astex/CCDC data set, we show that 53.9% (67.9%) of the predicted ligand poses have RMSD of <2 Å (<3 Å). Moreover, using binding sites predicted by recently developed eFindSite, eSimDock models ligand binding poses with an RMSD of 4 Å for 50.0-39.7% of the complexes at the protein homology level limited to 80-40%. Simulations against non-native receptor structures, whose mean backbone rearrangements vary from 0.5 to 5.0 Å Cα-RMSD, show that the ratio of docking accuracy and the estimated upper bound is at a constant level of ∼0.65. Pearson correlation coefficient between experimental and predicted by eSimDock Ki values for a large data set of the crystal structures of protein-ligand complexes from BindingDB is 0.58, which decreases only to 0.46 when target structures distorted to 3.0 Å Cα-RMSD are used. Finally, two case studies demonstrate that eSimDock can be customized to specific applications as well. These encouraging results show that the performance of eSimDock is largely unaffected by the deformations of ligand binding regions, thus it represents a practical strategy for across-proteome virtual screening using protein models. eSimDock is freely

  7. Cloud computing approaches for prediction of ligand binding poses and pathways.

    Science.gov (United States)

    Lawrenz, Morgan; Shukla, Diwakar; Pande, Vijay S

    2015-01-22

    We describe an innovative protocol for ab initio prediction of ligand crystallographic binding poses and highly effective analysis of large datasets generated for protein-ligand dynamics. We include a procedure for setup and performance of distributed molecular dynamics simulations on cloud computing architectures, a model for efficient analysis of simulation data, and a metric for evaluation of model convergence. We give accurate binding pose predictions for five ligands ranging in affinity from 7 nM to > 200 μM for the immunophilin protein FKBP12, for expedited results in cases where experimental structures are difficult to produce. Our approach goes beyond single, low energy ligand poses to give quantitative kinetic information that can inform protein engineering and ligand design.

  8. Characterization of the modes of binding between human sweet taste receptor and low-molecular-weight sweet compounds.

    Directory of Open Access Journals (Sweden)

    Katsuyoshi Masuda

    Full Text Available One of the most distinctive features of human sweet taste perception is its broad tuning to chemically diverse compounds ranging from low-molecular-weight sweeteners to sweet-tasting proteins. Many reports suggest that the human sweet taste receptor (hT1R2-hT1R3, a heteromeric complex composed of T1R2 and T1R3 subunits belonging to the class C G protein-coupled receptor family, has multiple binding sites for these sweeteners. However, it remains unclear how the same receptor recognizes such diverse structures. Here we aim to characterize the modes of binding between hT1R2-hT1R3 and low-molecular-weight sweet compounds by functional analysis of a series of site-directed mutants and by molecular modeling-based docking simulation at the binding pocket formed on the large extracellular amino-terminal domain (ATD of hT1R2. We successfully determined the amino acid residues responsible for binding to sweeteners in the cleft of hT1R2 ATD. Our results suggest that individual ligands have sets of specific residues for binding in correspondence with the chemical structures and other residues responsible for interacting with multiple ligands.

  9. Distinct modes of SMAD2 chromatin binding and remodeling shape the transcriptional response to NODAL/Activin signaling

    Science.gov (United States)

    Coda, Davide M; Gaarenstroom, Tessa; East, Philip; Patel, Harshil; Miller, Daniel S J; Lobley, Anna; Matthews, Nik; Stewart, Aengus; Hill, Caroline S

    2017-01-01

    NODAL/Activin signaling orchestrates key processes during embryonic development via SMAD2. How SMAD2 activates programs of gene expression that are modulated over time however, is not known. Here we delineate the sequence of events that occur from SMAD2 binding to transcriptional activation, and the mechanisms underlying them. NODAL/Activin signaling induces dramatic chromatin landscape changes, and a dynamic transcriptional network regulated by SMAD2, acting via multiple mechanisms. Crucially we have discovered two modes of SMAD2 binding. SMAD2 can bind pre-acetylated nucleosome-depleted sites. However, it also binds to unacetylated, closed chromatin, independently of pioneer factors, where it induces nucleosome displacement and histone acetylation. For a subset of genes, this requires SMARCA4. We find that long term modulation of the transcriptional responses requires continued NODAL/Activin signaling. Thus SMAD2 binding does not linearly equate with transcriptional kinetics, and our data suggest that SMAD2 recruits multiple co-factors during sustained signaling to shape the downstream transcriptional program. DOI: http://dx.doi.org/10.7554/eLife.22474.001 PMID:28191871

  10. Molecular docking study investigating the possible mode of binding of C.I. Acid Red 73 with DNA.

    Science.gov (United States)

    Guo, Yumei; Yue, Qinyan; Gao, Baoyu

    2011-07-01

    C.I. Acid Red 73 is a reactive azo dye with a variable potential carcinogenicity. The mechanism mediating interactions that occur between the dye and DNA have not been completely understood thus far. In this study, molecular docking techniques were applied to describe the most probable mode of DNA binding as well as the sequence selectivity of the C.I. Acid Red 73 dye. These docking experiments revealed that the dye is capable of interacting with the minor groove of the DNA on the basis of its curved shape, which fits well with the topology of double-stranded DNA. In addition, the dye can bind selectively to the minor groove of the DNA by applying CGT sequence selectivity. Further, the minor groove can be recognized although DNA targets present intercalation gaps. However, intercalative binding can also occur when the DNA target possesses an appropriate intercalation gap. Compared with the other eight DNA sequences that were studied, the DNA dodecamer d(CGCGATATCGCG)(2) (PDB ID: 1DNE) presents a very favorable target for the binding of C.I. Acid Red 73 to the minor groove, with the lowest binding free energy -9.19 kcal/mol. Results reported from this study are expected to provide useful information for research involving further simulations of molecular dynamics and toxicology investigations of the dye.

  11. A Study of the Predictive Relationships between Faculty Engagement, Learner Satisfaction and Outcomes in Multiple Learning Delivery Modes

    Science.gov (United States)

    Yen, Cherng-Jyh; Abdous, M'hammed

    2012-01-01

    This study assessed the predictive relationships between faculty engagement, learner satisfaction, and outcomes across multiple learning delivery modes (LDMs). Participants were enrolled in courses with the options of three learning delivery modes: face-to-face, satellite broadcasting, and live video-streaming. The predictive relationship between…

  12. Glycosaminoglycans are interactants of Langerin: comparison with gp120 highlights an unexpected calcium-independent binding mode.

    Directory of Open Access Journals (Sweden)

    Eric Chabrol

    Full Text Available Langerin is a C-type lectin specifically expressed in Langerhans cells. As recently shown for HIV, Langerin is thought to capture pathogens and mediate their internalisation into Birbeck Granules for elimination. However, the precise functions of Langerin remain elusive, mostly because of the lack of information on its binding properties and physiological ligands. Based on recent reports that Langerin binds to sulfated sugars, we conducted here a comparative analysis of Langerin interaction with mannose-rich HIV glycoprotein gp120 and glycosaminoglycan (GAGs, a family of sulfated polysaccharides expressed at the surface of most mammalian cells. Our results first revealed that Langerin bound to these different glycans through very distinct mechanisms and led to the identification of a novel, GAG-specific binding mode within Langerin. In contrast to the canonical lectin domain, this new binding site showed no Ca(2+-dependency, and could only be detected in entire, trimeric extracellular domains of Langerin. Interestingly binding to GAGs, did not simply rely on a net charge effect, but rather on more discrete saccharide features, such as 6-O-sulfation, or iduronic acid content. Using molecular modelling simulations, we proposed a model of Langerin/heparin complex, which located the GAG binding site at the interface of two of the three Carbohydrate-recognition domains of the protein, at the edge of the a-helix coiled-coil. To our knowledge, the binding properties that we have highlighted here for Langerin, have never been reported for C-type lectins before. These findings provide new insights towards the understanding of Langerin biological functions.

  13. Implementation of model predictive control for resistive wall mode stabilization on EXTRAP T2R

    Science.gov (United States)

    Setiadi, A. C.; Brunsell, P. R.; Frassinetti, L.

    2015-10-01

    A model predictive control (MPC) method for stabilization of the resistive wall mode (RWM) in the EXTRAP T2R reversed-field pinch is presented. The system identification technique is used to obtain a linearized empirical model of EXTRAP T2R. MPC employs the model for prediction and computes optimal control inputs that satisfy performance criterion. The use of a linearized form of the model allows for compact formulation of MPC, implemented on a millisecond timescale, that can be used for real-time control. The design allows the user to arbitrarily suppress any selected Fourier mode. The experimental results from EXTRAP T2R show that the designed and implemented MPC successfully stabilizes the RWM.

  14. Fault Tolerant Flight Control Using Sliding Modes and Subspace Identification-Based Predictive Control

    KAUST Repository

    Siddiqui, Bilal A.

    2016-07-26

    In this work, a cascade structure of a time-scale separated integral sliding mode and model predictive control is proposed as a viable alternative for fault-tolerant control. A multi-variable sliding mode control law is designed as the inner loop of the flight control system. Subspace identification is carried out on the aircraft in closed loop. The identified plant is then used for model predictive controllers in the outer loop. The overall control law demonstrates improved robustness to measurement noise, modeling uncertainties, multiple faults and severe wind turbulence and gusts. In addition, the flight control system employs filters and dead-zone nonlinear elements to reduce chattering and improve handling quality. Simulation results demonstrate the efficiency of the proposed controller using conventional fighter aircraft without control redundancy.

  15. Predictive Sliding Mode Control for Attitude Tracking of Hypersonic Vehicles Using Fuzzy Disturbance Observer

    Directory of Open Access Journals (Sweden)

    Xianlei Cheng

    2015-01-01

    Full Text Available We propose a predictive sliding mode control (PSMC scheme for attitude control of hypersonic vehicle (HV with system uncertainties and external disturbances based on an improved fuzzy disturbance observer (IFDO. First, for a class of uncertain affine nonlinear systems with system uncertainties and external disturbances, we propose a predictive sliding mode control based on fuzzy disturbance observer (FDO-PSMC, which is used to estimate the composite disturbances containing system uncertainties and external disturbances. Afterward, to enhance the composite disturbances rejection performance, an improved FDO-PSMC (IFDO-PSMC is proposed by incorporating a hyperbolic tangent function with FDO to compensate for the approximate error of FDO. Finally, considering the actuator dynamics, the proposed IFDO-PSMC is applied to attitude control system design for HV to track the guidance commands with high precision and strong robustness. Simulation results demonstrate the effectiveness and robustness of the proposed attitude control scheme.

  16. Predicting macrobending loss for large-mode area photonic crystal fibres

    DEFF Research Database (Denmark)

    Nielsen, Martin D.; Mortensen, Niels Asger; Albertsen, Maja

    2004-01-01

    We report on an easy-to-evaluate expression for the prediction of the bend-loss for a large mode area photonic crystal fiber (PCF) with a triangular air-hole lattice. The expression is based on a recently proposed formulation of the V-parameter for a PCF and contains no free parameters. The valid....... The validity of the expression is verified experimentally for varying fiber parameters as well as bend radius. The typical deviation between the position of the measured and the predicted bend loss edge is within measurement uncertainty....

  17. Cooperative binding mode of the inhibitors of R6K replication, pi dimers.

    Science.gov (United States)

    Bowers, Lisa M; Filutowicz, Marcin

    2008-03-28

    The replication initiator protein, pi, plays an essential role in the initiation of plasmid R6K replication. Both monomers and dimers of pi bind to iterons in the gamma origin of plasmid R6K, yet monomers facilitate open complex formation, while dimers, the predominant form in the cell, do not. Consequently, pi monomers activate replication, while pi dimers inhibit replication. Recently, it was shown that the monomeric form of pi binds multiple tandem iterons in a strongly cooperative fashion, which might explain how monomers outcompete dimers for replication initiation when plasmid copy number and pi supply are low. Here, we examine cooperative binding of pi dimers and explore the role that these interactions may have in the inactivation of gamma origin. To examine pi dimer/iteron interactions in the absence of competing pi monomer/iteron interactions using wild-type pi, constructs were made with key base changes to each iteron that eliminate pi monomer binding yet have no impact on pi dimer binding. Our results indicate that, in the absence of pi monomers, pi dimers bind with greater cooperativity to alternate iterons than to adjacent iterons, thus preferentially leaving intervening iterons unbound and the origin unsaturated. We discuss new insights into plasmid replication control by pi dimers.

  18. Improved Prediction of Preterm Delivery Using Empirical Mode Decomposition Analysis of Uterine Electromyography Signals.

    Directory of Open Access Journals (Sweden)

    Peng Ren

    Full Text Available Preterm delivery increases the risk of infant mortality and morbidity, and therefore developing reliable methods for predicting its likelihood are of great importance. Previous work using uterine electromyography (EMG recordings has shown that they may provide a promising and objective way for predicting risk of preterm delivery. However, to date attempts at utilizing computational approaches to achieve sufficient predictive confidence, in terms of area under the curve (AUC values, have not achieved the high discrimination accuracy that a clinical application requires. In our study, we propose a new analytical approach for assessing the risk of preterm delivery using EMG recordings which firstly employs Empirical Mode Decomposition (EMD to obtain their Intrinsic Mode Functions (IMF. Next, the entropy values of both instantaneous amplitude and instantaneous frequency of the first ten IMF components are computed in order to derive ratios of these two distinct components as features. Discrimination accuracy of this approach compared to those proposed previously was then calculated using six differently representative classifiers. Finally, three different electrode positions were analyzed for their prediction accuracy of preterm delivery in order to establish which uterine EMG recording location was optimal signal data. Overall, our results show a clear improvement in prediction accuracy of preterm delivery risk compared with previous approaches, achieving an impressive maximum AUC value of 0.986 when using signals from an electrode positioned below the navel. In sum, this provides a promising new method for analyzing uterine EMG signals to permit accurate clinical assessment of preterm delivery risk.

  19. PREDICTION OF MODE Ⅰ CRACK PROPAGATION DIRECTION IN CARBON-FIBER REINFORCED COMPOSITE PLATE

    Institute of Scientific and Technical Information of China (English)

    张少琴; 杨维阳

    2004-01-01

    A newly developed Z fracture criterion for the composite materials was introduced,the new concepts of in-plane average strain,in-plane dilatational strain energy density factor and reciprocal characteristic function were presented.Many experimental results show that the Z fracture criterion can be well used to predict the crack propagating direction for mode Ⅰ crack in carbon-fiber reinforced composite laminates.

  20. Prediction of MHC class II binding affinity using SMM-align, a novel stabilization matrix alignment method

    DEFF Research Database (Denmark)

    Nielsen, Morten; Lundegaard, Claus; Lund, Ole

    2007-01-01

    the correct alignment of a peptide in the binding groove a crucial part of identifying the core of an MHC class II binding motif. Here, we present a novel stabilization matrix alignment method, SMM-align, that allows for direct prediction of peptide:MHC binding affinities. The predictive performance...... of the method is validated on a large MHC class II benchmark data set covering 14 HLA-DR (human MHC) and three mouse H2-IA alleles. RESULTS: The predictive performance of the SMM-align method was demonstrated to be superior to that of the Gibbs sampler, TEPITOPE, SVRMHC, and MHCpred methods. Cross validation...... by favoring binding registers with a minimum PFR length of two amino acids. Visualizing the binding motif as obtained by the SMM-align and TEPITOPE methods highlights a series of fundamental discrepancies between the two predicted motifs. For the DRB1*1302 allele for instance, the TEPITOPE method favors basic...

  1. The Mode of Inhibitor Binding to Peptidyl-tRNA Hydrolase: Binding Studies and Structure Determination of Unbound and Bound Peptidyl-tRNA Hydrolase from Acinetobacter baumannii

    Science.gov (United States)

    Kaushik, Sanket; Singh, Nagendra; Yamini, Shavait; Singh, Avinash; Sinha, Mau; Arora, Ashish; Kaur, Punit; Sharma, Sujata; Singh, Tej P.

    2013-01-01

    The incidences of infections caused by an aerobic Gram-negative bacterium, Acinetobacter baumannii are very common in hospital environments. It usually causes soft tissue infections including urinary tract infections and pneumonia. It is difficult to treat due to acquired resistance to available antibiotics is well known. In order to design specific inhibitors against one of the important enzymes, peptidyl-tRNA hydrolase from Acinetobacter baumannii, we have determined its three-dimensional structure. Peptidyl-tRNA hydrolase (AbPth) is involved in recycling of peptidyl-tRNAs which are produced in the cell as a result of premature termination of translation process. We have also determined the structures of two complexes of AbPth with cytidine and uridine. AbPth was cloned, expressed and crystallized in unbound and in two bound states with cytidine and uridine. The binding studies carried out using fluorescence spectroscopic and surface plasmon resonance techniques revealed that both cytidine and uridine bound to AbPth at nanomolar concentrations. The structure determinations of the complexes revealed that both ligands were located in the active site cleft of AbPth. The introduction of ligands to AbPth caused a significant widening of the entrance gate to the active site region and in the process of binding, it expelled several water molecules from the active site. As a result of interactions with protein atoms, the ligands caused conformational changes in several residues to attain the induced tight fittings. Such a binding capability of this protein makes it a versatile molecule for hydrolysis of peptidyl-tRNAs having variable peptide sequences. These are the first studies that revealed the mode of inhibitor binding in Peptidyl-tRNA hydrolases which will facilitate the structure based ligand design. PMID:23844024

  2. The mode of inhibitor binding to peptidyl-tRNA hydrolase: binding studies and structure determination of unbound and bound peptidyl-tRNA hydrolase from Acinetobacter baumannii.

    Directory of Open Access Journals (Sweden)

    Sanket Kaushik

    Full Text Available The incidences of infections caused by an aerobic Gram-negative bacterium, Acinetobacter baumannii are very common in hospital environments. It usually causes soft tissue infections including urinary tract infections and pneumonia. It is difficult to treat due to acquired resistance to available antibiotics is well known. In order to design specific inhibitors against one of the important enzymes, peptidyl-tRNA hydrolase from Acinetobacter baumannii, we have determined its three-dimensional structure. Peptidyl-tRNA hydrolase (AbPth is involved in recycling of peptidyl-tRNAs which are produced in the cell as a result of premature termination of translation process. We have also determined the structures of two complexes of AbPth with cytidine and uridine. AbPth was cloned, expressed and crystallized in unbound and in two bound states with cytidine and uridine. The binding studies carried out using fluorescence spectroscopic and surface plasmon resonance techniques revealed that both cytidine and uridine bound to AbPth at nanomolar concentrations. The structure determinations of the complexes revealed that both ligands were located in the active site cleft of AbPth. The introduction of ligands to AbPth caused a significant widening of the entrance gate to the active site region and in the process of binding, it expelled several water molecules from the active site. As a result of interactions with protein atoms, the ligands caused conformational changes in several residues to attain the induced tight fittings. Such a binding capability of this protein makes it a versatile molecule for hydrolysis of peptidyl-tRNAs having variable peptide sequences. These are the first studies that revealed the mode of inhibitor binding in Peptidyl-tRNA hydrolases which will facilitate the structure based ligand design.

  3. Resolving the problem of trapped water in binding cavities: prediction of host-guest binding free energies in the SAMPL5 challenge by funnel metadynamics

    Science.gov (United States)

    Bhakat, Soumendranath; Söderhjelm, Pär

    2017-01-01

    The funnel metadynamics method enables rigorous calculation of the potential of mean force along an arbitrary binding path and thereby evaluation of the absolute binding free energy. A problem of such physical paths is that the mechanism characterizing the binding process is not always obvious. In particular, it might involve reorganization of the solvent in the binding site, which is not easily captured with a few geometrically defined collective variables that can be used for biasing. In this paper, we propose and test a simple method to resolve this trapped-water problem by dividing the process into an artificial host-desolvation step and an actual binding step. We show that, under certain circumstances, the contribution from the desolvation step can be calculated without introducing further statistical errors. We apply the method to the problem of predicting host-guest binding free energies in the SAMPL5 blind challenge, using two octa-acid hosts and six guest molecules. For one of the hosts, well-converged results are obtained and the prediction of relative binding free energies is the best among all the SAMPL5 submissions. For the other host, which has a narrower binding pocket, the statistical uncertainties are slightly higher; longer simulations would therefore be needed to obtain conclusive results.

  4. Combining features in a graphical model to predict protein binding sites.

    Science.gov (United States)

    Wierschin, Torsten; Wang, Keyu; Welter, Marlon; Waack, Stephan; Stanke, Mario

    2015-05-01

    Large efforts have been made in classifying residues as binding sites in proteins using machine learning methods. The prediction task can be translated into the computational challenge of assigning each residue the label binding site or non-binding site. Observational data comes from various possibly highly correlated sources. It includes the structure of the protein but not the structure of the complex. The model class of conditional random fields (CRFs) has previously successfully been used for protein binding site prediction. Here, a new CRF-approach is presented that models the dependencies of residues using a general graphical structure defined as a neighborhood graph and thus our model makes fewer independence assumptions on the labels than sequential labeling approaches. A novel node feature "change in free energy" is introduced into the model, which is then denoted by ΔF-CRF. Parameters are trained with an online large-margin algorithm. Using the standard feature class relative accessible surface area alone, the general graph-structure CRF already achieves higher prediction accuracy than the linear chain CRF of Li et al. ΔF-CRF performs significantly better on a large range of false positive rates than the support-vector-machine-based program PresCont of Zellner et al. on a homodimer set containing 128 chains. ΔF-CRF has a broader scope than PresCont since it is not constrained to protein subgroups and requires no multiple sequence alignment. The improvement is attributed to the advantageous combination of the novel node feature with the standard feature and to the adopted parameter training method.

  5. A comprehensive approach to ascertain the binding mode of curcumin with DNA

    Science.gov (United States)

    Haris, P.; Mary, Varughese; Aparna, P.; Dileep, K. V.; Sudarsanakumar, C.

    2017-03-01

    Curcumin is a natural phytochemical from the rhizoma of Curcuma longa, the popular Indian spice that exhibits a wide range of pharmacological properties like antioxidant, anticancer, anti-inflammatory, antitumor, and antiviral activities. In the published literatures we can see different studies and arguments on the interaction of curcumin with DNA. The intercalative binding, groove binding and no binding of curcumin with DNA were reported. In this context, we conducted a detailed study to understand the mechanism of recognition of dimethylsulfoxide-solubilized curcumin by DNA. The interaction of curcumin with calf thymus DNA (ctDNA) was confirmed by agarose gel electrophoresis. The nature of binding and energetics of interaction were studied by Isothermal Titration Calorimetry (ITC), Differential Scanning Calorimetry (DSC), UV-visible, fluorescence and melting temperature (Tm) analysis. The experimental data were compared with molecular modeling studies. Our investigation confirmed that dimethylsulfoxide-solubilized curcumin binds in the minor groove of the ctDNA without causing significant structural alteration to the DNA.

  6. Binding modes of decavanadate to myosin and inhibition of the actomyosin ATPase activity.

    Science.gov (United States)

    Tiago, Teresa; Martel, Paulo; Gutiérrez-Merino, Carlos; Aureliano, Manuel

    2007-04-01

    Decavanadate, a vanadate oligomer, is known to interact with myosin and to inhibit the ATPase activity, but the putative binding sites and the mechanism of inhibition are still to be clarified. We have previously proposed that the decavanadate (V(10)O(28)(6-)) inhibition of the actin-stimulated myosin ATPase activity is non-competitive towards both actin and ATP. A likely explanation for these results is that V(10) binds to the so-called back-door at the end of the Pi-tube opposite to the nucleotide-binding site. In order to further investigate this possibility, we have carried out molecular docking simulations of the V(10) oligomer on three different structures of the myosin motor domain of Dictyostelium discoideum, representing distinct states of the ATPase cycle. The results indicate a clear preference of V(10) to bind at the back-door, but only on the "open" structures where there is access to the phosphate binding-loop. It is suggested that V(10) acts as a "back-door stop" blocking the closure of the 50-kDa cleft necessary to carry out ATP-gamma-phosphate hydrolysis. This provides a simple explanation to the non-competitive behavior of V(10) and spurs the use of the oligomer as a tool to elucidate myosin back-door conformational changes in the process of muscle contraction.

  7. Structural analysis of the STING adaptor protein reveals a hydrophobic dimer interface and mode of cyclic di-GMP binding.

    Science.gov (United States)

    Ouyang, Songying; Song, Xianqiang; Wang, Yaya; Ru, Heng; Shaw, Neil; Jiang, Yan; Niu, Fengfeng; Zhu, Yanping; Qiu, Weicheng; Parvatiyar, Kislay; Li, Yang; Zhang, Rongguang; Cheng, Genhong; Liu, Zhi-Jie

    2012-06-29

    STING is an essential signaling molecule for DNA and cyclic di-GMP (c-di-GMP)-mediated type I interferon (IFN) production via TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3) pathway. It contains an N-terminal transmembrane region and a cytosolic C-terminal domain (CTD). Here, we describe crystal structures of STING CTD alone and complexed with c-di-GMP in a unique binding mode. The strictly conserved aa 153-173 region was shown to be cytosolic and participated in dimerization via hydrophobic interactions. The STING CTD functions as a dimer and the dimerization was independent of posttranslational modifications. Binding of c-di-GMP enhanced interaction of a shorter construct of STING CTD (residues 139-344) with TBK1. This suggests an extra TBK1 binding site, other than serine 358. This study provides a glimpse into the unique architecture of STING and sheds light on the mechanism of c-di-GMP-mediated TBK1 signaling.

  8. Quest for the binding mode of tetrabromobisphenol A with Calf thymus DNA

    Science.gov (United States)

    Wang, Yan-Qing; Zhang, Hong-Mei; Cao, Jian

    2014-10-01

    The binding interaction of tetrabromobisphenol A with Calf thymus DNA was studied by multi-spectroscopic and molecular modeling methods. The UV-vis study revealed that an obvious interaction between tetrabromobisphenol A and Calf thymus DNA happened. The π-π∗ transitions and the electron cloud of tetrabromobisphenol A might be changed by entering the groove of Calf thymus DNA. From the fluorescence spectral and thermodynamics studies, it was concluded that the hydrogen bonds and hydrophobic force played a major role in the binding of tetrabromobisphenol A to Calf thymus DNA. The molecular modeling study showed that the possible sites of tetrabromobisphenol A in the groove of DNA. Circular dichroism study also depicted that tetrabromobisphenol A bond to DNA. These above results would further advance our knowledge on the molecular mechanism of the binding interactions of brominated flame-retardants with nucleic acid.

  9. Biopartitioning micellar chromatography with sodium dodecyl sulfate as a pseudo α(1)-acid glycoprotein to the prediction of protein-drug binding.

    Science.gov (United States)

    Hadjmohammadi, Mohammadreza; Salary, Mina

    2013-01-01

    A simple and fast method is of urgent need to measure protein-drug binding affinity in order to meet the rapid development of new drugs. Biopartitioning micellar chromatography (BMC), a mode of micellar liquid chromatography (MLC) using micellar mobile phases in adequate experimental conditions, can be useful as an in vitro system in mimicking the drug-protein interactions. In this study, sodium dodecyl sulfate-micellar liquid chromatography (SDS-MLC) was used for the prediction of protein-drug binding based on the similar property of SDS micelles to α(1)-acid glycoprotein (AGP). The relationships between the BMC retention data of a heterogeneous set of 14 basic and neutral drugs and their plasma protein binding parameter were studied and the predictive ability of models was evaluated. Modeling of logk(BMC) of these compounds was established by multiple linear regression (MLR) and second-order polynomial models obtained in two different concentrations (0.07 and 0.09M) of SDS. The developed MLR models were characterized by both the descriptive and predictive ability (R(2)=0.882, R(CV)(2)=0.832 and R(2)=0.840, R(CV)(2)=0.765 for 0.07 and 0.09M SDS, respectively). The p values <0.01 also indicated that the relationships between the protein-drug binding and the logk(BMC) values were statistically significant at the 99% confidence level. The standard error of estimation showed the standard deviation of the regression to be 11.89 and 13.87 for 0.07 and 0.09M, respectively. The application of the developed model to a prediction set demonstrated that the model was also reliable with good predictive accuracy. The external and internal validation results showed that the predicted values were in good agreement with the experimental value.

  10. NEURAL NETWORK MODELING IN PROBLEMS OF PREDICTION MODES OF ELECTRICAL GRIDS

    Directory of Open Access Journals (Sweden)

    A.N. Moroz

    2016-03-01

    Full Text Available Purpose. Form a neuro-fuzzy network based on temperature monitoring of overhead transmission line for the prediction modes of the electrical network. Methodology. To predict the load capacity of the overhead line architecture provides the use of neuro-fuzzy network based on temperature monitoring of overhead line. The proposed neuro-fuzzy network has a four-layer architecture with direct transmission of information. To create a full mesh network architecture based on hybrid neural elements with power estimation accuracy of the following two stages of the procedure: - in the first stage a core network (without power estimation accuracy is generated; - in the second stage architecture and network parameters are fixed obtained during the first stage, and it is added to the block estimation accuracy, the input signals which are all input, internal and output signals of the core network, as well as additional input signals. Results. Formed neuro-fuzzy network based on temperature monitoring of overhead line. Originality. A distinctive feature of the proposed network is the ability to process information specified in the different scales of measurement, and high performance for prediction modes mains. Practical value. The monitoring system will become a tool parameter is measuring the temperature of the wire, which will, based on a retrospective analysis of the accumulated information on the parameters to predict the thermal resistance of the HV line and as a result carry out the calculation of load capacity in real time.

  11. SNBRFinder: A Sequence-Based Hybrid Algorithm for Enhanced Prediction of Nucleic Acid-Binding Residues.

    Directory of Open Access Journals (Sweden)

    Xiaoxia Yang

    Full Text Available Protein-nucleic acid interactions are central to various fundamental biological processes. Automated methods capable of reliably identifying DNA- and RNA-binding residues in protein sequence are assuming ever-increasing importance. The majority of current algorithms rely on feature-based prediction, but their accuracy remains to be further improved. Here we propose a sequence-based hybrid algorithm SNBRFinder (Sequence-based Nucleic acid-Binding Residue Finder by merging a feature predictor SNBRFinderF and a template predictor SNBRFinderT. SNBRFinderF was established using the support vector machine whose inputs include sequence profile and other complementary sequence descriptors, while SNBRFinderT was implemented with the sequence alignment algorithm based on profile hidden Markov models to capture the weakly homologous template of query sequence. Experimental results show that SNBRFinderF was clearly superior to the commonly used sequence profile-based predictor and SNBRFinderT can achieve comparable performance to the structure-based template methods. Leveraging the complementary relationship between these two predictors, SNBRFinder reasonably improved the performance of both DNA- and RNA-binding residue predictions. More importantly, the sequence-based hybrid prediction reached competitive performance relative to our previous structure-based counterpart. Our extensive and stringent comparisons show that SNBRFinder has obvious advantages over the existing sequence-based prediction algorithms. The value of our algorithm is highlighted by establishing an easy-to-use web server that is freely accessible at http://ibi.hzau.edu.cn/SNBRFinder.

  12. Bridging Binding Modes of Phosphine-Stabilized Nitrous Oxide to Zn(C6F5)2

    NARCIS (Netherlands)

    Neu, Rebecca C.; Otten, Edwin; Stephan, Douglas W.

    2009-01-01

    Reaction of [tBu3PN2O(B(C6H4F)3)] with 1, 1.5, or 2 equivalents of Zn(C6F5)2 affords the species [{tBu3PN2OZn(C6F5)2}2], [{tBu3PN2OZn(C6F5)2}2Zn(C6F5)2], and [tBu3PN2O{Zn(C6F5)2}2] displaying unique binding modes of Zn to the phosphine-stabilized N2O fragment.

  13. Probe the Binding Mode of Aristololactam-β-D-glucoside to Phenylalanine Transfer RNA in Silico

    DEFF Research Database (Denmark)

    Xiao, Xingqing; Zhao, Binwu; Yang, Li

    2016-01-01

    Understanding the interactions of drug molecules with biomacromolecules at a micro-scale level is essential to design potent drugs for the treatments of human genome diseases. To unravel the mechanism of binding of aristololactam-β-D-glucoside (ADG) and phenylalanine transfer RNA (tRNAPhe), an in......Understanding the interactions of drug molecules with biomacromolecules at a micro-scale level is essential to design potent drugs for the treatments of human genome diseases. To unravel the mechanism of binding of aristololactam-β-D-glucoside (ADG) and phenylalanine transfer RNA (t...

  14. SNP2TFBS – a database of regulatory SNPs affecting predicted transcription factor binding site affinity

    Science.gov (United States)

    Kumar, Sunil; Ambrosini, Giovanna; Bucher, Philipp

    2017-01-01

    SNP2TFBS is a computational resource intended to support researchers investigating the molecular mechanisms underlying regulatory variation in the human genome. The database essentially consists of a collection of text files providing specific annotations for human single nucleotide polymorphisms (SNPs), namely whether they are predicted to abolish, create or change the affinity of one or several transcription factor (TF) binding sites. A SNP's effect on TF binding is estimated based on a position weight matrix (PWM) model for the binding specificity of the corresponding factor. These data files are regenerated at regular intervals by an automatic procedure that takes as input a reference genome, a comprehensive SNP catalogue and a collection of PWMs. SNP2TFBS is also accessible over a web interface, enabling users to view the information provided for an individual SNP, to extract SNPs based on various search criteria, to annotate uploaded sets of SNPs or to display statistics about the frequencies of binding sites affected by selected SNPs. Homepage: http://ccg.vital-it.ch/snp2tfbs/. PMID:27899579

  15. Accurate prediction of DnaK-peptide binding via homology modelling and experimental data.

    Directory of Open Access Journals (Sweden)

    Joost Van Durme

    2009-08-01

    Full Text Available Molecular chaperones are essential elements of the protein quality control machinery that governs translocation and folding of nascent polypeptides, refolding and degradation of misfolded proteins, and activation of a wide range of client proteins. The prokaryotic heat-shock protein DnaK is the E. coli representative of the ubiquitous Hsp70 family, which specializes in the binding of exposed hydrophobic regions in unfolded polypeptides. Accurate prediction of DnaK binding sites in E. coli proteins is an essential prerequisite to understand the precise function of this chaperone and the properties of its substrate proteins. In order to map DnaK binding sites in protein sequences, we have developed an algorithm that combines sequence information from peptide binding experiments and structural parameters from homology modelling. We show that this combination significantly outperforms either single approach. The final predictor had a Matthews correlation coefficient (MCC of 0.819 when assessed over the 144 tested peptide sequences to detect true positives and true negatives. To test the robustness of the learning set, we have conducted a simulated cross-validation, where we omit sequences from the learning sets and calculate the rate of repredicting them. This resulted in a surprisingly good MCC of 0.703. The algorithm was also able to perform equally well on a blind test set of binders and non-binders, of which there was no prior knowledge in the learning sets. The algorithm is freely available at http://limbo.vib.be.

  16. Structure and Mode of Peptide Binding of Pheromone Receptor PrgZ

    NARCIS (Netherlands)

    Berntsson, Ronnie P. -A.; Schuurman-Wolters, Gea K.; Dunny, Gary; Slotboom, Dirk-Jan; Poolman, Bert

    2012-01-01

    Wepresent the crystal structure of the pheromone receptor protein PrgZ from Enterococcus faecalis in complex with the heptapeptide cCF10 (LVTLVFV), which is used in signaling between conjugative recipient and donor cells. Comparison of PrgZ with homologous oligopeptide-binding proteins (AppA and Opp

  17. RANKL employs distinct binding modes to engage RANK and the osteoprotegerin decoy receptor.

    Science.gov (United States)

    Nelson, Christopher A; Warren, Julia T; Wang, Michael W-H; Teitelbaum, Steven L; Fremont, Daved H

    2012-11-07

    Osteoprotegerin (OPG) and receptor activator of nuclear factor κB (RANK) are members of the tumor necrosis factor receptor (TNFR) superfamily that regulate osteoclast formation and function by competing for RANK ligand (RANKL). RANKL promotes osteoclast development through RANK activation, while OPG inhibits this process by sequestering RANKL. For comparison, we solved crystal structures of RANKL with RANK and RANKL with OPG. Complementary biochemical and functional studies reveal that the monomeric cytokine-binding region of OPG binds RANKL with ∼500-fold higher affinity than RANK and inhibits RANKL-stimulated osteoclastogenesis ∼150 times more effectively, in part because the binding cleft of RANKL makes unique contacts with OPG. Several side chains as well as the C-D and D-E loops of RANKL occupy different orientations when bound to OPG versus RANK. High affinity OPG binding requires a 90s loop Phe residue that is mutated in juvenile Paget's disease. These results suggest cytokine plasticity may help to fine-tune specific tumor necrosis factor (TNF)-family cytokine/receptor pair selectivity.

  18. Generalized Predictive Control of Dynamic Systems with Rigid-Body Modes

    Science.gov (United States)

    Kvaternik, Raymond G.

    2013-01-01

    Numerical simulations to assess the effectiveness of Generalized Predictive Control (GPC) for active control of dynamic systems having rigid-body modes are presented. GPC is a linear, time-invariant, multi-input/multi-output predictive control method that uses an ARX model to characterize the system and to design the controller. Although the method can accommodate both embedded (implicit) and explicit feedforward paths for incorporation of disturbance effects, only the case of embedded feedforward in which the disturbances are assumed to be unknown is considered here. Results from numerical simulations using mathematical models of both a free-free three-degree-of-freedom mass-spring-dashpot system and the XV-15 tiltrotor research aircraft are presented. In regulation mode operation, which calls for zero system response in the presence of disturbances, the simulations showed reductions of nearly 100%. In tracking mode operations, where the system is commanded to follow a specified path, the GPC controllers produced the desired responses, even in the presence of disturbances.

  19. NN-align. An artificial neural network-based alignment algorithm for MHC class II peptide binding prediction

    DEFF Research Database (Denmark)

    Nielsen, Morten; Lund, Ole

    2009-01-01

    through presentation of extracellularly derived peptides to helper T cells. Identification of which peptides will bind a given MHC molecule is thus of great importance for the understanding of host-pathogen interactions, and large efforts have been placed in developing algorithms capable of predicting...... this binding event. RESULTS: Here, we present a novel artificial neural network-based method, NN-align that allows for simultaneous identification of the MHC class II binding core and binding affinity. NN-align is trained using a novel training algorithm that allows for correction of bias in the training data...... class II alleles, and is demonstrated to outperform other state-of-the-art MHC class II prediction methods. CONCLUSION: The NN-align method is competitive with the state-of-the-art MHC class II peptide binding prediction algorithms. The method is publicly available at http...

  20. Predictions and observations of global beta-induced Alfven-acoustic modes in JET and NSTX

    Energy Technology Data Exchange (ETDEWEB)

    Gorelenkov, N N [Princeton Plasma Physics Laboratory, Princeton University, Princeton, NJ 08543 (United States); Berk, H L [Institute for Fusion Studies, University of Texas, Austin, TX 78712 (United States); Crocker, N A [Institute of Plasma and Fusion Research, University of California, Los Angeles, CA 90095-1354 (United States); Fredrickson, E D [Princeton Plasma Physics Laboratory, Princeton University, Princeton, NJ 08543 (United States); Kaye, S [Princeton Plasma Physics Laboratory, Princeton University, Princeton, NJ 08543 (United States); Kubota, S [Institute of Plasma and Fusion Research, University of California, Los Angeles, CA 90095-1354 (United States); Park, H [Princeton Plasma Physics Laboratory, Princeton University, Princeton, NJ 08543 (United States); Peebles, W [Institute of Plasma and Fusion Research, University of California, Los Angeles, CA 90095-1354 (United States); Sabbagh, S A [Department of Applied Physics, Columbia University, New York, NY 10027-6902 (United States); Sharapov, S E [Euroatom/UKAEA Fusion Association, Culham Science Centre, Abingdon, Oxfordshire OX14 3DB (United Kingdom); Stutmat, D [Department of Physics and Astronomy, Johns Hopkins University, Baltimore, MD 21218 (United States); Tritz, K [Department of Physics and Astronomy, Johns Hopkins University, Baltimore, MD 21218 (United States); Levinton, F M [Nova Photonics, One Oak Place, Princeton, NJ 08540 (United States); Yuh, H [Nova Photonics, One Oak Place, Princeton, NJ 08540 (United States)

    2007-12-15

    In this paper we report on observations and interpretations of a new class of global MHD eigenmode solutions arising in gaps in the low frequency Alfven-acoustic continuum below the geodesic acoustic mode frequency. These modes have been just reported (Gorelenkov et al 2007 Phys. Lett. 370 70-7) where preliminary comparisons indicate qualitative agreement between theory and experiment. Here we show a more quantitative comparison emphasizing recent NSTX experiments on the observations of the global eigenmodes, referred to as beta-induced Alfven-acoustic eigenmodes (BAAEs), which exist near the extrema of the Alfven-acoustic continuum. In accordance to the linear dispersion relations, the frequency of these modes may shift as the safety factor, q, profile relaxes. We show that BAAEs can be responsible for observations in JET plasmas at relatively low beta <2% as well as in NSTX plasmas at relatively high beta >20%. In NSTX plasma observed magnetic activity has the same properties as predicted by theory for the mode structure and the frequency. Found numerically in NOVA simulations BAAEs are used to explain the observed properties of relatively low frequency experimental signals seen in NSTX and JET tokamaks.

  1. LIGSITEcsc: predicting ligand binding sites using the Connolly surface and degree of conservation

    Directory of Open Access Journals (Sweden)

    Schroeder Michael

    2006-09-01

    Full Text Available Abstract Background Identifying pockets on protein surfaces is of great importance for many structure-based drug design applications and protein-ligand docking algorithms. Over the last ten years, many geometric methods for the prediction of ligand-binding sites have been developed. Results We present LIGSITEcsc, an extension and implementation of the LIGSITE algorithm. LIGSITEcsc is based on the notion of surface-solvent-surface events and the degree of conservation of the involved surface residues. We compare our algorithm to four other approaches, LIGSITE, CAST, PASS, and SURFNET, and evaluate all on a dataset of 48 unbound/bound structures and 210 bound-structures. LIGSITEcsc performs slightly better than the other tools and achieves a success rate of 71% and 75%, respectively. Conclusion The use of the Connolly surface leads to slight improvements, the prediction re-ranking by conservation to significant improvements of the binding site predictions. A web server for LIGSITEcsc and its source code is available at scoppi.biotec.tu-dresden.de/pocket.

  2. Identification, pharmacological evaluation and binding mode analysis of novel chromene and chromane based σ1 receptor ligands.

    Science.gov (United States)

    Laurini, Erik; Harel, Dipak; Marson, Domenico; Schepmann, Dirk; Schmidt, Thomas J; Pricl, Sabrina; Wünsch, Bernhard

    2014-08-18

    A set of aminoethyl substituted chromenes 3 and chromanes 4, originally developed as antiprotozoal drugs was evaluated as novel types of σ1 receptor ligands. Analysis of SAR showed that chromenes 3 have a higher σ1 affinity than chromanes 4. A distance of four bond lengths between the basic amino moiety and the phenyl ring (3c), an alicyclic N-substituent such as the cyclohexylmethyl moiety (3l), and methylation of the secondary amine to afford a tertiary amine (3n) result in very high σ1 affinity and selectivity over the σ2 subtype. Compounds 3a-n and 4a-e were docked into the putative binding site of the σ1 receptor model and the relevant binding mode was analyzed and scored. Specifically, for the best σ1 ligand 3n, a salt bridge between Asp126 and the protonated amino group, an H-bond between the receptor backbone NH group (Ala122-Glu123) and the methoxy moiety of 3n, a lipophilic protein cavity encasing the chromene ring, and a T-shaped π-π stacking between the indole ring of Trp121 and the phenyl ring of 3n represent the most important ligand/protein stabilizing interactions. The binding pose of 3n was compared with the binding poses of the non-methylated chromene 3c, the saturated chromane 4c, and the N-cyclohexylmethyl derivative 3l. The contribution of the single amino acids to the overall free binding enthalpy was analyzed.

  3. The PickPocket method for predicting binding specificities for receptors based on receptor pocket similarities: application to MHC-peptide binding

    DEFF Research Database (Denmark)

    Zhang, H.; Lund, Ole; Nielsen, M.

    2009-01-01

    of the specificities of MHC molecules in this library weighted by the similarity of their pocket-residues to the query. This PickPocket method is demonstrated to accurately predict MHC-peptide binding for a broad range of MHC alleles, including human and non-human species. In contrast to neural network-based pan......-specific methods, PickPocket was shown to be robust both when data is scarce and when the similarity to MHC molecules with characterized binding specificity is low. A consensus method combining the PickPocket and NetMHCpan methods was shown to achieve superior predictive performance. This study demonstrates how...

  4. Seasonal Prediction of the Global Precipitation Annual Modes with the Grid-Point Atmospheric Model of IAP LASG

    Institute of Scientific and Technical Information of China (English)

    WU Zhiwei; LI Jianping

    2009-01-01

    A right annual cycle is of critical importance for a model to improve its seasonal prediction skill. This work assesses the performance of the Grid-point Atmospheric Model of IAP LASG (GAMIL) in retrospective prediction of the global precipitation annual modes for the 1980-2004 period. The annual modes are gauged by a three-parameter metrics: the long-term annual mean and two major modes of annual cycle (AC), namely, a solstitial mode and an equinoctial asymmetric mode. The results demonstrate that the GAMIL one-month lead prediction is basically able to capture the major patterns of the long-term annual mean as well as the first AC mode (the solstitial monsoon mode). The GAMIL has deficiencies in reproducing the second AC mode (the equinoctial asymmetric mode). The magnitude of the GAMIL prediction tends to be greater than the observed precipitation, especially in the sea areas including the Arabian Sea, the Bay of Bengal (BOB), and the western North Pacific (WNP). These biases may be due to underestimation of the convective activity predicted in the tropics, especially over the western Pacific warm pool (WPWP) and its neighboring areas. It is suggested that a more accurate parameterization of convection in the tropics, especially in the Maritime Continent, the WPWP and its neighboring areas, may be critical for reproducing the more realistic annual modes, since the enhancement of convective activity over the WPWP and its vicinity can induce suppressed convection over the WNP, the BOB, and the South Indian Ocean where the GAMIL produces falsely vigorous convections. More efforts are needed to improve the simulation not only in monsoon seasons but also in transitional seasons when the second AC mode takes place. Selection of the one-tier or coupled atmosphere-ocean system may also reduce GAMIL seasonal prediction skill.

  5. Novel predicted RNA-binding domains associated with the translation machinery.

    Science.gov (United States)

    Aravind, L; Koonin, E V

    1999-03-01

    Two previously undetected domains were identified in a variety of RNA-binding proteins, particularly RNA-modifying enzymes, using methods for sequence profile analysis. A small domain consisting of 60-65 amino acid residues was detected in the ribosomal protein S4, two families of pseudouridine synthases, a novel family of predicted RNA methylases, a yeast protein containing a pseudouridine synthetase and a deaminase domain, bacterial tyrosyl-tRNA synthetases, and a number of uncharacterized, small proteins that may be involved in translation regulation. Another novel domain, designated PUA domain, after PseudoUridine synthase and Archaeosine transglycosylase, was detected in archaeal and eukaryotic pseudouridine synthases, archaeal archaeosine synthases, a family of predicted ATPases that may be involved in RNA modification, a family of predicted archaeal and bacterial rRNA methylases. Additionally, the PUA domain was detected in a family of eukaryotic proteins that also contain a domain homologous to the translation initiation factor eIF1/SUI1; these proteins may comprise a novel type of translation factors. Unexpectedly, the PUA domain was detected also in bacterial and yeast glutamate kinases; this is compatible with the demonstrated role of these enzymes in the regulation of the expression of other genes. We propose that the S4 domain and the PUA domain bind RNA molecules with complex folded structures, adding to the growing collection of nucleic acid-binding domains associated with DNA and RNA modification enzymes. The evolution of the translation machinery components containing the S4, PUA, and SUI1 domains must have included several events of lateral gene transfer and gene loss as well as lineage-specific domain fusions.

  6. Exploiting structural and topological information to improve prediction of RNA-protein binding sites

    Directory of Open Access Journals (Sweden)

    Yuan Zheng

    2009-10-01

    Full Text Available Abstract Background RNA-protein interactions are important for a wide range of biological processes. Current computational methods to predict interacting residues in RNA-protein interfaces predominately rely on sequence data. It is, however, known that interface residue propensity is closely correlated with structural properties. In this paper we systematically study information obtained from sequences and structures and compare their contributions in this prediction problem. Particularly, different geometrical and network topological properties of protein structures are evaluated to improve interface residue prediction accuracy. Results We have quantified the impact of structural information on the prediction accuracy in comparison to the purely sequence based approach using two machine learning techniques: Naïve Bayes classifiers and Support Vector Machines. The highest AUC of 0.83 was achieved by a Support Vector Machine, exploiting PSI-BLAST profile, accessible surface area, betweenness-centrality and retention coefficient as input features. Taking into account that our results are based on a larger non-redundant data set, the prediction accuracy is considerably higher than reported in previous, comparable studies. A protein-RNA interface predictor (PRIP and the data set have been made available at http://www.qfab.org/PRIP. Conclusion Graph-theoretic properties of residue contact maps derived from protein structures such as betweenness-centrality can supplement sequence or structure features to improve the prediction accuracy for binding residues in RNA-protein interactions. While Support Vector Machines perform better on this task, Naïve Bayes classifiers also have been found to achieve good prediction accuracies but require much less training time and are an attractive choice for large scale predictions.

  7. Bifurcation of resistive wall mode dynamics predicted by magnetohydrodynamic-kinetic hybrid theory

    Energy Technology Data Exchange (ETDEWEB)

    Yang, S. X.; Wang, Z. X., E-mail: zxwang@dlut.edu.cn [Key Laboratory of Materials Modification by Beams of the Ministry of Education, School of Physics and Optoelectronic Technology, Dalian University of Technology, Dalian 116024 (China); Wang, S.; Hao, G. Z., E-mail: haogz@swip.ac.cn; Song, X. M.; Wang, A. K. [Southwestern Institute of Physics, P.O.Box 432, Chengdu 610041 (China); Liu, Y. Q. [Culham Centre for Fusion Energy, Culham Science Centre, Abingdon OX14 3DB (United Kingdom); Southwestern Institute of Physics, P.O.Box 432, Chengdu 610041 (China)

    2015-09-15

    The magnetohydrodynamic-kinetic hybrid theory has been extensively and successfully applied for interpreting experimental observations of macroscopic, low frequency instabilities, such as the resistive wall mode, in fusion plasmas. In this work, it is discovered that an analytic version of the hybrid formulation predicts a bifurcation of the mode dynamics while varying certain physical parameters of the plasma, such as the thermal particle collisionality or the ratio of the thermal ion to electron temperatures. This bifurcation can robustly occur under reasonably large parameter spaces as well as with different assumptions, for instance, on the particle collision model. Qualitatively similar bifurcation features are also observed in full toroidal computations presented in this work, based on a non-perturbative hybrid formulation.

  8. Sliding Mode Predictive Control of Main Steam Pressure in Coal-fired Power Plant Boiler

    Institute of Scientific and Technical Information of China (English)

    史元浩; 王景成; 章云锋

    2012-01-01

    Since the combustion system of coal-fired boiler in thermal power plant is characterized as time varying, strongly coupled, and nonlinear, it is hard to achieve a satisfactory performance by the conventional proportional integral derivative (PID) control scheme. For the characteristics of the main steam pressure in coal-fired power plant boiler, the sliding mode control system with Smith predictive structure is proposed to look for performance and robustness improvement. First, internal model control (IMC) and Smith predictor (SP) is used to deal with the time delay, and sliding mode controller (SMCr) is designed to overcome the model mismatch. Simulation results show the effectiveness of the proposed controller compared with conventional ones.

  9. Direct demonstration of unique mode of natural peptide binding to the type 2 cholecystokinin receptor using photoaffinity labeling.

    Science.gov (United States)

    Dong, Maoqing; Miller, Laurence J

    2013-08-01

    Direct analysis of mode of peptide docking using intrinsic photoaffinity labeling has provided detailed insights for the molecular basis of cholecystokinin (CCK) interaction with the type 1 CCK receptor. In the current work, this technique has been applied to the closely related type 2 CCK receptor that also binds the natural full agonist peptide, CCK, with high affinity. A series of photolabile CCK analog probes with sites of covalent attachment extending from position 26 through 32 were characterized, with the highest affinity analogs that possessed full biological activity utilized in photoaffinity labeling. The position 29 probe, incorporating a photolabile benzoyl-phenylalanine in that position, was shown to bind with high affinity and to be a full agonist, with potency not different from that of natural CCK, and to covalently label the type 2 CCK receptor in a saturable, specific and efficient manner. Using proteolytic peptide mapping, mutagenesis, and radiochemical Edman degradation sequencing, this probe was shown to establish a covalent bond with type 2 CCK receptor residue Phe¹²⁰ in the first extracellular loop. This was in contrast to its covalent attachment to Glu³⁴⁵ in the third extracellular loop of the type 1 CCK receptor, directly documenting differences in mode of docking this peptide to these receptors.

  10. Ultrafast photoelectron migration in dye-sensitized solar cells: Influence of the binding mode and many-body interactions

    Science.gov (United States)

    Hermann, G.; Tremblay, J. C.

    2016-11-01

    In the present contribution, the ultrafast photoinduced electron migration dynamics at the interface between an alizarin dye and an anatase TiO2 thin film is investigated from first principles. Comparison between a time-dependent many-electron configuration interaction ansatz and a single active electron approach sheds light on the importance of many-body effects, stemming from uniquely defined initial conditions prior to photoexcitation. Particular emphasis is put on understanding the influence of the binding mode on the migration process. The dynamics is analyzed on the basis of a recently introduced toolset in the form of electron yields, electronic fluxes, and flux densities, to reveal microscopic details of the electron migration mechanism. From the many-body perspective, insight into the nature of electron-electron and hole-hole interactions during the charge transfer process is obtained. The present results reveal that the single active electron approach yields quantitatively and phenomenologically similar results as the many-electron ansatz. Furthermore, the charge migration processes in the dye-TiO2 model clusters with different binding modes exhibit similar mechanistic pathways but on largely different time scales.

  11. Implications of binding mode and active site flexibility for inhibitor potency against the salicylate synthase from Mycobacterium tuberculosis.

    Science.gov (United States)

    Chi, Gamma; Manos-Turvey, Alexandra; O'Connor, Patrick D; Johnston, Jodie M; Evans, Genevieve L; Baker, Edward N; Payne, Richard J; Lott, J Shaun; Bulloch, Esther M M

    2012-06-19

    MbtI is the salicylate synthase that catalyzes the first committed step in the synthesis of the iron chelating compound mycobactin in Mycobacterium tuberculosis. We previously developed a series of aromatic inhibitors against MbtI based on the reaction intermediate for this enzyme, isochorismate. The most potent of these inhibitors had hydrophobic substituents, ranging in size from a methyl to a phenyl group, appended to the terminal alkene of the enolpyruvyl group. These compounds exhibited low micromolar inhibition constants against MbtI and were at least an order of magnitude more potent than the parental compound for the series, which carries a native enolpyruvyl group. In this study, we sought to understand how the substituted enolpyruvyl group confers greater potency, by determining cocrystal structures of MbtI with six inhibitors from the series. A switch in binding mode at the MbtI active site is observed for inhibitors carrying a substituted enolpyruvyl group, relative to the parental compound. Computational studies suggest that the change in binding mode, and higher potency, is due to the effect of the substituents on the conformational landscape of the core inhibitor structure. The crystal structures and fluorescence-based thermal shift assays indicate that substituents larger than a methyl group are accommodated in the MbtI active site through significant but localized flexibility in the peptide backbone. These findings have implications for the design of improved inhibitors of MbtI, as well as other chorismate-utilizing enzymes from this family.

  12. Reliability analysis and prediction of mixed mode load using Markov Chain Model

    Energy Technology Data Exchange (ETDEWEB)

    Nikabdullah, N. [Department of Mechanical and Materials Engineering, Faculty of Engineering and Built Environment, Universiti Kebangsaan Malaysia and Institute of Space Science (ANGKASA), Faculty of Engineering and Built Environment, Universiti Kebangsaan Malaysia (Malaysia); Singh, S. S. K.; Alebrahim, R.; Azizi, M. A. [Department of Mechanical and Materials Engineering, Faculty of Engineering and Built Environment, Universiti Kebangsaan Malaysia (Malaysia); K, Elwaleed A. [Institute of Space Science (ANGKASA), Faculty of Engineering and Built Environment, Universiti Kebangsaan Malaysia (Malaysia); Noorani, M. S. M. [School of Mathematical Sciences, Faculty of Science and Technology, Universiti Kebangsaan Malaysia (Malaysia)

    2014-06-19

    The aim of this paper is to present the reliability analysis and prediction of mixed mode loading by using a simple two state Markov Chain Model for an automotive crankshaft. The reliability analysis and prediction for any automotive component or structure is important for analyzing and measuring the failure to increase the design life, eliminate or reduce the likelihood of failures and safety risk. The mechanical failures of the crankshaft are due of high bending and torsion stress concentration from high cycle and low rotating bending and torsional stress. The Markov Chain was used to model the two states based on the probability of failure due to bending and torsion stress. In most investigations it revealed that bending stress is much serve than torsional stress, therefore the probability criteria for the bending state would be higher compared to the torsion state. A statistical comparison between the developed Markov Chain Model and field data was done to observe the percentage of error. The reliability analysis and prediction was derived and illustrated from the Markov Chain Model were shown in the Weibull probability and cumulative distribution function, hazard rate and reliability curve and the bathtub curve. It can be concluded that Markov Chain Model has the ability to generate near similar data with minimal percentage of error and for a practical application; the proposed model provides a good accuracy in determining the reliability for the crankshaft under mixed mode loading.

  13. Recognition and prediction of individual and combined muscular activation modes via surface EMG analysis

    Directory of Open Access Journals (Sweden)

    Daniel Graupe

    2010-09-01

    Full Text Available The paper discusses how recognition of individual and combined muscular activation modes (functions and the prediction of intended such modes can be accomplished by identifying parameters of noninvasive surface EMG signals. It outlines the mathematical analysis of surface EMG signal to facilitate such recognition and related prediction, including recognition of intention (in terms of attempts to activate motor functions from the EMG, without accessing the CNS itself, in cases where a patient, say, a high-level amputee does not have the final-activation muscles and joints. The EMG activity thus allows to interpret and recognize CNS commands from minute variations in the parameters of surface EMG signals that record changes in the firing of motor neurons triggering contractions in related muscle fibers. We note that although in popular media this is sometimes referred to as detection of “thoughts”, no thoughts are detected, but only motor-outcomes of thoughts as found in the EMG signal. Examples of concrete cases where such recognition or prediction were accomplished in the author’s lab and in devices that came out of that lab, are given as are references to these in the literature over the last 35 years.

  14. Binding Mode and Selectivity of Steroids towards Glucose-6-phosphate Dehydrogenase from the Pathogen Trypanosoma cruzi.

    Science.gov (United States)

    Ortiz, Cecilia; Moraca, Francesca; Medeiros, Andrea; Botta, Maurizio; Hamilton, Niall; Comini, Marcelo A

    2016-03-17

    Glucose-6-phosphate dehydrogenase (G6PDH) plays a housekeeping role in cell metabolism by generating reducing power (NADPH) and fueling the production of nucleotide precursors (ribose-5-phosphate). Based on its indispensability for pathogenic parasites from the genus Trypanosoma, G6PDH is considered a drug target candidate. Several steroid-like scaffolds were previously reported to target the activity of G6PDH. Epiandrosterone (EA) is an uncompetitive inhibitor of trypanosomal G6PDH for which its binding site to the enzyme remains unknown. Molecular simulation studies with the structure of Trypanosoma cruzi G6PDH revealed that EA binds in a pocket close to the G6P binding-site and protrudes into the active site blocking the interaction between substrates and hence catalysis. Site directed mutagenesis revealed the important steroid-stabilizing effect of residues (L80, K83 and K84) located on helix α-1 of T. cruzi G6PDH. The higher affinity and potency of 16α-Br EA by T. cruzi G6PDH is explained by the formation of a halogen bond with the hydrogen from the terminal amide of the NADP+-nicotinamide. At variance with the human enzyme, the inclusion of a 21-hydroxypregnane-20-one moiety to a 3β-substituted steroid is detrimental for T. cruzi G6PDH inhibition. The species-specificity of certain steroid derivatives towards the parasite G6PDH and the corresponding biochemically validated binding models disclosed in this work may prove valuable for the development of selective inhibitors against the pathogen's enzyme.

  15. The Mode of Hedgehog Binding to Ihog Homologues is Not Conserved Across Different Phyla

    Energy Technology Data Exchange (ETDEWEB)

    McLellan, J.; Zheng, X; Hauk, G; Ghirlando, R; Beachy, P; Leahy, D

    2008-01-01

    Hedgehog (Hh) proteins specify tissue pattern in metazoan embryos by forming gradients that emanate from discrete sites of expression and elicit concentration-dependent cellular differentiation or proliferation responses1, 2. Cellular responses to Hh and the movement of Hh through tissues are both precisely regulated, and abnormal Hh signalling has been implicated in human birth defects and cancer3, 4, 5, 6, 7. Hh signalling is mediated by its amino-terminal domain (HhN), which is dually lipidated and secreted as part of a multivalent lipoprotein particle8, 9, 10. Reception of the HhN signal is modulated by several cell-surface proteins on responding cells, including Patched (Ptc), Smoothened (Smo), Ihog (known as CDO or CDON in mammals) and the vertebrate-specific proteins Hip (also known as Hhip) and Gas1 (ref. 11). Drosophila Ihog and its vertebrate homologues CDO and BOC contain multiple immunoglobulin and fibronectin type III (FNIII) repeats, and the first FNIII repeat of Ihog binds Drosophila HhN in a heparin-dependent manner12, 13. Surprisingly, pull-down experiments suggest that a mammalian Sonic hedgehog N-terminal domain (ShhN) binds a non-orthologous FNIII repeat of CDO12, 14. Here we report biochemical, biophysical and X-ray structural studies of a complex between ShhN and the third FNIII repeat of CDO. We show that the ShhN-CDO interaction is completely unlike the HhN-Ihog interaction and requires calcium, which binds at a previously undetected site on ShhN. This site is conserved in nearly all Hh proteins and is a hotspot for mediating interactions between ShhN and CDO, Ptc, Hip and Gas1. Mutations in vertebrate Hh proteins causing holoprosencephaly and brachydactyly type A1 map to this calcium-binding site and disrupt interactions with these partners.

  16. Dual binding mode in cohesin-dockerin complexes as assessed through stretching studies

    Science.gov (United States)

    Wojciechowski, Michał; Cieplak, Marek

    2016-10-01

    A recent experimental study by Jobst et al. of stretching of a wild-type (WT) cohesin-dockerin complex has identified two kinds of the force-displacement patterns, with a single or double-peaked final rupture, which are termed "short" and "long" here. This duality has been interpreted as arising from the existence of two kinds of binding. Here, we analyze the separation of two cohesin-dockerin complexes of C. thermocellum theoretically. We use a coarse-grained structure-based model and the values of the pulling speeds are nearly experimental. In their native states, the two systems differ in the mutual binding orientations of the molecules in the complex. We demonstrate that the WT complex (PDB:1OHZ) unravels along two possible pathways that are qualitatively consistent with the presence of the short and long patterns observed experimentally. On the other hand, the mutated complex (PDB:2CCL) leads only to short trajectories. The short and long stretching pathways also appear in the cohesin-dockerin-Xmodule complex (PDB:4IU3, WT) of R. flavefaciens. Thus the duality in the stretching patterns need not be necessarily due to the duality in binding.

  17. Calculating the contribution of different binding modes to Quinacrine - DNA complex formation from polarized fluorescence data

    CERN Document Server

    Voloshin, Igor; Karachevtsev, Victor; Zozulya, Victor

    2013-01-01

    Binding of acridine derivative quinacrine (QA) to chicken erythrocyte DNA was studied by methods of absorption and polarized fluorescent spectroscopy. Measurements were carried out in aqueous buffered solutions (pH 6.9) of different dye concentrations (QA concentration range from $10^{-6}$ till $10^{-4}$ M) and ionic strengths ($Na^{+}$ concentration rang from $10^{-3}$ till 0.15 M) in a wide range of phosphate-to-dye molar ratios ($P/D$). It is established that the minimum of fluorescent titration curve plotted as relative fluorescence intensity $vs$ $P/D$ is conditioned by the competition between the two types of QA binding to DNA which posses by different emission parameters: (i) intercalative one dominating under high $P/D$ values, and (ii) outside electrostatic binding dominating under low $P/D$ values, which is accompanied by the formation of non-fluorescent dye associates on the DNA backbone. Absorption and fluorescent characteristics of complexes formed were determined. The method of calculation of di...

  18. A Novel, ;Double-Clamp; Binding Mode for Human Heme Oxygenase-1 Inhibition

    Energy Technology Data Exchange (ETDEWEB)

    Rahman, Mona N.; Vlahakis, Jason Z.; Vukomanovic, Dragic; Lee, Wallace; Szarek, Walter A.; Nakatsu, Kanji; Jia, Zongchao (Queens)

    2012-08-01

    The development of heme oxygenase (HO) inhibitors is critical in dissecting and understanding the HO system and for potential therapeutic applications. We have established a program to design and optimize HO inhibitors using structure-activity relationships in conjunction with X-ray crystallographic analyses. One of our previous complex crystal structures revealed a putative secondary hydrophobic binding pocket which could be exploited for a new design strategy by introducing a functional group that would fit into this potential site. To test this hypothesis and gain further insights into the structural basis of inhibitor binding, we have synthesized and characterized 1-(1H-imidazol-1-yl)-4,4-diphenyl-2-butanone (QC-308). Using a carbon monoxide (CO) formation assay on rat spleen microsomes, the compound was found to be {approx}15 times more potent (IC{sub 50} = 0.27{+-}0.07 {mu}M) than its monophenyl analogue, which is already a potent compound in its own right (QC-65; IC{sub 50} = 4.0{+-}1.8 {mu}M). The crystal structure of hHO-1 with QC-308 revealed that the second phenyl group in the western region of the compound is indeed accommodated by a definitive secondary proximal hydrophobic pocket. Thus, the two phenyl moieties are each stabilized by distinct hydrophobic pockets. This 'double-clamp' binding offers additional inhibitor stabilization and provides a new route for improvement of human heme oxygenase inhibitors.

  19. Binding Mode Analysis of Zerumbone to Key Signal Proteins in the Tumor Necrosis Factor Pathway

    Directory of Open Access Journals (Sweden)

    Ayesha Fatima

    2015-01-01

    Full Text Available Breast cancer is the second most common cancer among women worldwide. Several signaling pathways have been implicated as causative and progression agents. The tumor necrosis factor (TNF α protein plays a dual role in promoting and inhibiting cancer depending largely on the pathway initiated by the binding of the protein to its receptor. Zerumbone, an active constituent of Zingiber zerumbet, Smith, is known to act on the tumor necrosis factor pathway upregulating tumour necrosis factor related apoptosis inducing ligand (TRAIL death receptors and inducing apoptosis in cancer cells. Zerumbone is a sesquiterpene that is able to penetrate into the hydrophobic pockets of proteins to exert its inhibiting activity with several proteins. We found a good binding with the tumor necrosis factor, kinase κB (IKKβ and the Nuclear factor κB (NF-κB component proteins along the TNF pathway. Our results suggest that zerumbone can exert its apoptotic activities by inhibiting the cytoplasmic proteins. It inhibits the IKKβ kinase that activates the NF-κB and also binds to the NF-κB complex in the TNF pathway. Blocking both proteins can lead to inhibition of cell proliferating proteins to be downregulated and possibly ultimate induction of apoptosis.

  20. Biomolecular mode of action of metformin in relation to its copper binding properties.

    Science.gov (United States)

    Repiščák, Peter; Erhardt, Stefan; Rena, Graham; Paterson, Martin J

    2014-02-04

    Metformin (Metf), the most commonly used type 2 diabetes drug, is known to affect the cellular housekeeping of copper. Recently, we discovered that the structurally closely related propanediimidamide (PDI) shows a cellular behavior different from that of Metf. Here we investigate the binding of these compounds to copper, to compare their binding strength. Furthermore, we take a closer look at the electronic properties of these compounds and their copper complexes such as molecular orbital interactions and electrostatic potential surfaces. Our results clearly show that the copper binding energies cannot alone be the cause of the biochemical differentiation between Metf and PDI. We conclude that other factors such as pKa values and hydrophilicity of the compounds play a crucial role in their cellular activity. Metf in contrast to PDI can occur as an anion in aqueous medium at moderate pH, forming much stronger complexes particularly with Cu(II) ions, suggesting that biguanides but not PDI may induce easy oxidation of Cu(I) ions extracted from proteins. The higher hydrophobicity and the lack of planarity of PDI may further differentiate it from biguanides in terms of their molecular recognition characteristics. These different properties could hold the key to metformin's mitochondrial activity because they suggest that the drug could act at least in part as a pro-oxidant of accessible protein-bound Cu(I) ions.

  1. Binding modes of phosphonic acid derivatives adsorbed on TiO2 surfaces: Assignments of experimental IR and NMR spectra based on DFT/PBC calculations

    Science.gov (United States)

    Geldof, D.; Tassi, M.; Carleer, R.; Adriaensens, P.; Roevens, A.; Meynen, V.; Blockhuys, F.

    2017-01-01

    A DFT study on the adsorption of a series of phosphonic acids (PAs) on the TiO2 anatase (101) and (001) surfaces was performed. The adsorption energies and geometries of the most stable binding modes were compared to literature data and the effect of the inclusion of dispersion forces in the energy calculations was gauged. As the (101) surface is the most exposed surface of TiO2 anatase, the calculated chemical shifts and vibrational frequencies of PAs adsorbed on this surface were compared to experimental 31P and 17O NMR and IR data in order to assign the two possible binding modes (mono- and bidentate) to peaks and bands in these spectra; due to the corrugated nature of anatase (101) tridentate binding is not possible on this surface. Analysis of the calculated and experimental 31P chemical shifts indicates that both monodentate and bidentate binding modes are present. For the reactive (001) surface, the results of the calculations indicate that both bi- and tridentate binding modes result in stable systems. Due to the particular sensitivity of 17O chemical shifts to hydrogen bonding and solvent effects, the model used is insufficient to assign these spectra at present. Comparison of calculated and experimental IR spectra leads to the conclusion that IR spectroscopy is not suitable for the characterization of the different binding modes of the adsorption complexes.

  2. MULTIPRED2: A computational system for large-scale identification of peptides predicted to bind to HLA supertypes and alleles

    DEFF Research Database (Denmark)

    Zhang, Guang Lan; DeLuca, David S.; Keskin, Derin B.;

    2011-01-01

    MULTIPRED2 is a computational system for facile prediction of peptide binding to multiple alleles belonging to human leukocyte antigen (HLA) class I and class II DR molecules. It enables prediction of peptide binding to products of individual HLA alleles, combination of alleles, or HLA supertypes...... groups in North America. MULTIPRED2 is an important tool to complement wet-lab experimental methods for identification of T-cell epitopes. It is available at http://cvc.dfci.harvard.edu/multipred2/....

  3. Detailed Analysis of the Binding Mode of Vanilloids to Transient Receptor Potential Vanilloid Type I (TRPV1) by a Mutational and Computational Study

    Science.gov (United States)

    Mori, Yoshikazu; Ogawa, Kazuo; Warabi, Eiji; Yamamoto, Masahiro; Hirokawa, Takatsugu

    2016-01-01

    Transient receptor potential vanilloid type 1 (TRPV1) is a non-selective cation channel and a multimodal sensor protein. Since the precise structure of TRPV1 was obtained by electron cryo-microscopy, the binding mode of representative agonists such as capsaicin and resiniferatoxin (RTX) has been extensively characterized; however, detailed information on the binding mode of other vanilloids remains lacking. In this study, mutational analysis of human TRPV1 was performed, and four agonists (capsaicin, RTX, [6]-shogaol and [6]-gingerol) were used to identify amino acid residues involved in ligand binding and/or modulation of proton sensitivity. The detailed binding mode of each ligand was then simulated by computational analysis. As a result, three amino acids (L518, F591 and L670) were newly identified as being involved in ligand binding and/or modulation of proton sensitivity. In addition, in silico docking simulation and a subsequent mutational study suggested that [6]-gingerol might bind to and activate TRPV1 in a unique manner. These results provide novel insights into the binding mode of various vanilloids to the channel and will be helpful in developing a TRPV1 modulator. PMID:27606946

  4. Structural Insights into the Distinct Binding Mode of Cyclic Di-AMP with SaCpaA_RCK.

    Science.gov (United States)

    Chin, Ko-Hsin; Liang, Juin-Ming; Yang, Jauo-Guey; Shih, Min-Shao; Tu, Zhi-Le; Wang, Yu-Chuang; Sun, Xing-Han; Hu, Nien-Jen; Liang, Zhao-Xun; Dow, J Maxwell; Ryan, Robert P; Chou, Shan-Ho

    2015-08-11

    Cyclic di-AMP (c-di-AMP) is a relatively new member of the family of bacterial cyclic dinucleotide second messengers. It has attracted significant attention in recent years because of the abundant roles it plays in a variety of Gram-positive bacteria. The structural features that allow diverse bacterial proteins to bind c-di-AMP are not fully understood. Here we report the biophysical and structural studies of c-di-AMP in complex with a bacterial cation-proton antiporter (CpaA) RCK (regulator of the conductance of K(+)) protein from Staphylococcus aureus (Sa). The crystal structure of the SaCpaA_RCK C-terminal domain (CTD) in complex with c-di-AMP was determined to a resolution of 1.81 Å. This structure revealed two well-liganded water molecules, each interacting with one of the adenine bases by a unique H2Olp-π interaction to stabilize the complex. Sequence blasting using the SaCpaA_RCK primary sequence against the bacterial genome database returned many CpaA analogues, and alignment of these sequences revealed that the active site residues are all well-conserved, indicating a universal c-di-AMP binding mode for CpaA_RCK. A proteoliposome activity assay using the full-length SaCpaA membrane protein indicated that c-di-AMP binding alters its antiporter activity by approximately 40%. A comparison of this structure to all other reported c-di-AMP-receptor complex structures revealed that c-di-AMP binds to receptors in either a "U-shape" or "V-shape" mode. The two adenine rings are stabilized in the inner interaction zone by a variety of CH-π, cation-π, backbone-π, or H2Olp-π interaction, but more commonly in the outer interaction zone by hydrophobic CH-π or π-π interaction. The structures determined to date provide an understanding of the mechanisms by which a single c-di-AMP can interact with a variety of receptor proteins, and how c-di-AMP binds receptor proteins in a special way different from that of c-di-GMP.

  5. Molecular Dynamics Simulations to Investigate the Binding Mode of the Natural Product Liphagal with Phosphoinositide 3-Kinase α

    Directory of Open Access Journals (Sweden)

    Yanjuan Gao

    2016-06-01

    Full Text Available Phosphatidylinositol 3-kinase α (PI3Kα is an attractive target for anticancer drug design. Liphagal, isolated from the marine sponge Aka coralliphaga, possesses the special “liphagane” meroterpenoid carbon skeleton and has been demonstrated as a PI3Kα inhibitor. Molecular docking and molecular dynamics simulations were performed to explore the dynamic behaviors of PI3Kα binding with liphagal, and free energy calculations and energy decomposition analysis were carried out by use of molecular mechanics/Poisson-Boltzmann (generalized Born surface area (MM/PB(GBSA methods. The results reveal that the heteroatom rich aromatic D-ring of liphagal extends towards the polar region of the binding site, and the D-ring 15-hydroxyl and 16-hydroxyl form three hydrogen bonds with Asp810 and Tyr836. The cyclohexyl A-ring projects up into the upper pocket of the lipophilic region, and the hydrophobic/van der Waals interactions with the residues Met772, Trp780, Ile800, Ile848, Val850, Met922, Phe930, Ile932 could be the key interactions for the affinity of liphagal to PI3Kα. Thus, a new strategy for the rational design of more potent analogs of liphagal against PI3Kα is provided. Our proposed PI3Kα/liphagal binding mode would be beneficial for the discovery of new active analogs of liphagal against PI3Kα.

  6. Predicting a DNA-binding protein using random forest with multiple mathematical features.

    Science.gov (United States)

    Guan, Changge; Niu, Xiaohui; Shi, Feng; Yang, Kun; Li, Nana

    2015-01-01

    DNA-binding proteins are involved and play a crucial role in a lot of important biological processes. Hence, the identification of the DNA-binding proteins is a challenging and significant problem. In order to reveal the intrinsic information correlated to DNA-binding, nine classes of candidate features based on different mathematical fields are applied to construct the prediction model with random forest. They are fractal dimension, conjoint triad feature, Hilbert-Huang Transformation, amino acid composition, dipeptide composition, chaos game representation, and the corresponding information entropies. These mathematical expressions are evaluated with 5-fold cross validation test. The results of numerical simulations show that the mathematical features consisted of amino acid composition, fractal dimension and information entropies of amino acid and chaos game representation achieve the best performance. Its accuracy is 0.8157, and Matthew's correlation coefficient (MCC) achieves 0.5968 on the benchmark dataset from DNA-Prot. By analyzing the components of top combination of the nine candidate features, the concepts of fractal dimension and information entropy are the effective and vital features, which can provide complementary sequence-order information on the basis of amino acid composition.

  7. Quantitative predictions of binding free energy changes in drug-resistant influenza neuraminidase.

    Directory of Open Access Journals (Sweden)

    Daniel R Ripoll

    Full Text Available Quantitatively predicting changes in drug sensitivity associated with residue mutations is a major challenge in structural biology. By expanding the limits of free energy calculations, we successfully identified mutations in influenza neuraminidase (NA that confer drug resistance to two antiviral drugs, zanamivir and oseltamivir. We augmented molecular dynamics (MD with Hamiltonian Replica Exchange and calculated binding free energy changes for H274Y, N294S, and Y252H mutants. Based on experimental data, our calculations achieved high accuracy and precision compared with results from established computational methods. Analysis of 15 micros of aggregated MD trajectories provided insights into the molecular mechanisms underlying drug resistance that are at odds with current interpretations of the crystallographic data. Contrary to the notion that resistance is caused by mutant-induced changes in hydrophobicity of the binding pocket, our simulations showed that drug resistance mutations in NA led to subtle rearrangements in the protein structure and its dynamics that together alter the active-site electrostatic environment and modulate inhibitor binding. Importantly, different mutations confer resistance through different conformational changes, suggesting that a generalized mechanism for NA drug resistance is unlikely.

  8. Diverse modes of binding in structures of Leishmania majorN-myristoyltransferase with selective inhibitors

    Directory of Open Access Journals (Sweden)

    James A. Brannigan

    2014-07-01

    Full Text Available The leishmaniases are a spectrum of global diseases of poverty associated with immune dysfunction and are the cause of high morbidity. Despite the long history of these diseases, no effective vaccine is available and the currently used drugs are variously compromised by moderate efficacy, complex side effects and the emergence of resistance. It is therefore widely accepted that new therapies are needed. N-Myristoyltransferase (NMT has been validated pre-clinically as a target for the treatment of fungal and parasitic infections. In a previously reported high-throughput screening program, a number of hit compounds with activity against NMT from Leishmania donovani have been identified. Here, high-resolution crystal structures of representative compounds from four hit series in ternary complexes with myristoyl-CoA and NMT from the closely related L. major are reported. The structures reveal that the inhibitors associate with the peptide-binding groove at a site adjacent to the bound myristoyl-CoA and the catalytic α-carboxylate of Leu421. Each inhibitor makes extensive apolar contacts as well as a small number of polar contacts with the protein. Remarkably, the compounds exploit different features of the peptide-binding groove and collectively occupy a substantial volume of this pocket, suggesting that there is potential for the design of chimaeric inhibitors with significantly enhanced binding. Despite the high conservation of the active sites of the parasite and human NMTs, the inhibitors act selectively over the host enzyme. The role of conformational flexibility in the side chain of Tyr217 in conferring selectivity is discussed.

  9. Default Mode Network Activity Predicts Early Memory Decline in Healthy Young Adults Aged 18-31.

    Science.gov (United States)

    Nelson, Steven M; Savalia, Neil K; Fishell, Andrew K; Gilmore, Adrian W; Zou, Fan; Balota, David A; McDermott, Kathleen B

    2016-08-01

    Functional magnetic resonance imaging (fMRI) research conducted in healthy young adults is typically done with the assumption that this sample is largely homogeneous. However, studies from cognitive psychology suggest that long-term memory and attentional control begin to diminish in the third decade of life. Here, 100 participants between the ages of 18 and 31 learned Lithuanian translations of English words in an individual differences study using fMRI. Long-term memory ability was operationalized for each participant by deriving a memory score from 3 convergent measures. Age of participant predicted memory score in this cohort. In addition, degree of deactivation during initial encoding in a set of regions occurring largely in the default mode network (DMN) predicted both age and memory score. The current study demonstrates that early memory decline may partially be accounted for by failure to modulate activity in the DMN.

  10. Advances and applications of binding affinity prediction methods in drug discovery.

    Science.gov (United States)

    Parenti, Marco Daniele; Rastelli, Giulio

    2012-01-01

    Nowadays, the improvement of R&D productivity is the primary commitment in pharmaceutical research, both in big pharma and smaller biotech companies. To reduce costs, to speed up the discovery process and to increase the chance of success, advanced methods of rational drug design are very helpful, as demonstrated by several successful applications. Among these, computational methods able to predict the binding affinity of small molecules to specific biological targets are of special interest because they can accelerate the discovery of new hit compounds. Here we provide an overview of the most widely used methods in the field of binding affinity prediction, as well as of our own work in developing BEAR, an innovative methodology specifically devised to overtake some limitations in existing approaches. The BEAR method was successfully validated against different biological targets, and proved its efficacy in retrieving active compounds from virtual screening campaigns. The results obtained so far indicate that BEAR may become a leading tool in the drug discovery pipeline. We primarily discuss advantages and drawbacks of each technique and show relevant examples and applications in drug discovery.

  11. Proteochemometric model for predicting the inhibition of penicillin-binding proteins

    Science.gov (United States)

    Nabu, Sunanta; Nantasenamat, Chanin; Owasirikul, Wiwat; Lawung, Ratana; Isarankura-Na-Ayudhya, Chartchalerm; Lapins, Maris; Wikberg, Jarl E. S.; Prachayasittikul, Virapong

    2015-02-01

    Neisseria gonorrhoeae infection threatens to become an untreatable sexually transmitted disease in the near future owing to the increasing emergence of N. gonorrhoeae strains with reduced susceptibility and resistance to the extended-spectrum cephalosporins (ESCs), i.e. ceftriaxone and cefixime, which are the last remaining option for first-line treatment of gonorrhea. Alteration of the penA gene, encoding penicillin-binding protein 2 (PBP2), is the main mechanism conferring penicillin resistance including reduced susceptibility and resistance to ESCs. To predict and investigate putative amino acid mutations causing β-lactam resistance particularly for ESCs, we applied proteochemometric modeling to generalize N. gonorrhoeae susceptibility data for predicting the interaction of PBP2 with therapeutic β-lactam antibiotics. This was afforded by correlating publicly available data on antimicrobial susceptibility of wild-type and mutant N. gonorrhoeae strains for penicillin-G, cefixime and ceftriaxone with 50 PBP2 protein sequence data using partial least-squares projections to latent structures. The generated model revealed excellent predictability ( R 2 = 0.91, Q 2 = 0.77, Q Ext 2 = 0.78). Moreover, our model identified amino acid mutations in PBP2 with the highest impact on antimicrobial susceptibility and provided information on physicochemical properties of amino acid mutations affecting antimicrobial susceptibility. Our model thus provided insight into the physicochemical basis for resistance development in PBP2 suggesting its use for predicting and monitoring novel PBP2 mutations that may emerge in the future.

  12. Salmonella Enterica Serovar Typhimurium BipA Exhibits Two Distinct Ribosome Binding Modes

    Energy Technology Data Exchange (ETDEWEB)

    deLivron, M.; Robinson, V

    2008-01-01

    BipA is a highly conserved prokaryotic GTPase that functions to influence numerous cellular processes in bacteria. In Escherichia coli and Salmonella enterica serovar Typhimurium, BipA has been implicated in controlling bacterial motility, modulating attachment and effacement processes, and upregulating the expression of virulence genes and is also responsible for avoidance of host defense mechanisms. In addition, BipA is thought to be involved in bacterial stress responses, such as those associated with virulence, temperature, and symbiosis. Thus, BipA is necessary for securing bacterial survival and successful invasion of the host. Steady-state kinetic analysis and pelleting assays were used to assess the GTPase and ribosome-binding properties of S. enterica BipA. Under normal bacterial growth, BipA associates with the ribosome in the GTP-bound state. However, using sucrose density gradients, we demonstrate that the association of BipA and the ribosome is altered under stress conditions in bacteria similar to those experienced during virulence. The data show that this differential binding is brought about by the presence of ppGpp, an alarmone that signals the onset of stress-related events in bacteria.

  13. NN-align. An artificial neural network-based alignment algorithm for MHC class II peptide binding prediction

    Directory of Open Access Journals (Sweden)

    Lund Ole

    2009-09-01

    Full Text Available Abstract Background The major histocompatibility complex (MHC molecule plays a central role in controlling the adaptive immune response to infections. MHC class I molecules present peptides derived from intracellular proteins to cytotoxic T cells, whereas MHC class II molecules stimulate cellular and humoral immunity through presentation of extracellularly derived peptides to helper T cells. Identification of which peptides will bind a given MHC molecule is thus of great importance for the understanding of host-pathogen interactions, and large efforts have been placed in developing algorithms capable of predicting this binding event. Results Here, we present a novel artificial neural network-based method, NN-align that allows for simultaneous identification of the MHC class II binding core and binding affinity. NN-align is trained using a novel training algorithm that allows for correction of bias in the training data due to redundant binding core representation. Incorporation of information about the residues flanking the peptide-binding core is shown to significantly improve the prediction accuracy. The method is evaluated on a large-scale benchmark consisting of six independent data sets covering 14 human MHC class II alleles, and is demonstrated to outperform other state-of-the-art MHC class II prediction methods. Conclusion The NN-align method is competitive with the state-of-the-art MHC class II peptide binding prediction algorithms. The method is publicly available at http://www.cbs.dtu.dk/services/NetMHCII-2.0.

  14. Interaction of the N-(3-Methylpyridin-2-ylamide Derivatives of Flurbiprofen and Ibuprofen with FAAH: Enantiomeric Selectivity and Binding Mode.

    Directory of Open Access Journals (Sweden)

    Jessica Karlsson

    Full Text Available Combined fatty acid amide hydrolase (FAAH and cyclooxygenase (COX inhibition is a promising approach for pain-relief. The Flu-AM1 and Ibu-AM5 derivatives of flurbiprofen and ibuprofen retain similar COX-inhibitory properties and are more potent inhibitors of FAAH than the parent compounds. However, little is known as to the nature of their interaction with FAAH, or to the importance of their chirality. This has been explored here.FAAH inhibitory activity was measured in rat brain homogenates and in lysates expressing either wild-type or FAAH(T488A-mutated enzyme. Molecular modelling was undertaken using both docking and molecular dynamics. The (R- and (S-enantiomers of Flu-AM1 inhibited rat FAAH with similar potencies (IC50 values of 0.74 and 0.99 μM, respectively, whereas the (S-enantiomer of Ibu-AM5 (IC50 0.59 μM was more potent than the (R-enantiomer (IC50 5.7 μM. Multiple inhibition experiments indicated that both (R-Flu-AM1 and (S-Ibu-AM5 inhibited FAAH in a manner mutually exclusive to carprofen. Computational studies indicated that the binding site for the Flu-AM1 and Ibu-AM5 enantiomers was located between the acyl chain binding channel and the membrane access channel, in a site overlapping the carprofen binding site, and showed a binding mode in line with that proposed for carprofen and other non-covalent ligands. The potency of (R-Flu-AM1 was lower towards lysates expressing FAAH mutated at the proposed carprofen binding area than in lysates expressing wild-type FAAH.The study provides kinetic and structural evidence that the enantiomers of Flu-AM1 and Ibu-AM5 bind in the substrate channel of FAAH. This information will be useful in aiding the design of novel dual-action FAAH: COX inhibitors.

  15. Mode-locking neurodynamics predict human auditory brainstem responses to musical intervals.

    Science.gov (United States)

    Lerud, Karl D; Almonte, Felix V; Kim, Ji Chul; Large, Edward W

    2014-02-01

    The auditory nervous system is highly nonlinear. Some nonlinear responses arise through active processes in the cochlea, while others may arise in neural populations of the cochlear nucleus, inferior colliculus and higher auditory areas. In humans, auditory brainstem recordings reveal nonlinear population responses to combinations of pure tones, and to musical intervals composed of complex tones. Yet the biophysical origin of central auditory nonlinearities, their signal processing properties, and their relationship to auditory perception remain largely unknown. Both stimulus components and nonlinear resonances are well represented in auditory brainstem nuclei due to neural phase-locking. Recently mode-locking, a generalization of phase-locking that implies an intrinsically nonlinear processing of sound, has been observed in mammalian auditory brainstem nuclei. Here we show that a canonical model of mode-locked neural oscillation predicts the complex nonlinear population responses to musical intervals that have been observed in the human brainstem. The model makes predictions about auditory signal processing and perception that are different from traditional delay-based models, and may provide insight into the nature of auditory population responses. We anticipate that the application of dynamical systems analysis will provide the starting point for generic models of auditory population dynamics, and lead to a deeper understanding of nonlinear auditory signal processing possibly arising in excitatory-inhibitory networks of the central auditory nervous system. This approach has the potential to link neural dynamics with the perception of pitch, music, and speech, and lead to dynamical models of auditory system development.

  16. Binding mode of an α-amino acid-linked quinoxaline-2,3-dione analogue at glutamate receptor subtype GluK1.

    Science.gov (United States)

    Demmer, Charles S; Møller, Charlotte; Brown, Patricia M G E; Han, Liwei; Pickering, Darryl S; Nielsen, Birgitte; Bowie, Derek; Frydenvang, Karla; Kastrup, Jette S; Bunch, Lennart

    2015-06-17

    Two α-amino acid-functionalized quinoxalines, 1a (CNG-10301) and 1b (CNG-10300), of a quinoxaline moiety coupled to an amino acid moiety were designed, synthesized, and characterized pharmacologically. While 1a displayed low affinity at native AMPA, KA, and NMDA receptors, and at homomeric GluK1,3 receptors, the affinity for GluK2 was in the midmicromolar range (Ki = 136 μM), 1b displayed low to midmicromolar range binding affinity at all the iGluRs (Ki = 9-126 μM). In functional experiments (outside-out patches excised from transfected HEK293T cells), 100 μM 1a partially blocked GluK1 (33% peak response), while GluK2 was unaffected (96% peak response). Furthermore, 1a was shown not to be an agonist at GluK1 and GluK2 at 100 μM. On the other hand, 100 μM 1b fully antagonized GluK1 (8% peak response) but only partially blocked GluK2 (33% peak response). An X-ray structure at 2.3 Å resolution of 1b in the GluK1-LBD (ligand-binding domain) disclosed an unexpected binding mode compared to the predictions made during the design phase; the quinoxaline moiety remains to act as an amino acid bioisostere, but the amino acid moiety is oriented into a new area within the GluK1 receptor. The structure of the GluK1-LBD with 1b showed a large variation in domain openings of the three molecules from 25° to 49°, demonstrating that the GluK1-LBD is capable of undergoing major domain movements.

  17. Quantitative predictions of peptide binding to MHC class I molecules using specificity matrices and anchor-stratified calibrations

    DEFF Research Database (Denmark)

    Lauemøller, S L; Holm, A; Hilden, J;

    2001-01-01

    predictions, we have measured the MHC class I binding of a large number of peptides. In an attempt to further improve predictions and to include sequence dependency, we subdivided the panel of peptides according to whether the peptides had zero, one or two primary anchor residues. This allowed us to define......Peptides are key immune targets. They are generated by fragmentation of antigenic proteins, selected by major histocompatibility complex (MHC) molecules and subsequently presented to T cells. One of the most selective requirements is that of peptide binding to MHC. Accurate descriptions...... and predictions of peptide-MHC interactions are therefore important. Quantitative matrices representing MHC class I specificity can be used to search any query protein for the presence of MHC binding peptides. Assuming that each peptide residue contributes to binding in an additive and sequence independent manner...

  18. Predicting copper-, iron- and zinc-binding proteins in pathogenic species of the Paracoccidioides genus

    Directory of Open Access Journals (Sweden)

    Gabriel B Tristao

    2015-01-01

    Full Text Available Approximately one-third of all proteins have been estimated to contain at least one metal cofactor, and these proteins are referred to as metalloproteins. These represent one of the most diverse classes of proteins, containing metal ions that bind to specific sites to perform catalytic, regulatory and structural functions. Bioinformatic tools have been developed to predict metalloproteins encoded by an organism based only on its genome sequence. Its function and the type of metal binder can also be predicted via a bioinformatics approach. Paracoccidioides complex includes termodimorphic pathogenic fungi that are found as saprobic mycelia in the environment and as yeast, the parasitic form, in host tissues. They are the etiologic agents of Paracoccidioidomycosis, a prevalent systemic mycosis in Latin America. Many metalloproteins are important for the virulence of several pathogenic microorganisms. Accordingly, the present work aimed to predict the cooper, iron and zinc proteins encoded by the genomes of three phylogenetic species of Paracoccidioides (Pb01, Pb03 and Pb18. The metalloproteins were identified using bioinformatics approaches based on structure, annotation and domains. Cu-, Fe- and Zn-binding proteins represent 7% of the total proteins encoded by Paracoccidioides spp. genomes. Zinc proteins were the most abundant metalloproteins, representing 5.7% of the fungus proteome, whereas copper and iron proteins represent 0.3% and 1.2%, respectively. Functional classification revealed that metalloproteins are related to many cellular processes. Furthermore, it was observed that many of these metalloproteins serve as virulence factors in the biology of the fungus. Thus, it is concluded that the Cu, Fe and Zn metalloproteomes of the Paracoccidioides spp. are of the utmost importance for the biology and virulence of these particular human pathogens.

  19. On the binding mode of urease active site inhibitors: A density functional study

    Science.gov (United States)

    Leopoldini, M.; Marino, T.; Russo, N.; Toscano, M.

    The way with which boric acid, a rapid reversible competitive inhibitor, binds the urease active site was explored at density functional B3LYP level of theory. The catalytic core of the enzyme was simulated by two models of different size. In both cases, amino acid residues belonging to the inner and to the outer coordination spheres of nickel ions were replaced by smaller molecular species. Contrary to the experimental indication that attributes the inhibitory ability of this acid to the lack of a nucleophilic attack by the enzyme to the boron atom, we instead found that another possibility exists based on the presence of a strong covalent sigma bond between boron and urease that we think can be hardly broken to allow any course of the reaction.

  20. Structural combination of established 5-HT(2A) receptor ligands: new aspects of the binding mode

    DEFF Research Database (Denmark)

    Kramer, Vasko; Herth, Matthias M; Santini, Martin A;

    2010-01-01

    MH.MZ, MDL 100907, and altanserin are structurally similar 4-benzoyl-piperidine derivatives and are well accommodated to receptor interaction models. We combined structural elements of different high-affinity and selective 5-HT(2A) antagonists, as MH.MZ, altanserin, and SR 46349B, to improve......) with a moderate affinity toward the 5-HT(2A) receptor (K(i) = 57 nm). The remarkably reduced affinity of other compounds (4a), (4b), and (4c) (K(i) = 411, 360 and 356 nm respectively) indicates that MH.MZ can only bind to the 5-HT(2A) receptor with the p-fluorophenylethyl residue in a sterically restricted...

  1. Sensitive quantitative predictions of peptide-MHC binding by a 'Query by Committee' artificial neural network approach

    DEFF Research Database (Denmark)

    Buus, S.; Lauemoller, S.L.; Worning, Peder;

    2003-01-01

    We have generated Artificial Neural Networks (ANN) capable of performing sensitive, quantitative predictions of peptide binding to the MHC class I molecule, HLA-A*0204. We have shown that such quantitative ANN are superior to conventional classification ANN, that have been trained to predict...

  2. Bayesian probabilistic model for life prediction and fault mode classification of solid state luminaires

    Energy Technology Data Exchange (ETDEWEB)

    Lall, Pradeep [Auburn Univ., Auburn, AL (United States); Wei, Junchao [Auburn Univ., Auburn, AL (United States); Sakalaukus, Peter [Auburn Univ., Auburn, AL (United States)

    2014-06-22

    A new method has been developed for assessment of the onset of degradation in solid state luminaires to classify failure mechanisms by using metrics beyond lumen degradation that are currently used for identification of failure. Luminous Flux output, Correlated Color Temperature Data on Philips LED Lamps has been gathered under 85°C/85%RH till lamp failure. Failure modes of the test population of the lamps have been studied to understand the failure mechanisms in 85°C/85%RH accelerated test. Results indicate that the dominant failure mechanism is the discoloration of the LED encapsulant inside the lamps which is the likely cause for the luminous flux degradation and the color shift. The acquired data has been used in conjunction with Bayesian Probabilistic Models to identify luminaires with onset of degradation much prior to failure through identification of decision boundaries between lamps with accrued damage and lamps beyond the failure threshold in the feature space. In addition luminaires with different failure modes have been classified separately from healthy pristine luminaires. The α-λ plots have been used to evaluate the robustness of the proposed methodology. Results show that the predicted degradation for the lamps tracks the true degradation observed during 85°C/85%RH during accelerated life test fairly closely within the ±20% confidence bounds. Correlation of model prediction with experimental results indicates that the presented methodology allows the early identification of the onset of failure much prior to development of complete failure distributions and can be used for assessing the damage state of SSLs in fairly large deployments. It is expected that, the new prediction technique will allow the development of failure distributions without testing till L70 life for the manifestation of failure.

  3. Thermodynamics and binding mode of novel structurally related 1,2,4-thiadiazole derivatives with native and modified cyclodextrins

    Science.gov (United States)

    Terekhova, Irina V.; Chislov, Mikhail V.; Brusnikina, Maria A.; Chibunova, Ekaterina S.; Volkova, Tatyana V.; Zvereva, Irina A.; Proshin, Alexey N.

    2017-03-01

    Study of complex formation of cyclodextrins with 1,2,4-thiadiazole derivatives intended for Alzheimer's disease treatment was carried out using 1H NMR, ITC and phase solubility methods. Structure of cyclodextrins and thiadiazoles affects the binding mode and thermodynamics of complexation. The larger cavity of β- and γ-cyclodextrins is more appropriate for deeper insertion of 1,2,4-thiadiazole derivatives which is accompanied by intensive dehydration and solvent reorganization. Benzene ring of the thiadiazoles is located inside macrocyclic cavity while piperidine ring is placed outside the cavity and can form H-bonds with cyclodextrin exterior. Complexation with cyclodextrins induces the enhancement of aqueous solubility of 1,2,4-thiadiazole derivatives.

  4. Prediction of MHC class II binding affinity using SMM-align, a novel stabilization matrix alignment method

    Directory of Open Access Journals (Sweden)

    Lund Ole

    2007-07-01

    Full Text Available Abstract Background Antigen presenting cells (APCs sample the extra cellular space and present peptides from here to T helper cells, which can be activated if the peptides are of foreign origin. The peptides are presented on the surface of the cells in complex with major histocompatibility class II (MHC II molecules. Identification of peptides that bind MHC II molecules is thus a key step in rational vaccine design and developing methods for accurate prediction of the peptide:MHC interactions play a central role in epitope discovery. The MHC class II binding groove is open at both ends making the correct alignment of a peptide in the binding groove a crucial part of identifying the core of an MHC class II binding motif. Here, we present a novel stabilization matrix alignment method, SMM-align, that allows for direct prediction of peptide:MHC binding affinities. The predictive performance of the method is validated on a large MHC class II benchmark data set covering 14 HLA-DR (human MHC and three mouse H2-IA alleles. Results The predictive performance of the SMM-align method was demonstrated to be superior to that of the Gibbs sampler, TEPITOPE, SVRMHC, and MHCpred methods. Cross validation between peptide data set obtained from different sources demonstrated that direct incorporation of peptide length potentially results in over-fitting of the binding prediction method. Focusing on amino terminal peptide flanking residues (PFR, we demonstrate a consistent gain in predictive performance by favoring binding registers with a minimum PFR length of two amino acids. Visualizing the binding motif as obtained by the SMM-align and TEPITOPE methods highlights a series of fundamental discrepancies between the two predicted motifs. For the DRB1*1302 allele for instance, the TEPITOPE method favors basic amino acids at most anchor positions, whereas the SMM-align method identifies a preference for hydrophobic or neutral amino acids at the anchors. Conclusion

  5. Molecular dynamics simulation of tryptophan hydroxylase-1: binding modes and free energy analysis to phenylalanine derivative inhibitors.

    Science.gov (United States)

    Zhong, Hao; Huang, Wei; He, Gu; Peng, Cheng; Wu, Fengbo; Ouyang, Liang

    2013-05-10

    Serotonin is a neurotransmitter that modulates many central and peripheral functions. Tryptophan hydroxylase-1 (TPH1) is a key enzyme of serotonin synthesis. In the current study, the interaction mechanism of phenylalanine derivative TPH1 inhibitors was investigated using molecular dynamics (MD) simulations, free energy calculations, free energy decomposition analysis and computational alanine scanning. The predicted binding free energies of these complexes are consistent with the experimental data. The analysis of the individual energy terms indicates that although the van der Waals and electrostatics interaction contributions are important in distinguishing the binding affinities of these inhibitors, the electrostatic contribution plays a more crucial role in that. Moreover, it is observed that different configurations of the naphthalene substituent could form different binding patterns with protein, yet lead to similar inhibitory potency. The combination of different molecular modeling techniques is an efficient way to interpret the interaction mechanism of inhibitors and our work could provide valuable information for the TPH1 inhibitor design in the future.

  6. Molecular Dynamics Simulation of Tryptophan Hydroxylase-1: Binding Modes and Free Energy Analysis to Phenylalanine Derivative Inhibitors

    Directory of Open Access Journals (Sweden)

    Liang Ouyang

    2013-05-01

    Full Text Available Serotonin is a neurotransmitter that modulates many central and peripheral functions. Tryptophan hydroxylase-1 (TPH1 is a key enzyme of serotonin synthesis. In the current study, the interaction mechanism of phenylalanine derivative TPH1 inhibitors was investigated using molecular dynamics (MD simulations, free energy calculations, free energy decomposition analysis and computational alanine scanning. The predicted binding free energies of these complexes are consistent with the experimental data. The analysis of the individual energy terms indicates that although the van der Waals and electrostatics interaction contributions are important in distinguishing the binding affinities of these inhibitors, the electrostatic contribution plays a more crucial role in that. Moreover, it is observed that different configurations of the naphthalene substituent could form different binding patterns with protein, yet lead to similar inhibitory potency. The combination of different molecular modeling techniques is an efficient way to interpret the interaction mechanism of inhibitors and our work could provide valuable information for the TPH1 inhibitor design in the future.

  7. Fast Prediction of Differential Mode Noise Input Filter Requirements for FLyback and Boost Unity Power Factor Converters

    DEFF Research Database (Denmark)

    Andersen, Michael Andreas E.

    1997-01-01

    Two new and simple methods to make predictions of the differential mode (DM) input filter requirements are presented, one for flyback and one for boost unity power factor converters. They have been verified by measurements. They give the designer the ability to predict the DM input noise filter...

  8. Co-solvation effect on the binding mode of the α-mangostin/β-cyclodextrin inclusion complex

    Directory of Open Access Journals (Sweden)

    Chompoonut Rungnim

    2015-11-01

    Full Text Available Cyclodextrins (CDs have been extensively utilized as host molecules to enhance the solubility, stability and bioavailability of hydrophobic drug molecules through the formation of inclusion complexes. It was previously reported that the use of co-solvents in such studies may result in ternary (host:guest:co-solvent complex formation. The objective of this work was to investigate the effect of ethanol as a co-solvent on the inclusion complex formation between α-mangostin (α-MGS and β-CD, using both experimental and theoretical studies. Experimental phase-solubility studies were carried out in order to assess complex formation, with the mechanism of association being probed using a mathematical model. It was found that α-MGS was poorly soluble at low ethanol concentrations (0–10% v/v, but higher concentrations (10–40% v/v resulted in better α-MGS solubility at all β-CD concentrations studied (0–10 mM. From the equilibrium constant calculation, the inclusion complex is still a binary complex (1:1, even in the presence of ethanol. The results from our theoretical study confirm that the binding mode is binary complex and the presence of ethanol as co-solvent enhances the solubility of α-MGS with some effects on the binding affinity with β-CD, depending on the concentration employed.

  9. Evolutionary Limitation and Opportunities for Developing tRNA Synthetase Inhibitors with 5-Binding-Mode Classification

    Directory of Open Access Journals (Sweden)

    Pengfei Fang

    2015-12-01

    Full Text Available Aminoacyl-tRNA synthetases (aaRSs are enzymes that catalyze the transfer of amino acids to their cognate tRNAs as building blocks for translation. Each of the aaRS families plays a pivotal role in protein biosynthesis and is indispensable for cell growth and survival. In addition, aaRSs in higher species have evolved important non-translational functions. These translational and non-translational functions of aaRS are attractive for developing antibacterial, antifungal, and antiparasitic agents and for treating other human diseases. The interplay between amino acids, tRNA, ATP, EF-Tu and non-canonical binding partners, had shaped each family with distinct pattern of key sites for regulation, with characters varying among species across the path of evolution. These sporadic variations in the aaRSs offer great opportunity to target these essential enzymes for therapy. Up to this day, growing numbers of aaRS inhibitors have been discovered and developed. Here, we summarize the latest developments and structural studies of aaRS inhibitors, and classify them with distinct binding modes into five categories.

  10. Chinese Stock Index Futures Price Fluctuation Analysis and Prediction Based on Complementary Ensemble Empirical Mode Decomposition

    Directory of Open Access Journals (Sweden)

    Ruoyang Chen

    2016-01-01

    Full Text Available Since the CSI 300 index futures officially began trading on April 15, 2010, analysis and predictions of the price fluctuations of Chinese stock index futures prices have become a popular area of active research. In this paper, the Complementary Ensemble Empirical Mode Decomposition (CEEMD method is used to decompose the sequences of Chinese stock index futures prices into residue terms, low-frequency terms, and high-frequency terms to reveal the fluctuation characteristics over different time scales of the sequences. Then, the CEEMD method is combined with the Particle Swarm Optimization (PSO algorithm-based Support Vector Machine (SVM model to forecast Chinese stock index futures prices. The empirical results show that the residue term determines the long-term trend of stock index futures prices. The low-frequency term, which represents medium-term price fluctuations, is mainly affected by policy regulations under the analysis of the Iterated Cumulative Sums of Squares (ICSS algorithm, whereas short-term market disequilibrium, which is represented by the high-frequency term, plays an important local role in stock index futures price fluctuations. In addition, in forecasting the daily or even intraday price data of Chinese stock index futures, the combination prediction model is superior to the single SVM model, which implies that the accuracy of predicting Chinese stock index futures prices will be improved by considering fluctuation characteristics in different time scales.

  11. Combined effects of estrogenic chemicals with the same mode of action using an estrogen receptor binding bioassay.

    Science.gov (United States)

    Yang, Rong; Li, Na; Ma, Mei; Wang, Zijian

    2014-11-01

    The increasing amounts of various estrogenic chemicals coexisting in the aquatic environment may pose environmental risks. While the concept of estradiol equivalent (EEQ) has been frequently applied in studying estrogenic mixtures, few experiments have been done to prove its reliability. In this study, the reliability of EEQ and the related model concentration addition (CA) was verified based on the two-hybrid recombinant yeast bioassay when all mixture components had the same mode of action and target of action. Our results showed that the measured estrogenic effects could be well predicted by CA and EEQ for all laboratory-made mixtures using two designs, despite the varying estrogenic activity, concentration levels and ratios of the test chemicals. This suggests that when an appropriate endpoint and its relevant bioassay are chosen, CA should be valid and the application of EEQ in predicting the effect of non-equi-effect mixtures is feasible.

  12. Determination of the binding mode for anti-inflammatory natural product xanthohumol with myeloid differentiation protein 2

    Directory of Open Access Journals (Sweden)

    Fu W

    2016-01-01

    Full Text Available Weitao Fu,1,* Lingfeng Chen,1,* Zhe Wang,1 Chengwei Zhao,1 Gaozhi Chen,1 Xing Liu,1 Yuanrong Dai,2 Yuepiao Cai,1 Chenglong Li,1,3 Jianmin Zhou,1 Guang Liang1 1Chemical Biology Research Center, School of Pharmaceutical Sciences, 2Department of Respiratory Medicine, the Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 3Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Ohio State University, Columbus, OH, USA *These authors contributed equally to this work Abstract: It is recognized that myeloid differentiation protein 2 (MD-2, a coreceptor of toll-like receptor 4 (TLR4 for innate immunity, plays an essential role in activation of the lipopolysaccharide signaling pathway. MD-2 is known as a neoteric and suitable therapeutical target. Therefore, there is great interest in the development of a potent MD-2 inhibitor for anti-inflammatory therapeutics. Several studies have reported that xanthohumol (XN, an anti-inflammatory natural product from hops and beer, can block the TLR4 signaling by binding to MD-2 directly. However, the interaction between MD-2 and XN remains unknown. Herein, our work aims at characterizing interactions between MD-2 and XN. Using a combination of experimental and theoretical modeling analysis, we found that XN can embed into the hydrophobic pocket of MD-2 and form two stable hydrogen bonds with residues ARG-90 and TYR-102 of MD-2. Moreover, we confirmed that ARG-90 and TYR-102 were two necessary residues during the recognition process of XN binding to MD-2. Results from this study identified the atomic interactions between the MD-2 and XN, which will contribute to future structural design of novel MD-2-targeting molecules for the treatment of inflammatory diseases. Keywords: myeloid differentiation 2, xanthohumol, binding mode, inflammation, molecular dynamics simulation 

  13. Electrostatic component of binding energy: Interpreting predictions from poisson-boltzmann equation and modeling protocols.

    Science.gov (United States)

    Chakavorty, Arghya; Li, Lin; Alexov, Emil

    2016-10-30

    Macromolecular interactions are essential for understanding numerous biological processes and are typically characterized by the binding free energy. Important component of the binding free energy is the electrostatics, which is frequently modeled via the solutions of the Poisson-Boltzmann Equations (PBE). However, numerous works have shown that the electrostatic component (ΔΔGelec ) of binding free energy is very sensitive to the parameters used and modeling protocol. This prompted some researchers to question the robustness of PBE in predicting ΔΔGelec . We argue that the sensitivity of the absolute ΔΔGelec calculated with PBE using different input parameters and definitions does not indicate PBE deficiency, rather this is what should be expected. We show how the apparent sensitivity should be interpreted in terms of the underlying changes in several numerous and physical parameters. We demonstrate that PBE approach is robust within each considered force field (CHARMM-27, AMBER-94, and OPLS-AA) once the corresponding structures are energy minimized. This observation holds despite of using two different molecular surface definitions, pointing again that PBE delivers consistent results within particular force field. The fact that PBE delivered ΔΔGelec values may differ if calculated with different modeling protocols is not a deficiency of PBE, but natural results of the differences of the force field parameters and potential functions for energy minimization. In addition, while the absolute ΔΔGelec values calculated with different force field differ, their ordering remains practically the same allowing for consistent ranking despite of the force field used. © 2016 Wiley Periodicals, Inc.

  14. Prediction of binding free energy for adsorption of antimicrobial peptide lactoferricin B on a POPC membrane

    Science.gov (United States)

    Vivcharuk, Victor; Tomberli, Bruno; Tolokh, Igor S.; Gray, C. G.

    2008-03-01

    Molecular dynamics (MD) simulations are used to study the interaction of a zwitterionic palmitoyl-oleoyl-phosphatidylcholine (POPC) bilayer with the cationic antimicrobial peptide bovine lactoferricin (LFCinB) in a 100 mM NaCl solution at 310 K. The interaction of LFCinB with POPC is used as a model system for studying the details of membrane-peptide interactions, with the peptide selected because of its antimicrobial nature. Seventy-two 3 ns MD simulations, with six orientations of LFCinB at 12 different distances from a POPC membrane, are carried out to determine the potential of mean force (PMF) or free energy profile for the peptide as a function of the distance between LFCinB and the membrane surface. To calculate the PMF for this relatively large system a new variant of constrained MD and thermodynamic integration is developed. A simplified method for relating the PMF to the LFCinB-membrane binding free energy is described and used to predict a free energy of adsorption (or binding) of -1.05±0.39kcal/mol , and corresponding maximum binding force of about 20 pN, for LFCinB-POPC. The contributions of the ions-LFCinB and the water-LFCinB interactions to the PMF are discussed. The method developed will be a useful starting point for future work simulating peptides interacting with charged membranes and interactions involved in the penetration of membranes, features necessary to understand in order to rationally design peptides as potential alternatives to traditional antibiotics.

  15. A new mixed-mode model for interpreting and predicting protein elution during isoelectric chromatofocusing.

    Science.gov (United States)

    Choy, Derek Y C; Creagh, A Louise; von Lieres, Eric; Haynes, Charles

    2014-05-01

    Experimental data are combined with classic theories describing electrolytes in solution and at surfaces to define the primary mechanisms influencing protein retention and elution during isoelectric chromatofocusing (ICF) of proteins and protein mixtures. Those fundamental findings are used to derive a new model to understand and predict elution times of proteins during ICF. The model uses a modified form of the steric mass action (SMA) isotherm to account for both ion exchange and isoelectric focusing contributions to protein partitioning. The dependence of partitioning on pH is accounted for through the characteristic charge parameter m of the SMA isotherm and the application of Gouy-Chapman theory to define the dependence of the equilibrium binding constant Kbi on both m and ionic strength. Finally, the effects of changes in matrix surface pH on protein retention are quantified through a Donnan equilibrium type model. By accounting for isoelectric focusing, ion binding and exchange, and surface pH contributions to protein retention and elution, the model is shown to accurately capture the dependence of protein elution times on column operating conditions.

  16. Sequence-based prediction of protein-binding sites in DNA: comparative study of two SVM models.

    Science.gov (United States)

    Park, Byungkyu; Im, Jinyong; Tuvshinjargal, Narankhuu; Lee, Wook; Han, Kyungsook

    2014-11-01

    As many structures of protein-DNA complexes have been known in the past years, several computational methods have been developed to predict DNA-binding sites in proteins. However, its inverse problem (i.e., predicting protein-binding sites in DNA) has received much less attention. One of the reasons is that the differences between the interaction propensities of nucleotides are much smaller than those between amino acids. Another reason is that DNA exhibits less diverse sequence patterns than protein. Therefore, predicting protein-binding DNA nucleotides is much harder than predicting DNA-binding amino acids. We computed the interaction propensity (IP) of nucleotide triplets with amino acids using an extensive dataset of protein-DNA complexes, and developed two support vector machine (SVM) models that predict protein-binding nucleotides from sequence data alone. One SVM model predicts protein-binding nucleotides using DNA sequence data alone, and the other SVM model predicts protein-binding nucleotides using both DNA and protein sequences. In a 10-fold cross-validation with 1519 DNA sequences, the SVM model that uses DNA sequence data only predicted protein-binding nucleotides with an accuracy of 67.0%, an F-measure of 67.1%, and a Matthews correlation coefficient (MCC) of 0.340. With an independent dataset of 181 DNAs that were not used in training, it achieved an accuracy of 66.2%, an F-measure 66.3% and a MCC of 0.324. Another SVM model that uses both DNA and protein sequences achieved an accuracy of 69.6%, an F-measure of 69.6%, and a MCC of 0.383 in a 10-fold cross-validation with 1519 DNA sequences and 859 protein sequences. With an independent dataset of 181 DNAs and 143 proteins, it showed an accuracy of 67.3%, an F-measure of 66.5% and a MCC of 0.329. Both in cross-validation and independent testing, the second SVM model that used both DNA and protein sequence data showed better performance than the first model that used DNA sequence data. To the best of

  17. Machine learning competition in immunology – Prediction of HLA class I binding peptides

    DEFF Research Database (Denmark)

    Zhang, Guang Lan; Ansari, Hifzur Rahman; Bradley, Phil

    2011-01-01

    from pathogens or cancer proteomes involve either reverse immunology or high-throughput mass spectrometry (HTMS). Reverse immunology approaches involve pre-screening of proteomes by computational algorithms, followed by experimental validation of selected targets ( [Mora et al., 2006], [De Groot et al......). Hundreds of naturally processed HLA class I associated peptides have been identified in individual studies using HTMS in normal (Escobar et al., 2008), cancer ( [Antwi et al., 2009] and [Bassani-Sternberg et al., 2010]), autoimmunity-related (Ben Dror et al., 2010), and infected samples (Wahl et al, 2010......). Computational algorithms are essential steps in high-throughput identification of T-cell epitope candidates using both reverse immunology and HTMS approaches. Peptide binding to MHC molecules is the single most selective step in defining T cell epitope and the accuracy of computational algorithms for prediction...

  18. Prediction on the binding domain between human interleukin-6 and its receptor

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Based on the spatial conformations of human interleukin-6 (hIL-6) derived from nuclear magnetic resonance analysis and human interleukin-6 receptor (hIL-6R) modeled with homology modeling method using human growth hormone receptor as template, the interaction between hIL-6 and its receptor (hIL-6R) is studied with docking program according to the surface electrostatic potential analysis and spatial conformation complement. The stable region structure composed of hIL-6 and hIL-6R is obtained on the basis of molecular mechanism optimization and molecular dynamics simulation. The binding domain between hIL-6 and hIL-6R is predicted theoretically. Furthermore, the especial binding sites that influence the interaction between hIL-6 and hIL-6R are confirmed. The results lay a theoretical foundation for confirming the active regions of hIL-6 and designing novel antagonist with computer-guided techniques.

  19. Prediction on the binding domain between human interleukin-6 and its receptor

    Institute of Scientific and Technical Information of China (English)

    冯健男; 任蕴芳; 沈倍奋

    2000-01-01

    Based on the spatial conformations of human interleukin-6 (hlL-6) derived from nuclear magnetic resonance analysis and human interleukin-6 receptor (hlL-6R) modeled with homology modeling method using human growth hormone receptor as template, the interaction between hlL-6 and its receptor (hIL-6R) is studied with docking program according to the surface electrostatic potential analysis and spatial conformation complement. The stable region structure composed of hlL-6 and hlL-6R is obtained on the basis of molecular mechanism optimization and molecular dynamics simulation. The binding domain between hIL-6 and hIL-6R is predicted theoretically. Furthermore, the especial binding sites that influence the interaction between hlL-6 and hlL-6R are confirmed. The results lay a theoretical foundation for confirming the active regions of hlL-6 and designing novel antagonist with computer-guided techniques.

  20. Binding mode analyses and pharmacophore model development for stilbene derivatives as a novel and competitive class of α-glucosidase inhibitors.

    Science.gov (United States)

    Lee, Yuno; Kim, Songmi; Kim, Jun Young; Arooj, Mahreen; Kim, Siu; Hwang, Swan; Kim, Byeong-Woo; Park, Ki Hun; Lee, Keun Woo

    2014-01-01

    Stilbene urea derivatives as a novel and competitive class of non-glycosidic α-glucosidase inhibitors are effective for the treatment of type II diabetes and obesity. The main purposes of our molecular modeling study are to explore the most suitable binding poses of stilbene derivatives with analyzing the binding affinity differences and finally to develop a pharmacophore model which would represents critical features responsible for α-glucosidase inhibitory activity. Three-dimensional structure of S. cerevisiae α-glucosidase was built by homology modeling method and the structure was used for the molecular docking study to find out the initial binding mode of compound 12, which is the most highly active one. The initial structure was subjected to molecular dynamics (MD) simulations for protein structure adjustment at compound 12-bound state. Based on the adjusted conformation, the more reasonable binding modes of the stilbene urea derivatives were obtained from molecular docking and MD simulations. The binding mode of the derivatives was validated by correlation analysis between experimental Ki value and interaction energy. Our results revealed that the binding modes of the potent inhibitors were engaged with important hydrogen bond, hydrophobic, and π-interactions. With the validated compound 12-bound structure obtained from combining approach of docking and MD simulation, a proper four featured pharmacophore model was generated. It was also validated by comparison of fit values with the Ki values. Thus, these results will be helpful for understanding the relationship between binding mode and bioactivity and for designing better inhibitors from stilbene derivatives.

  1. Subordinate regulatory mode and leader power: Interpersonal regulatory complementarity predicts task performance

    NARCIS (Netherlands)

    Hamstra, M.R.W.; Orehek, E.; Holleman, M.

    2014-01-01

    This research examines the implications of locomotion regulatory mode (orientation toward making progress on goals) and assessment regulatory mode (orientation toward critically evaluating alternatives) for employees' performance. Regulatory mode theory suggests that, although these are both integra

  2. Identification of co-regulated genes through Bayesian clustering of predicted regulatory binding sites.

    Science.gov (United States)

    Qin, Zhaohui S; McCue, Lee Ann; Thompson, William; Mayerhofer, Linda; Lawrence, Charles E; Liu, Jun S

    2003-04-01

    The identification of co-regulated genes and their transcription-factor binding sites (TFBS) are key steps toward understanding transcription regulation. In addition to effective laboratory assays, various computational approaches for the detection of TFBS in promoter regions of coexpressed genes have been developed. The availability of complete genome sequences combined with the likelihood that transcription factors and their cognate sites are often conserved during evolution has led to the development of phylogenetic footprinting. The modus operandi of this technique is to search for conserved motifs upstream of orthologous genes from closely related species. The method can identify hundreds of TFBS without prior knowledge of co-regulation or coexpression. Because many of these predicted sites are likely to be bound by the same transcription factor, motifs with similar patterns can be put into clusters so as to infer the sets of co-regulated genes, that is, the regulons. This strategy utilizes only genome sequence information and is complementary to and confirmative of gene expression data generated by microarray experiments. However, the limited data available to characterize individual binding patterns, the variation in motif alignment, motif width, and base conservation, and the lack of knowledge of the number and sizes of regulons make this inference problem difficult. We have developed a Gibbs sampling-based Bayesian motif clustering (BMC) algorithm to address these challenges. Tests on simulated data sets show that BMC produces many fewer errors than hierarchical and K-means clustering methods. The application of BMC to hundreds of predicted gamma-proteobacterial motifs correctly identified many experimentally reported regulons, inferred the existence of previously unreported members of these regulons, and suggested novel regulons.

  3. Identical phosphatase mechanisms achieved through distinct modes of binding phosphoprotein substrate

    Energy Technology Data Exchange (ETDEWEB)

    Pazy, Y.; Motaleb, M.A.; Guarnieri, M.T.; Charon, N.W.; Zhao, R.; Silversmith, R.E. (WVU); (UNC); (Colorado); (EC Uni.)

    2010-04-05

    Two-component signal transduction systems are widespread in prokaryotes and control numerous cellular processes. Extensive investigation of sensor kinase and response regulator proteins from many two-component systems has established conserved sequence, structural, and mechanistic features within each family. In contrast, the phosphatases which catalyze hydrolysis of the response regulator phosphoryl group to terminate signal transduction are poorly understood. Here we present structural and functional characterization of a representative of the CheC/CheX/FliY phosphatase family. The X-ray crystal structure of Borrelia burgdorferi CheX complexed with its CheY3 substrate and the phosphoryl analogue BeF{sub 3}{sup -} reveals a binding orientation between a response regulator and an auxiliary protein different from that shared by every previously characterized example. The surface of CheY3 containing the phosphoryl group interacts directly with a long helix of CheX which bears the conserved (E - X{sub 2} - N) motif. Conserved CheX residues Glu96 and Asn99, separated by a single helical turn, insert into the CheY3 active site. Structural and functional data indicate that CheX Asn99 and CheY3 Thr81 orient a water molecule for hydrolytic attack. The catalytic residues of the CheX-CheY3 complex are virtually superimposable on those of the Escherichia coli CheZ phosphatase complexed with CheY, even though the active site helices of CheX and CheZ are oriented nearly perpendicular to one other. Thus, evolution has found two structural solutions to achieve the same catalytic mechanism through different helical spacing and side chain lengths of the conserved acid/amide residues in CheX and CheZ.

  4. Substrate Binding Mode and its Implication on Drug Design for Botulinum Neurotoxin A

    Energy Technology Data Exchange (ETDEWEB)

    Kumaran, D.; Rawat, R; Ahmed, A; Swaminathan, S

    2008-01-01

    The seven antigenically distinct serotypes of Clostridium botulinum neurotoxins, the causative agents of botulism, block the neurotransmitter release by specifically cleaving one of the three SNARE proteins and induce flaccid paralysis. The Centers for Disease Control and Prevention (CDC) has declared them as Category A biowarfare agents. The most potent among them, botulinum neurotoxin type A (BoNT/A), cleaves its substrate synaptosome-associated protein of 25 kDa (SNAP-25). An efficient drug for botulism can be developed only with the knowledge of interactions between the substrate and enzyme at the active site. Here, we report the crystal structures of the catalytic domain of BoNT/A with its uncleavable SNAP-25 peptide 197QRATKM202 and its variant 197RRATKM202 to 1.5 A and 1.6 A, respectively. This is the first time the structure of an uncleavable substrate bound to an active botulinum neurotoxin is reported and it has helped in unequivocally defining S1 to S5? sites. These substrate peptides make interactions with the enzyme predominantly by the residues from 160, 200, 250 and 370 loops. Most notably, the amino nitrogen and carbonyl oxygen of P1 residue (Gln197) chelate the zinc ion and replace the nucleophilic water. The P1?-Arg198, occupies the S1? site formed by Arg363, Thr220, Asp370, Thr215, Ile161, Phe163 and Phe194. The S2? subsite is formed by Arg363, Asn368 and Asp370, while S3? subsite is formed by Tyr251, Leu256, Val258, Tyr366, Phe369 and Asn388. P4?-Lys201 makes hydrogen bond with Gln162. P5?-Met202 binds in the hydrophobic pocket formed by the residues from the 250 and 200 loop. Knowledge of interactions between the enzyme and substrate peptide from these complex structures should form the basis for design of potent inhibitors for this neurotoxin.

  5. Substrate binding mode and its implication on drug design for botulinum neurotoxin A.

    Directory of Open Access Journals (Sweden)

    Desigan Kumaran

    Full Text Available The seven antigenically distinct serotypes of Clostridium botulinum neurotoxins, the causative agents of botulism, block the neurotransmitter release by specifically cleaving one of the three SNARE proteins and induce flaccid paralysis. The Centers for Disease Control and Prevention (CDC has declared them as Category A biowarfare agents. The most potent among them, botulinum neurotoxin type A (BoNT/A, cleaves its substrate synaptosome-associated protein of 25 kDa (SNAP-25. An efficient drug for botulism can be developed only with the knowledge of interactions between the substrate and enzyme at the active site. Here, we report the crystal structures of the catalytic domain of BoNT/A with its uncleavable SNAP-25 peptide (197QRATKM(202 and its variant (197RRATKM(202 to 1.5 A and 1.6 A, respectively. This is the first time the structure of an uncleavable substrate bound to an active botulinum neurotoxin is reported and it has helped in unequivocally defining S1 to S5' sites. These substrate peptides make interactions with the enzyme predominantly by the residues from 160, 200, 250 and 370 loops. Most notably, the amino nitrogen and carbonyl oxygen of P1 residue (Gln197 chelate the zinc ion and replace the nucleophilic water. The P1'-Arg198, occupies the S1' site formed by Arg363, Thr220, Asp370, Thr215, Ile161, Phe163 and Phe194. The S2' subsite is formed by Arg363, Asn368 and Asp370, while S3' subsite is formed by Tyr251, Leu256, Val258, Tyr366, Phe369 and Asn388. P4'-Lys201 makes hydrogen bond with Gln162. P5'-Met202 binds in the hydrophobic pocket formed by the residues from the 250 and 200 loop. Knowledge of interactions between the enzyme and substrate peptide from these complex structures should form the basis for design of potent inhibitors for this neurotoxin.

  6. The versatile binding mode of transition-state analogue inhibitors of tyrosinase towards dicopper(II) model complexes: experimental and theoretical investigations.

    Science.gov (United States)

    Orio, Maylis; Bochot, Constance; Dubois, Carole; Gellon, Gisèle; Hardré, Renaud; Jamet, Hélène; Luneau, Dominique; Philouze, Christian; Réglier, Marius; Serratrice, Guy; Belle, Catherine

    2011-11-25

    We describe 2-mercaptopyridine-N-oxide (HSPNO) as a new and efficient competitive inhibitor of mushroom tyrosinase (K(IC) =3.7 μM). Binding studies of HSPNO and 2-hydroxypyridine-N-oxide (HOPNO) on dinuclear copper(II) complexes [Cu(2)(BPMP)(μ-OH)](ClO(4))(2) (1; HBPMP=2,6-bis[bis(2-pyridylmethyl)aminomethyl]-4-methylphenol) and [Cu(2)(BPEP)(μ-OH)](ClO(4))(2)) (2; HBPEP=2,6-bis{bis[2-(2-pyridyl)ethyl]aminomethyl}-4-methylphenol), known to be functional models for the tyrosinase diphenolase activity, have been performed. A combination of structural data, spectroscopic studies, and DFT calculations evidenced the adaptable binding mode (bridging versus chelating) of HOPNO in relation to the geometry and chelate size of the dicopper center. For comparison, binding studies of HSPNO and kojic acid (5-hydroxy-2-(hydroxymethyl)-4-pyrone) on dinuclear complexes were performed. A theoretical approach has been developed and validated on HOPNO adducts to compare the binding mode on the model complexes. It has been applied for HSPNO and kojic acid. Although results for HSPNO were in line with those obtained with HOPNO, thus reflecting their chemical similarity, we showed that the bridging mode was the most preferential binding mode for kojic acid on both complexes.

  7. Prediction of radial breathing-like modes of double-walled carbon nanotubes with arbitrary chirality

    Energy Technology Data Exchange (ETDEWEB)

    Ghavanloo, Esmaeal, E-mail: ghavanloo@shirazu.ac.ir; Fazelzadeh, S. Ahmad

    2014-10-15

    The radial breathing-like modes (RBLMs) of double-walled carbon nanotubes (DWCNTs) with arbitrary chirality are investigated by a simple analytical model. For this purpose, DWCNT is considered as double concentric elastic thin cylindrical shells, which are coupled through van der Waals (vdW) forces between two adjacent tubes. Lennard-Jones potential and a molecular mechanics model are used to calculate the vdW forces and to predict the mechanical properties, respectively. The validity of these theoretical results is confirmed through the comparison of the experimental results. Finally, a new approach is proposed to determine the diameters and the chiral indices of the inner and outer tubes of the DWCNTs with high precision.

  8. Prediction of radial breathing-like modes of double-walled carbon nanotubes with arbitrary chirality

    Science.gov (United States)

    Ghavanloo, Esmaeal; Fazelzadeh, S. Ahmad

    2014-10-01

    The radial breathing-like modes (RBLMs) of double-walled carbon nanotubes (DWCNTs) with arbitrary chirality are investigated by a simple analytical model. For this purpose, DWCNT is considered as double concentric elastic thin cylindrical shells, which are coupled through van der Waals (vdW) forces between two adjacent tubes. Lennard-Jones potential and a molecular mechanics model are used to calculate the vdW forces and to predict the mechanical properties, respectively. The validity of these theoretical results is confirmed through the comparison of the experimental results. Finally, a new approach is proposed to determine the diameters and the chiral indices of the inner and outer tubes of the DWCNTs with high precision.

  9. Predicting the creep life and failure mode of low-alloy steel weldments

    Energy Technology Data Exchange (ETDEWEB)

    Brear, J.M.; Middleton, C.J.; Aplin, P.F. [ERA Technology Ltd., Leatherhead (United Kingdom)

    1998-12-31

    This presentation reviews and consolidates experience gained through a number of research projects and practical plant assessments in predicting both the life and the likely failure mode and location in low alloy steel weldments. The approach adopted begins with the recognition that the relative strength difference between the microstructural regions is a key factor controlling both life and failure location. Practical methods based on hardness measurement and adaptable to differing weld geometries are presented and evidence for correlations between hardness ratio, damage accumulation and strain development is discussed. Predictor diagrams relating weld life and failure location to the service conditions and the hardness of the individual microstructural constituents are suggested and comments are given on the implications for identifying the circumstances in which Type IV cracking is to be expected. (orig.) 6 refs.

  10. Love to win or hate to lose? Asymmetry of dopamine D2 receptor binding predicts sensitivity to reward vs. punishment

    Science.gov (United States)

    Tomer, Rachel; Slagter, Heleen A; Christian, Bradley T; Fox, Andrew S; King, Carlye R; Murali, Dhanabalan; Gluck, Mark A; Davidson, Richard J

    2014-01-01

    Humans show consistent differences in the extent to which their behavior reflects a bias towards appetitive approach-related behavior or avoidance of aversive stimuli (Elliot, 2008). We examined the hypothesis that in healthy subjects this motivational bias (assessed by self-report and by a probabilistic learning task that allows direct comparison of the relative sensitivity to reward and punishment) reflects lateralization of dopamine signaling. Using [F-18]fallypride to measure D2/D3 binding , we found that self-reported motivational bias was predicted by the asymmetry of frontal D2 binding. Similarly, striatal and frontal asymmetries in D2 dopamine receptor binding, rather than absolute binding levels, predicted individual differences in learning from reward vs. punishment. These results suggest that normal variation in asymmetry of dopamine signaling may, in part, underlie human personality and cognition. PMID:24345165

  11. Binding-affinity predictions of HSP90 in the D3R Grand Challenge 2015 with docking, MM/GBSA, QM/MM, and free-energy simulations.

    Science.gov (United States)

    Misini Ignjatović, Majda; Caldararu, Octav; Dong, Geng; Muñoz-Gutierrez, Camila; Adasme-Carreño, Francisco; Ryde, Ulf

    2016-09-01

    We have estimated the binding affinity of three sets of ligands of the heat-shock protein 90 in the D3R grand challenge blind test competition. We have employed four different methods, based on five different crystal structures: first, we docked the ligands to the proteins with induced-fit docking with the Glide software and calculated binding affinities with three energy functions. Second, the docked structures were minimised in a continuum solvent and binding affinities were calculated with the MM/GBSA method (molecular mechanics combined with generalised Born and solvent-accessible surface area solvation). Third, the docked structures were re-optimised by combined quantum mechanics and molecular mechanics (QM/MM) calculations. Then, interaction energies were calculated with quantum mechanical calculations employing 970-1160 atoms in a continuum solvent, combined with energy corrections for dispersion, zero-point energy and entropy, ligand distortion, ligand solvation, and an increase of the basis set to quadruple-zeta quality. Fourth, relative binding affinities were estimated by free-energy simulations, using the multi-state Bennett acceptance-ratio approach. Unfortunately, the results were varying and rather poor, with only one calculation giving a correlation to the experimental affinities larger than 0.7, and with no consistent difference in the quality of the predictions from the various methods. For one set of ligands, the results could be strongly improved (after experimental data were revealed) if it was recognised that one of the ligands displaced one or two water molecules. For the other two sets, the problem is probably that the ligands bind in different modes than in the crystal structures employed or that the conformation of the ligand-binding site or the whole protein changes.

  12. Binding-affinity predictions of HSP90 in the D3R Grand Challenge 2015 with docking, MM/GBSA, QM/MM, and free-energy simulations

    Science.gov (United States)

    Misini Ignjatović, Majda; Caldararu, Octav; Dong, Geng; Muñoz-Gutierrez, Camila; Adasme-Carreño, Francisco; Ryde, Ulf

    2016-09-01

    We have estimated the binding affinity of three sets of ligands of the heat-shock protein 90 in the D3R grand challenge blind test competition. We have employed four different methods, based on five different crystal structures: first, we docked the ligands to the proteins with induced-fit docking with the Glide software and calculated binding affinities with three energy functions. Second, the docked structures were minimised in a continuum solvent and binding affinities were calculated with the MM/GBSA method (molecular mechanics combined with generalised Born and solvent-accessible surface area solvation). Third, the docked structures were re-optimised by combined quantum mechanics and molecular mechanics (QM/MM) calculations. Then, interaction energies were calculated with quantum mechanical calculations employing 970-1160 atoms in a continuum solvent, combined with energy corrections for dispersion, zero-point energy and entropy, ligand distortion, ligand solvation, and an increase of the basis set to quadruple-zeta quality. Fourth, relative binding affinities were estimated by free-energy simulations, using the multi-state Bennett acceptance-ratio approach. Unfortunately, the results were varying and rather poor, with only one calculation giving a correlation to the experimental affinities larger than 0.7, and with no consistent difference in the quality of the predictions from the various methods. For one set of ligands, the results could be strongly improved (after experimental data were revealed) if it was recognised that one of the ligands displaced one or two water molecules. For the other two sets, the problem is probably that the ligands bind in different modes than in the crystal structures employed or that the conformation of the ligand-binding site or the whole protein changes.

  13. Relative binding affinity does not predict biological response to xenoestrogens in rat endometrial adenocarcinoma cells.

    Science.gov (United States)

    Strunck, E; Stemmann, N; Hopert, A; Wünsche, W; Frank, K; Vollmer, G

    2000-10-01

    RUCA-I cells represent a valuable endometrial derived model system to assess the relative potencies and the molecular mode of action of environmental estrogens in vitro. Our results further show that no intimate correlation exists between the relative binding affinity and the biological response of these compounds. Therefore, data obtained from single-parametric analyses may result in misleading conclusions. On the other hand, the presented in vitro data will provide us with tools to study the activity of xenoestrogens in vivo and thus carry risk assessment one step further.

  14. The Drosophila hnRNP F/H Homolog Glorund Uses Two Distinct RNA-Binding Modes to Diversify Target Recognition

    Energy Technology Data Exchange (ETDEWEB)

    Tamayo, Joel V.; Teramoto, Takamasa; Chatterjee, Seema; Hall, Traci M. Tanaka; Gavis, Elizabeth R.

    2017-04-01

    The Drosophila hnRNP F/H homolog, Glorund (Glo), regulates nanos mRNA translation by interacting with a structured UA-rich motif in the nanos 3' untranslated region. Glo regulates additional RNAs, however, and mammalian homologs bind G-tract sequences to regulate alternative splicing, suggesting that Glo also recognizes G-tract RNA. To gain insight into how Glo recognizes both structured UA-rich and G-tract RNAs, we used mutational analysis guided by crystal structures of Glo’s RNA-binding domains and identified two discrete RNA-binding surfaces that allow Glo to recognize both RNA motifs. By engineering Glo variants that favor a single RNA-binding mode, we show that a subset of Glo’s functions in vivo is mediated solely by the G-tract binding mode, whereas regulation of nanos requires both recognition modes. Our findings suggest a molecular mechanism for the evolution of dual RNA motif recognition in Glo that may be applied to understanding the functional diversity of other RNA-binding proteins.

  15. Genome wide prediction of HNF4alpha functional binding sites by the use of local and global sequence context.

    Science.gov (United States)

    Kel, Alexander E; Niehof, Monika; Matys, Volker; Zemlin, Rüdiger; Borlak, Jürgen

    2008-01-01

    We report an application of machine learning algorithms that enables prediction of the functional context of transcription factor binding sites in the human genome. We demonstrate that our method allowed de novo identification of hepatic nuclear factor (HNF)4alpha binding sites and significantly improved an overall recognition of faithful HNF4alpha targets. When applied to published findings, an unprecedented high number of false positives were identified. The technique can be applied to any transcription factor.

  16. On the predictability of convective mode in high resolution WRF ensembles

    Science.gov (United States)

    Gallus, William; Lawson, John

    2015-04-01

    Convective mode has been shown to be associated with different distributions of severe weather reports. For instance, bow echoes are often associated with severe straight-line winds, while isolated supercell thunderstorms are perhaps more likely to produce tornadoes. Recent research has suggested that the WRF model when run with 3 km horizontal grid spacing has particular problems with some types of convective mode. It does not produce nearly enough bow echoes, and also fails to produce squall lines with trailing stratiform rain regions as often as are observed. It also is more likely to show broken lines of cells instead of squall lines lacking stratiform rain. Our current research is examining two bow echo events through the use of three different types of ensemble design. WRF ensembles are being created using (i) 12 mixed microphysical schemes, (ii) 11 members with perturbed initial and lateral boundary conditions via the GEFS reforecast version 2 dataset, and (iii) 10 members using the stochastic kinetic energy backscatter scheme (SKEB). In addition, one ensemble of 12 members has also been constructed using both SKEB and mixed microphysics. For one of the events, all three ensembles seem to do a reasonable job simulating a strong bow echo. However, for the other case, few of the ensemble members reproduce a bow echo, with state-sized positional errors. It is found that changing the microphysics can alter the forecasts in the case where bow echoes are generally simulated. Research will be discussed about the variations in spread seen in these different ensembles, along with the synoptic backgrounds as a method to determine why some cases apparently have very low predictability while others are much more predictable. Preliminary results suggest that the spread of the system position is reduced in the mixed microphysics and SKEB ensembles, but the structure of the thunderstorm systems still varies. Mode and structure are very sensitive to small changes, while

  17. Model-based Comparative Prediction of Transcription-Factor Binding Motifs in Anabolic Responses in Bone

    Institute of Scientific and Technical Information of China (English)

    Andy; B.; Chen; Kazunori; Hamamura; Guohua; Wang; Weirong; Xing; Subburaman; Mohan; Hiroki; Yokota; Yunlong; Liu

    2007-01-01

    Understanding the regulatory mechanism that controls the alteration of global gene expression patterns continues to be a challenging task in computational biology. We previously developed an ant algorithm, a biologically-inspired computational technique for microarray data, and predicted putative transcription-factor binding motifs (TFBMs) through mimicking interactive behaviors of natural ants. Here we extended the algorithm into a set of web-based software, Ant Modeler, and applied it to investigate the transcriptional mechanism underlying bone formation. Mechanical loading and administration of bone morphogenic proteins (BMPs) are two known treatments to strengthen bone. We addressed a question: Is there any TFBM that stimulates both "anabolic responses of mechanical loading" and "BMP-mediated osteogenic signaling"? Although there is no significant overlap among genes in the two responses, a comparative model-based analysis suggests that the two independent osteogenic processes employ common TFBMs, such as a stress responsive element and a motif for peroxisome proliferator-activated recep- tor (PPAR). The post-modeling in vitro analysis using mouse osteoblast cells sup- ported involvements of the predicted TFBMs such as PPAR, Ikaros 3, and LMO2 in response to mechanical loading. Taken together, the results would be useful to derive a set of testable hypotheses and examine the role of specific regulators in complex transcriptional control of bone formation.

  18. Neural network and SVM classifiers accurately predict lipid binding proteins, irrespective of sequence homology.

    Science.gov (United States)

    Bakhtiarizadeh, Mohammad Reza; Moradi-Shahrbabak, Mohammad; Ebrahimi, Mansour; Ebrahimie, Esmaeil

    2014-09-07

    Due to the central roles of lipid binding proteins (LBPs) in many biological processes, sequence based identification of LBPs is of great interest. The major challenge is that LBPs are diverse in sequence, structure, and function which results in low accuracy of sequence homology based methods. Therefore, there is a need for developing alternative functional prediction methods irrespective of sequence similarity. To identify LBPs from non-LBPs, the performances of support vector machine (SVM) and neural network were compared in this study. Comprehensive protein features and various techniques were employed to create datasets. Five-fold cross-validation (CV) and independent evaluation (IE) tests were used to assess the validity of the two methods. The results indicated that SVM outperforms neural network. SVM achieved 89.28% (CV) and 89.55% (IE) overall accuracy in identification of LBPs from non-LBPs and 92.06% (CV) and 92.90% (IE) (in average) for classification of different LBPs classes. Increasing the number and the range of extracted protein features as well as optimization of the SVM parameters significantly increased the efficiency of LBPs class prediction in comparison to the only previous report in this field. Altogether, the results showed that the SVM algorithm can be run on broad, computationally calculated protein features and offers a promising tool in detection of LBPs classes. The proposed approach has the potential to integrate and improve the common sequence alignment based methods.

  19. Interactome-wide prediction of protein-protein binding sites reveals effects of protein sequence variation in Arabidopsis thaliana.

    Directory of Open Access Journals (Sweden)

    Felipe Leal Valentim

    Full Text Available The specificity of protein-protein interactions is encoded in those parts of the sequence that compose the binding interface. Therefore, understanding how changes in protein sequence influence interaction specificity, and possibly the phenotype, requires knowing the location of binding sites in those sequences. However, large-scale detection of protein interfaces remains a challenge. Here, we present a sequence- and interactome-based approach to mine interaction motifs from the recently published Arabidopsis thaliana interactome. The resultant proteome-wide predictions are available via www.ab.wur.nl/sliderbio and set the stage for further investigations of protein-protein binding sites. To assess our method, we first show that, by using a priori information calculated from protein sequences, such as evolutionary conservation and residue surface accessibility, we improve the performance of interface prediction compared to using only interactome data. Next, we present evidence for the functional importance of the predicted sites, which are under stronger selective pressure than the rest of protein sequence. We also observe a tendency for compensatory mutations in the binding sites of interacting proteins. Subsequently, we interrogated the interactome data to formulate testable hypotheses for the molecular mechanisms underlying effects of protein sequence mutations. Examples include proteins relevant for various developmental processes. Finally, we observed, by analysing pairs of paralogs, a correlation between functional divergence and sequence divergence in interaction sites. This analysis suggests that large-scale prediction of binding sites can cast light on evolutionary processes that shape protein-protein interaction networks.

  20. Development and Application of Benchmark Examples for Mode II Static Delamination Propagation and Fatigue Growth Predictions

    Science.gov (United States)

    Krueger, Ronald

    2011-01-01

    The development of benchmark examples for static delamination propagation and cyclic delamination onset and growth prediction is presented and demonstrated for a commercial code. The example is based on a finite element model of an End-Notched Flexure (ENF) specimen. The example is independent of the analysis software used and allows the assessment of the automated delamination propagation, onset and growth prediction capabilities in commercial finite element codes based on the virtual crack closure technique (VCCT). First, static benchmark examples were created for the specimen. Second, based on the static results, benchmark examples for cyclic delamination growth were created. Third, the load-displacement relationship from a propagation analysis and the benchmark results were compared, and good agreement could be achieved by selecting the appropriate input parameters. Fourth, starting from an initially straight front, the delamination was allowed to grow under cyclic loading. The number of cycles to delamination onset and the number of cycles during delamination growth for each growth increment were obtained from the automated analysis and compared to the benchmark examples. Again, good agreement between the results obtained from the growth analysis and the benchmark results could be achieved by selecting the appropriate input parameters. The benchmarking procedure proved valuable by highlighting the issues associated with choosing the input parameters of the particular implementation. Selecting the appropriate input parameters, however, was not straightforward and often required an iterative procedure. Overall the results are encouraging, but further assessment for mixed-mode delamination is required.

  1. Binding modes of aromatic ligands to mammalian heme peroxidases with associated functional implications: crystal structures of lactoperoxidase complexes with acetylsalicylic acid, salicylhydroxamic acid, and benzylhydroxamic acid.

    Science.gov (United States)

    Singh, Amit K; Singh, Nagendra; Sinha, Mau; Bhushan, Asha; Kaur, Punit; Srinivasan, Alagiri; Sharma, Sujata; Singh, Tej P

    2009-07-24

    The binding and structural studies of bovine lactoperoxidase with three aromatic ligands, acetylsalicylic acid (ASA), salicylhydoxamic acid (SHA), and benzylhydroxamic acid (BHA) show that all the three compounds bind to lactoperoxidase at the substrate binding site on the distal heme side. The binding of ASA occurs without perturbing the position of conserved heme water molecule W-1, whereas both SHA and BHA displace it by the hydroxyl group of their hydroxamic acid moieties. The acetyl group carbonyl oxygen atom of ASA forms a hydrogen bond with W-1, which in turn makes three other hydrogen-bonds, one each with heme iron, His-109 N(epsilon2), and Gln-105 N(epsilon2). In contrast, in the complexes of SHA and BHA, the OH group of hydroxamic acid moiety in both complexes interacts with heme iron directly with Fe-OH distances of 3.0 and 3.2A respectively. The OH is also hydrogen bonded to His-109 N(epsilon2) and Gln-105N(epsilon2). The plane of benzene ring of ASA is inclined at 70.7 degrees from the plane of heme moiety, whereas the aromatic planes of SHA and BHA are nearly parallel to the heme plane with inclinations of 15.7 and 6.2 degrees , respectively. The mode of ASA binding provides the information about the mechanism of action of aromatic substrates, whereas the binding characteristics of SHA and BHA indicate the mode of inhibitor binding.

  2. Insights into cytochrome bc 1 complex binding mode of antimalarial 2-hydroxy-1,4-naphthoquinones through molecular modelling

    Science.gov (United States)

    Sodero, Ana Carolina Rennó; Abrahim-Vieira, Bárbara; Torres, Pedro Henrique Monteiro; Pascutti, Pedro Geraldo; Garcia, Célia RS; Ferreira, Vitor Francisco; da Rocha, David Rodrigues; Ferreira, Sabrina Baptista; Silva, Floriano Paes

    2017-01-01

    BACKGROUND Malaria persists as a major public health problem. Atovaquone is a drug that inhibits the respiratory chain of Plasmodium falciparum, but with serious limitations like known resistance, low bioavailability and high plasma protein binding. OBJECTIVES The aim of this work was to perform molecular modelling studies of 2-hydroxy-1,4-naphthoquinones analogues of atovaquone on the Qo site of P. falciparum cytochrome bc 1 complex (Pfbc1) to suggest structural modifications that could improve their antimalarial activity. METHODS We have built the homology model of the cytochrome b (CYB) and Rieske iron-sulfur protein (ISP) subunits from Pfbc1 and performed the molecular docking of 41 2-hydroxy-1,4-naphthoquinones with known in vitro antimalarial activity and predicted to act on this target. FINDINGS Results suggest that large hydrophobic R2 substituents may be important for filling the deep hydrophobic Qo site pocket. Moreover, our analysis indicates that the H-donor 2-hydroxyl group may not be crucial for efficient binding and inhibition of Pfbc1 by these atovaquone analogues. The C1 carbonyl group (H-acceptor) is more frequently involved in the important hydrogen bonding interaction with His152 of the Rieske ISP subunit. MAIN CONCLUSIONS Additional interactions involving residues such as Ile258 and residues required for efficient catalysis (e.g., Glu261) could be explored in drug design to avoid development of drug resistance by the parasite. PMID:28327793

  3. A Rat α-Fetoprotein Binding Activity Prediction Model to Facilitate Assessment of the Endocrine Disruption Potential of Environmental Chemicals

    Directory of Open Access Journals (Sweden)

    Huixiao Hong

    2016-03-01

    Full Text Available Endocrine disruptors such as polychlorinated biphenyls (PCBs, diethylstilbestrol (DES and dichlorodiphenyltrichloroethane (DDT are agents that interfere with the endocrine system and cause adverse health effects. Huge public health concern about endocrine disruptors has arisen. One of the mechanisms of endocrine disruption is through binding of endocrine disruptors with the hormone receptors in the target cells. Entrance of endocrine disruptors into target cells is the precondition of endocrine disruption. The binding capability of a chemical with proteins in the blood affects its entrance into the target cells and, thus, is very informative for the assessment of potential endocrine disruption of chemicals. α-fetoprotein is one of the major serum proteins that binds to a variety of chemicals such as estrogens. To better facilitate assessment of endocrine disruption of environmental chemicals, we developed a model for α-fetoprotein binding activity prediction using the novel pattern recognition method (Decision Forest and the molecular descriptors calculated from two-dimensional structures by Mold2 software. The predictive capability of the model has been evaluated through internal validation using 125 training chemicals (average balanced accuracy of 69% and external validations using 22 chemicals (balanced accuracy of 71%. Prediction confidence analysis revealed the model performed much better at high prediction confidence. Our results indicate that the model is useful (when predictions are in high confidence in endocrine disruption risk assessment of environmental chemicals though improvement by increasing number of training chemicals is needed.

  4. A Rat α-Fetoprotein Binding Activity Prediction Model to Facilitate Assessment of the Endocrine Disruption Potential of Environmental Chemicals.

    Science.gov (United States)

    Hong, Huixiao; Shen, Jie; Ng, Hui Wen; Sakkiah, Sugunadevi; Ye, Hao; Ge, Weigong; Gong, Ping; Xiao, Wenming; Tong, Weida

    2016-03-25

    Endocrine disruptors such as polychlorinated biphenyls (PCBs), diethylstilbestrol (DES) and dichlorodiphenyltrichloroethane (DDT) are agents that interfere with the endocrine system and cause adverse health effects. Huge public health concern about endocrine disruptors has arisen. One of the mechanisms of endocrine disruption is through binding of endocrine disruptors with the hormone receptors in the target cells. Entrance of endocrine disruptors into target cells is the precondition of endocrine disruption. The binding capability of a chemical with proteins in the blood affects its entrance into the target cells and, thus, is very informative for the assessment of potential endocrine disruption of chemicals. α-fetoprotein is one of the major serum proteins that binds to a variety of chemicals such as estrogens. To better facilitate assessment of endocrine disruption of environmental chemicals, we developed a model for α-fetoprotein binding activity prediction using the novel pattern recognition method (Decision Forest) and the molecular descriptors calculated from two-dimensional structures by Mold² software. The predictive capability of the model has been evaluated through internal validation using 125 training chemicals (average balanced accuracy of 69%) and external validations using 22 chemicals (balanced accuracy of 71%). Prediction confidence analysis revealed the model performed much better at high prediction confidence. Our results indicate that the model is useful (when predictions are in high confidence) in endocrine disruption risk assessment of environmental chemicals though improvement by increasing number of training chemicals is needed.

  5. Sequence-Based Prediction of RNA-Binding Proteins Using Random Forest with Minimum Redundancy Maximum Relevance Feature Selection

    Directory of Open Access Journals (Sweden)

    Xin Ma

    2015-01-01

    Full Text Available The prediction of RNA-binding proteins is one of the most challenging problems in computation biology. Although some studies have investigated this problem, the accuracy of prediction is still not sufficient. In this study, a highly accurate method was developed to predict RNA-binding proteins from amino acid sequences using random forests with the minimum redundancy maximum relevance (mRMR method, followed by incremental feature selection (IFS. We incorporated features of conjoint triad features and three novel features: binding propensity (BP, nonbinding propensity (NBP, and evolutionary information combined with physicochemical properties (EIPP. The results showed that these novel features have important roles in improving the performance of the predictor. Using the mRMR-IFS method, our predictor achieved the best performance (86.62% accuracy and 0.737 Matthews correlation coefficient. High prediction accuracy and successful prediction performance suggested that our method can be a useful approach to identify RNA-binding proteins from sequence information.

  6. Very low zero-dispersion wavelength predicted for single-mode modified-total-internal-reflection crystal fibre

    DEFF Research Database (Denmark)

    Jacobsen, Rune Shim; Lægsgaard, Jesper; Bjarklev, Anders Overgaard

    2004-01-01

    A zero-dispersion wavelength (lgr/sub ZD/) below 600 nm has been predicted for a pure silica modified-total-internal-reflection (M-TIR) single-mode crystal fibre with a 1 mm pitch. The fibre is single mode from at least 250 nm, i.e., from well below lgr/sub ZD/. Both a method for designing single......-mode crystal fibres using an anti-guiding structure and a fast calculation scheme for investigating the structure for different pitch sizes are proposed....

  7. Prediction of vitamin interacting residues in a vitamin binding protein using evolutionary information

    Directory of Open Access Journals (Sweden)

    Panwar Bharat

    2013-02-01

    Full Text Available Abstract Background The vitamins are important cofactors in various enzymatic-reactions. In past, many inhibitors have been designed against vitamin binding pockets in order to inhibit vitamin-protein interactions. Thus, it is important to identify vitamin interacting residues in a protein. It is possible to detect vitamin-binding pockets on a protein, if its tertiary structure is known. Unfortunately tertiary structures of limited proteins are available. Therefore, it is important to develop in-silico models for predicting vitamin interacting residues in protein from its primary structure. Results In this study, first we compared protein-interacting residues of vitamins with other ligands using Two Sample Logo (TSL. It was observed that ATP, GTP, NAD, FAD and mannose preferred {G,R,K,S,H}, {G,K,T,S,D,N}, {T,G,Y}, {G,Y,W} and {Y,D,W,N,E} residues respectively, whereas vitamins preferred {Y,F,S,W,T,G,H} residues for the interaction with proteins. Furthermore, compositional information of preferred and non-preferred residues along with patterns-specificity was also observed within different vitamin-classes. Vitamins A, B and B6 preferred {F,I,W,Y,L,V}, {S,Y,G,T,H,W,N,E} and {S,T,G,H,Y,N} interacting residues respectively. It suggested that protein-binding patterns of vitamins are different from other ligands, and motivated us to develop separate predictor for vitamins and their sub-classes. The four different prediction modules, (i vitamin interacting residues (VIRs, (ii vitamin-A interacting residues (VAIRs, (iii vitamin-B interacting residues (VBIRs and (iv pyridoxal-5-phosphate (vitamin B6 interacting residues (PLPIRs have been developed. We applied various classifiers of SVM, BayesNet, NaiveBayes, ComplementNaiveBayes, NaiveBayesMultinomial, RandomForest and IBk etc., as machine learning techniques, using binary and Position-Specific Scoring Matrix (PSSM features of protein sequences. Finally, we selected best performing SVM modules and

  8. The telomeric protein Pot1 from Schizosaccharomyces pombe binds ssDNA in two modes with differing 3′ end availability

    Science.gov (United States)

    Dickey, Thayne H.; Wuttke, Deborah S.

    2014-01-01

    Telomere protection and length regulation are important processes for aging, cancer and several other diseases. At the heart of these processes lies the single-stranded DNA (ssDNA)-binding protein Pot1, a component of the telomere maintenance complex shelterin, which is present in species ranging from fission yeast to humans. Pot1 contains a dual OB-fold DNA-binding domain (DBD) that fully confers its high affinity for telomeric ssDNA. Studies of S. pombe Pot1-DBD and its individual OB-fold domains revealed a complex non-additive behavior of the two OB-folds in the context of the complete Pot1 protein. This behavior includes the use of multiple distinct binding modes and an ability to form higher order complexes. Here we use NMR and biochemical techniques to investigate the structural features of the complete Pot1-DBD. These experiments reveal one binding mode characterized by only subtle alternations to the individual OB-fold subdomain structures, resulting in an inaccessible 3′ end of the ssDNA. The second binding mode, which has equivalent affinity, interacts differently with the 3′ end, rendering it available for interaction with other proteins. These findings suggest a structural switch that contributes to telomere end-protection and length regulation. PMID:25074378

  9. ProBiS-CHARMMing: Web Interface for Prediction and Optimization of Ligands in Protein Binding Sites.

    Science.gov (United States)

    Konc, Janez; Miller, Benjamin T; Štular, Tanja; Lešnik, Samo; Woodcock, H Lee; Brooks, Bernard R; Janežič, Dušanka

    2015-11-23

    Proteins often exist only as apo structures (unligated) in the Protein Data Bank, with their corresponding holo structures (with ligands) unavailable. However, apoproteins may not represent the amino-acid residue arrangement upon ligand binding well, which is especially problematic for molecular docking. We developed the ProBiS-CHARMMing web interface by connecting the ProBiS ( http://probis.cmm.ki.si ) and CHARMMing ( http://www.charmming.org ) web servers into one functional unit that enables prediction of protein-ligand complexes and allows for their geometry optimization and interaction energy calculation. The ProBiS web server predicts ligands (small compounds, proteins, nucleic acids, and single-atom ligands) that may bind to a query protein. This is achieved by comparing its surface structure against a nonredundant database of protein structures and finding those that have binding sites similar to that of the query protein. Existing ligands found in the similar binding sites are then transposed to the query according to predictions from ProBiS. The CHARMMing web server enables, among other things, minimization and potential energy calculation for a wide variety of biomolecular systems, and it is used here to optimize the geometry of the predicted protein-ligand complex structures using the CHARMM force field and to calculate their interaction energies with the corresponding query proteins. We show how ProBiS-CHARMMing can be used to predict ligands and their poses for a particular binding site, and minimize the predicted protein-ligand complexes to obtain representations of holoproteins. The ProBiS-CHARMMing web interface is freely available for academic users at http://probis.nih.gov.

  10. Structure of Bacillus subtilis γ-glutamyltranspeptidase in complex with acivicin: diversity of the binding mode of a classical and electrophilic active-site-directed glutamate analogue

    Energy Technology Data Exchange (ETDEWEB)

    Ida, Tomoyo [Osaka University, Toyonaka, Osaka 560-0043 (Japan); Suzuki, Hideyuki [Kyoto Institute of Technology, Goshokaido-cho, Matsugasaki, Sakyo-ku, Kyoto 606-8585 (Japan); Fukuyama, Keiichi [Osaka University, Toyonaka, Osaka 560-0043 (Japan); Hiratake, Jun [Kyoto University, Uji, Kyoto 611-0011 (Japan); Wada, Kei, E-mail: keiwada@med.miyazaki-u.ac.jp [University of Miyazaki, Miyazaki 889-1692 (Japan); Osaka University, Toyonaka, Osaka 560-0043 (Japan)

    2014-02-01

    The binding modes of acivicin, a classical and an electrophilic active-site-directed glutamate analogue, to bacterial γ-glutamyltranspeptidases were found to be diverse. γ-Glutamyltranspeptidase (GGT) is an enzyme that plays a central role in glutathione metabolism, and acivicin is a classical inhibitor of GGT. Here, the structure of acivicin bound to Bacillus subtilis GGT determined by X-ray crystallography to 1.8 Å resolution is presented, in which it binds to the active site in a similar manner to that in Helicobacter pylori GGT, but in a different binding mode to that in Escherichia coli GGT. In B. subtilis GGT, acivicin is bound covalently through its C3 atom with sp{sup 2} hybridization to Thr403 O{sup γ}, the catalytic nucleophile of the enzyme. The results show that acivicin-binding sites are common, but the binding manners and orientations of its five-membered dihydroisoxazole ring are diverse in the binding pockets of GGTs.

  11. Computational prediction of binding affinity for CYP1A2-ligand complexes using empirical free energy calculations

    DEFF Research Database (Denmark)

    Poongavanam, Vasanthanathan; Olsen, Lars; Jørgensen, Flemming Steen;

    2010-01-01

    , and methods based on statistical mechanics. In the present investigation, we started from an LIE model to predict the binding free energy of structurally diverse compounds of cytochrome P450 1A2 ligands, one of the important human metabolizing isoforms of the cytochrome P450 family. The data set includes both...... substrates and inhibitors. It appears that the electrostatic contribution to the binding free energy becomes negligible in this particular protein and a simple empirical model was derived, based on a training set of eight compounds. The root mean square error for the training set was 3.7 kJ/mol. Subsequent......Predicting binding affinities for receptor-ligand complexes is still one of the challenging processes in computational structure-based ligand design. Many computational methods have been developed to achieve this goal, such as docking and scoring methods, the linear interaction energy (LIE) method...

  12. Quantitative predictions of peptide binding to any HLA-DR molecule of known sequence: NetMHCIIpan

    DEFF Research Database (Denmark)

    Nielsen, Morten; Lundegaard, Claus; Blicher, Thomas

    2008-01-01

    class II molecules is therefore of pivotal importance for rational discovery of immune epitopes. HLA-DR is a prominent example of a human MHC class II. Here, we present a method, NetMHCIIpan, that allows for pan-specific predictions of peptide binding to any HLA-DR molecule of known sequence. The method...

  13. MetalDetector v2.0: predicting the geometry of metal binding sites from protein sequence

    OpenAIRE

    Passerini, A; Lippi, M.; P. Frasconi

    2011-01-01

    MetalDetector identifies CYS and HIS involved in transition metal protein binding sites, starting from sequence alone. A major new feature of release 2.0 is the ability to predict which residues are jointly involved in the coordination of the same metal ion. The server is available at http://metaldetector.dsi.unifi.it/v2.0/.

  14. Urinary liver-type fatty acid-binding protein predicts progression to nephropathy in type 1 diabetic patients

    DEFF Research Database (Denmark)

    Nielsen, Stine Elkjaer; Sugaya, Takeshi; Hovind, Peter;

    2010-01-01

    Urinary liver-type fatty acid-binding protein (u-LFABP) is a marker of tubulointerstitial inflammation and has been shown to be increased in patients with type 1 diabetes and is further increased in patients who progress to micro- and macroalbuminuria. Our aim was to evaluate u-LFABP as a predict...

  15. Predicting transcription factor binding sites using local over-representation and comparative genomics

    Directory of Open Access Journals (Sweden)

    Touzet Hélène

    2006-08-01

    Full Text Available Abstract Background Identifying cis-regulatory elements is crucial to understanding gene expression, which highlights the importance of the computational detection of overrepresented transcription factor binding sites (TFBSs in coexpressed or coregulated genes. However, this is a challenging problem, especially when considering higher eukaryotic organisms. Results We have developed a method, named TFM-Explorer, that searches for locally overrepresented TFBSs in a set of coregulated genes, which are modeled by profiles provided by a database of position weight matrices. The novelty of the method is that it takes advantage of spatial conservation in the sequence and supports multiple species. The efficiency of the underlying algorithm and its robustness to noise allow weak regulatory signals to be detected in large heterogeneous data sets. Conclusion TFM-Explorer provides an efficient way to predict TFBS overrepresentation in related sequences. Promising results were obtained in a variety of examples in human, mouse, and rat genomes. The software is publicly available at http://bioinfo.lifl.fr/TFM-Explorer.

  16. MOAtox: A comprehensive mode of action and acute aquatic toxicity database for predictive model development (SETAC abstract)

    Science.gov (United States)

    The mode of toxic action (MOA) has been recognized as a key determinant of chemical toxicity and as an alternative to chemical class-based predictive toxicity modeling. However, the development of quantitative structure activity relationship (QSAR) and other models has been limit...

  17. A Bayesian network model for predicting aquatic toxicity mode of action using two dimensional theoretical molecular descriptors

    Science.gov (United States)

    The mode of toxic action (MoA) has been recognized as a key determinant of chemical toxicity, but development of predictive MoA classification models in aquatic toxicology has been limited. We developed a Bayesian network model to classify aquatic toxicity MoA using a recently pu...

  18. Structure of the Staphylococcus aureus AgrA LytTR Domain Bound to DNA Reveals a Beta Fold with an Unusual Mode of Binding

    Energy Technology Data Exchange (ETDEWEB)

    Sidote,D.; Barbieri, C.; Wu, T.; Stock, A.

    2008-01-01

    The LytTR domain is a DNA-binding motif found within the AlgR/AgrA/LytR family of transcription factors that regulate virulence factor and toxin gene expression in pathogenic bacteria. This previously uncharacterized domain lacks sequence similarity with proteins of known structure. The crystal structure of the DNA-binding domain of Staphylococcus aureus AgrA complexed with a DNA pentadecamer duplex has been determined at 1.6 Angstroms resolution. The structure establishes a 10-stranded {beta} fold for the LytTR domain and reveals its mode of interaction with DNA. Residues within loop regions of AgrA contact two successive major grooves and the intervening minor groove on one face of the oligonucleotide duplex, inducing a substantial bend in the DNA. Loss of DNA binding upon substitution of key interacting residues in AgrA supports the observed binding mode. This mode of protein-DNA interaction provides a potential target for future antimicrobial drug design.

  19. Predicting Binding Free Energy Change Caused by Point Mutations with Knowledge-Modified MM/PBSA Method.

    Directory of Open Access Journals (Sweden)

    Marharyta Petukh

    2015-07-01

    Full Text Available A new methodology termed Single Amino Acid Mutation based change in Binding free Energy (SAAMBE was developed to predict the changes of the binding free energy caused by mutations. The method utilizes 3D structures of the corresponding protein-protein complexes and takes advantage of both approaches: sequence- and structure-based methods. The method has two components: a MM/PBSA-based component, and an additional set of statistical terms delivered from statistical investigation of physico-chemical properties of protein complexes. While the approach is rigid body approach and does not explicitly consider plausible conformational changes caused by the binding, the effect of conformational changes, including changes away from binding interface, on electrostatics are mimicked with amino acid specific dielectric constants. This provides significant improvement of SAAMBE predictions as indicated by better match against experimentally determined binding free energy changes over 1300 mutations in 43 proteins. The final benchmarking resulted in a very good agreement with experimental data (correlation coefficient 0.624 while the algorithm being fast enough to allow for large-scale calculations (the average time is less than a minute per mutation.

  20. PiRaNhA: a server for the computational prediction of RNA-binding residues in protein sequences

    Science.gov (United States)

    Murakami, Yoichi; Spriggs, Ruth V.; Nakamura, Haruki; Jones, Susan

    2010-01-01

    The PiRaNhA web server is a publicly available online resource that automatically predicts the location of RNA-binding residues (RBRs) in protein sequences. The goal of functional annotation of sequences in the field of RNA binding is to provide predictions of high accuracy that require only small numbers of targeted mutations for verification. The PiRaNhA server uses a support vector machine (SVM), with position-specific scoring matrices, residue interface propensity, predicted residue accessibility and residue hydrophobicity as features. The server allows the submission of up to 10 protein sequences, and the predictions for each sequence are provided on a web page and via email. The prediction results are provided in sequence format with predicted RBRs highlighted, in text format with the SVM threshold score indicated and as a graph which enables users to quickly identify those residues above any specific SVM threshold. The graph effectively enables the increase or decrease of the false positive rate. When tested on a non-redundant data set of 42 protein sequences not used in training, the PiRaNhA server achieved an accuracy of 85%, specificity of 90% and a Matthews correlation coefficient of 0.41 and outperformed other publicly available servers. The PiRaNhA prediction server is freely available at http://www.bioinformatics.sussex.ac.uk/PIRANHA. PMID:20507911

  1. Two modes of interaction of the single-stranded DNA-binding protein of bacteriophage T7 with the DNA polymerase-thioredoxin complex

    KAUST Repository

    Ghosh, Sharmistha

    2010-04-06

    The DNA polymerase encoded by bacteriophage T7 has low processivity. Escherichia coli thioredoxin binds to a segment of 76 residues in the thumb subdomain of the polymerase and increases the processivity. The binding of thioredoxin leads to the formation of two basic loops, loops A and B, located within the thioredoxin-binding domain (TBD). Both loops interact with the acidic C terminus of the T7 helicase. A relatively weak electrostatic mode involves the C-terminal tail of the helicase and the TBD, whereas a high affinity interaction that does not involve the C-terminal tail occurs when the polymerase is in a polymerization mode. T7 gene 2.5 single-stranded DNA-binding protein (gp2.5) also has an acidic C-terminal tail. gp2.5 also has two modes of interaction with the polymerase, but both involve the C-terminal tail of gp2.5. An electrostatic interaction requires the basic residues in loops A and B, and gp2.5 binds to both loops with similar affinity as measured by surface plasmon resonance. When the polymerase is in a polymerization mode, the C terminus of gene 2.5 protein interacts with the polymerase in regions outside the TBD.gp2.5 increases the processivity of the polymerase-helicase complex during leading strand synthesis. When loop B of the TBD is altered, abortive DNA products are observed during leading strand synthesis. Loop B appears to play an important role in communication with the helicase and gp2.5, whereas loop A plays a stabilizing role in these interactions. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.

  2. In silico engineering and optimization of Transcription Activator-Like Effectors and their derivatives for improved DNA binding predictions.

    KAUST Repository

    Piatek, Marek J.

    2015-12-01

    Transcription Activator-Like Effectors (TALEs) can be used as adaptable DNAbinding modules to create site-specific chimeric nucleases or synthetic transcriptional regulators. The central repeat domain mediates specific DNA binding via hypervariable repeat di-residues (RVDs). This DNA-Binding Domain can be engineered to bind preferentially to any user-selected DNA sequence if engineered appropriately. Therefore, TALEs and their derivatives have become indispensable molecular tools in site-specific manipulation of genes and genomes. This thesis revolves around two problems: in silico design and improved binding site prediction of TALEs. In the first part, a study is shown where TALEs are successfully designed in silico and validated in laboratory to yield the anticipated effects on selected genes. Software is developed to accompany the process of designing and prediction of binding sites. I expanded the functionality of the software to be used as a more generic set of tools for the design, target and offtarget searching. Part two contributes a method and associated toolkit developed to allow users to design in silico optimized synthetic TALEs with user-defined specificities for various experimental purposes. This method is based on a mutual relationship of three consecutive tandem repeats in the DNA-binding domain. This approach revealed positional and compositional bias behind the binding of TALEs to DNA. In conclusion, I developed methods, approaches, and software to enhance the functionality of synthetic TALEs, which should improve understanding of TALEs biology and will further advance genome-engineering applications in various organisms and cell types.

  3. An activating mutation reveals a second binding mode of the integrin α2 I domain to the GFOGER motif in collagens.

    Directory of Open Access Journals (Sweden)

    Federico Carafoli

    Full Text Available The GFOGER motif in collagens (O denotes hydroxyproline represents a high-affinity binding site for all collagen-binding integrins. Other GxOGER motifs require integrin activation for maximal binding. The E318W mutant of the integrin α2β1 I domain displays a relaxed collagen specificity, typical of an active state. E318W binds more strongly than the wild-type α2 I domain to GMOGER, and forms a 2:1 complex with a homotrimeric, collagen-like, GFOGER peptide. Crystal structure analysis of this complex reveals two E318W I domains, A and B, bound to a single triple helix. The E318W I domains are virtually identical to the collagen-bound wild-type I domain, suggesting that the E318W mutation activates the I domain by destabilising the unligated conformation. E318W I domain A interacts with two collagen chains similarly to wild-type I domain (high-affinity mode. E318W I domain B makes favourable interactions with only one collagen chain (low-affinity mode. This observation suggests that single GxOGER motifs in the heterotrimeric collagens V and IX may support binding of activated integrins.

  4. The binding mode of second-generation sulfonamide inhibitors of MurD: clues for rational design of potent MurD inhibitors.

    Directory of Open Access Journals (Sweden)

    Mihael Simčič

    Full Text Available A series of optimized sulfonamide derivatives was recently reported as novel inhibitors of UDP-N-acetylmuramoyl-L-alanine:D-glutamate ligase (MurD. These are based on naphthalene-N-sulfonyl-D-glutamic acid and have the D-glutamic acid replaced with rigidified mimetics. Here we have defined the binding site of these novel ligands to MurD using (1H/(13C heteronuclear single quantum correlation. The MurD protein was selectively (13C-labeled on the methyl groups of Ile (δ1 only, Leu and Val, and was isolated and purified. Crucial Ile, Leu and Val methyl groups in the vicinity of the ligand binding site were identified by comparison of chemical shift perturbation patterns among the ligands with various structural elements and known binding modes. The conformational and dynamic properties of the bound ligands and their binding interactions were examined using the transferred nuclear Overhauser effect and saturation transfer difference. In addition, the binding mode of these novel inhibitors was thoroughly examined using unrestrained molecular dynamics simulations. Our results reveal the complex dynamic behavior of ligand-MurD complexes and its influence on ligand-enzyme contacts. We further present important findings for the rational design of potent Mur ligase inhibitors.

  5. Dopamine transporter comparative molecular modeling and binding site prediction using the LeuT(Aa) leucine transporter as a template.

    Science.gov (United States)

    Indarte, Martín; Madura, Jeffry D; Surratt, Christopher K

    2008-02-15

    Pharmacological and behavioral studies indicate that binding of cocaine and the amphetamines by the dopamine transporter (DAT) protein is principally responsible for initiating the euphoria and addiction associated with these drugs. The lack of an X-ray crystal structure for the DAT or any other member of the neurotransmitter:sodium symporter (NSS) family has hindered understanding of psychostimulant recognition at the atomic level; structural information has been obtained largely from mutagenesis and biophysical studies. The recent publication of a crystal structure for the bacterial leucine transporter LeuT(Aa), a distantly related NSS family homolog, provides for the first time a template for three-dimensional comparative modeling of NSS proteins. A novel computational modeling approach using the capabilities of the Molecular Operating Environment program MOE 2005.06 in conjunction with other comparative modeling servers generated the LeuT(Aa)-directed DAT model. Probable dopamine and amphetamine binding sites were identified within the DAT model using multiple docking approaches. Binding sites for the substrate ligands (dopamine and amphetamine) overlapped substantially with the analogous region of the LeuT(Aa) crystal structure for the substrate leucine. The docking predictions implicated DAT side chains known to be critical for high affinity ligand binding and suggest novel mutagenesis targets in elucidating discrete substrate and inhibitor binding sites. The DAT model may guide DAT ligand QSAR studies, and rational design of novel DAT-binding therapeutics.

  6. An integrative approach to CTL epitope prediction: A combined algorithm integrating MHC class I binding, TAP transport efficiency, and proteasomal cleavage predictions

    DEFF Research Database (Denmark)

    Larsen, Mette Voldby; Lundegaard, Claus; Lamberth, K;

    2005-01-01

    Reverse immunogenetic approaches attempt to optimize the selection of candidate epitopes, and thus minimize the experimental effort needed to identify new epitopes. When predicting cytotoxic T cell epitopes, the main focus has been on the highly specific MHC class I binding event. Methods have al.......The method is available at http://www.cbs.dtu.dk/services/NetCTL. Supplementary material is available at http://www.cbs.dtu.dk/suppl/immunology/CTL.php....

  7. PROCARB: A Database of Known and Modelled Carbohydrate-Binding Protein Structures with Sequence-Based Prediction Tools

    Directory of Open Access Journals (Sweden)

    Adeel Malik

    2010-01-01

    Full Text Available Understanding of the three-dimensional structures of proteins that interact with carbohydrates covalently (glycoproteins as well as noncovalently (protein-carbohydrate complexes is essential to many biological processes and plays a significant role in normal and disease-associated functions. It is important to have a central repository of knowledge available about these protein-carbohydrate complexes as well as preprocessed data of predicted structures. This can be significantly enhanced by tools de novo which can predict carbohydrate-binding sites for proteins in the absence of structure of experimentally known binding site. PROCARB is an open-access database comprising three independently working components, namely, (i Core PROCARB module, consisting of three-dimensional structures of protein-carbohydrate complexes taken from Protein Data Bank (PDB, (ii Homology Models module, consisting of manually developed three-dimensional models of N-linked and O-linked glycoproteins of unknown three-dimensional structure, and (iii CBS-Pred prediction module, consisting of web servers to predict carbohydrate-binding sites using single sequence or server-generated PSSM. Several precomputed structural and functional properties of complexes are also included in the database for quick analysis. In particular, information about function, secondary structure, solvent accessibility, hydrogen bonds and literature reference, and so forth, is included. In addition, each protein in the database is mapped to Uniprot, Pfam, PDB, and so forth.

  8. Interaction of the amyloid precursor protein-like protein 1 (APLP1) E2 domain with heparan sulfate involves two distinct binding modes

    Energy Technology Data Exchange (ETDEWEB)

    Dahms, Sven O., E-mail: sdahms@fli-leibniz.de [Leibniz Institute for Age Research (FLI), Beutenbergstrasse 11, 07745 Jena (Germany); Mayer, Magnus C. [Freie Universität Berlin, Thielallee 63, 14195 Berlin (Germany); Miltenyi Biotec GmbH, Robert-Koch-Strasse 1, 17166 Teterow (Germany); Roeser, Dirk [Leibniz Institute for Age Research (FLI), Beutenbergstrasse 11, 07745 Jena (Germany); Multhaup, Gerd [McGill University Montreal, Montreal, Quebec H3G 1Y6 (Canada); Than, Manuel E., E-mail: sdahms@fli-leibniz.de [Leibniz Institute for Age Research (FLI), Beutenbergstrasse 11, 07745 Jena (Germany)

    2015-03-01

    Two X-ray structures of APLP1 E2 with and without a heparin dodecasaccharide are presented, revealing two distinct binding modes of the protein to heparan sulfate. The data provide a mechanistic explanation of how APP-like proteins bind to heparan sulfates and how they specifically recognize nonreducing structures of heparan sulfates. Beyond the pathology of Alzheimer’s disease, the members of the amyloid precursor protein (APP) family are essential for neuronal development and cell homeostasis in mammals. APP and its paralogues APP-like protein 1 (APLP1) and APP-like protein 2 (APLP2) contain the highly conserved heparan sulfate (HS) binding domain E2, which effects various (patho)physiological functions. Here, two crystal structures of the E2 domain of APLP1 are presented in the apo form and in complex with a heparin dodecasaccharide at 2.5 Å resolution. The apo structure of APLP1 E2 revealed an unfolded and hence flexible N-terminal helix αA. The (APLP1 E2){sub 2}–(heparin){sub 2} complex structure revealed two distinct binding modes, with APLP1 E2 explicitly recognizing the heparin terminus but also interacting with a continuous heparin chain. The latter only requires a certain register of the sugar moieties that fits to a positively charged surface patch and contributes to the general heparin-binding capability of APP-family proteins. Terminal binding of APLP1 E2 to heparin specifically involves a structure of the nonreducing end that is very similar to heparanase-processed HS chains. These data reveal a conserved mechanism for the binding of APP-family proteins to HS and imply a specific regulatory role of HS modifications in the biology of APP and APP-like proteins.

  9. A new mode of DNA binding distinguishes Capicua from other HMG-box factors and explains its mutation patterns in cancer

    Science.gov (United States)

    Forés, Marta; Samper, Núria; Barbacid, Mariano

    2017-01-01

    HMG-box proteins, including Sox/SRY (Sox) and TCF/LEF1 (TCF) family members, bind DNA via their HMG-box. This binding, however, is relatively weak and both Sox and TCF factors employ distinct mechanisms for enhancing their affinity and specificity for DNA. Here we report that Capicua (CIC), an HMG-box transcriptional repressor involved in Ras/MAPK signaling and cancer progression, employs an additional distinct mode of DNA binding that enables selective recognition of its targets. We find that, contrary to previous assumptions, the HMG-box of CIC does not bind DNA alone but instead requires a distant motif (referred to as C1) present at the C-terminus of all CIC proteins. The HMG-box and C1 domains are both necessary for binding specific TGAATGAA-like sites, do not function via dimerization, and are active in the absence of cofactors, suggesting that they form a bipartite structure for sequence-specific binding to DNA. We demonstrate that this binding mechanism operates throughout Drosophila development and in human cells, ensuring specific regulation of multiple CIC targets. It thus appears that HMG-box proteins generally depend on auxiliary DNA binding mechanisms for regulating their appropriate genomic targets, but that each sub-family has evolved unique strategies for this purpose. Finally, the key role of C1 in DNA binding also explains the fact that this domain is a hotspot for inactivating mutations in oligodendroglioma and other tumors, while being preserved in oncogenic CIC-DUX4 fusion chimeras associated to Ewing-like sarcomas. PMID:28278156

  10. Progress in analytical methods to predict and control azimuthal combustion instability modes in annular chambers

    Science.gov (United States)

    Bauerheim, M.; Nicoud, F.; Poinsot, T.

    2016-02-01

    Longitudinal low-frequency thermoacoustic unstable modes in combustion chambers have been intensively studied experimentally, numerically, and theoretically, leading to significant progress in both understanding and controlling these acoustic modes. However, modern annular gas turbines may also exhibit azimuthal modes, which are much less studied and feature specific mode structures and dynamic behaviors, leading to more complex situations. Moreover, dealing with 10-20 burners mounted in the same chamber limits the use of high fidelity simulations or annular experiments to investigate these modes because of their complexity and costs. Consequently, for such circumferential acoustic modes, theoretical tools have been developed to uncover underlying phenomena controlling their stability, nature, and dynamics. This review presents recent progress in this field. First, Galerkin and network models are described with their pros and cons in both the temporal and frequency framework. Then, key features of such acoustic modes are unveiled, focusing on their specificities such as symmetry breaking, non-linear modal coupling, forcing by turbulence. Finally, recent works on uncertainty quantifications, guided by theoretical studies and applied to annular combustors, are presented. The objective is to provide a global view of theoretical research on azimuthal modes to highlight their complexities and potential.

  11. A community resource benchmarking predictions of peptide binding to MHC-I molecules

    DEFF Research Database (Denmark)

    Peters, B; Bui, HH; Pletscher-Frankild, Sune

    2006-01-01

    on the internet. While differences in the data used to generate these predictions hamper direct comparisons, we do conclude that tools based on combinatorial peptide libraries perform remarkably well. The transparent prediction evaluation on this dataset provides tool developers with a benchmark for comparison...... to identify promising features of prediction methods and providing guidance to immunologists regarding the reliability of prediction tools....

  12. Predicting the Effect of Mutations on Protein-Protein Binding Interactions through Structure-Based Interface Profiles.

    Science.gov (United States)

    Brender, Jeffrey R; Zhang, Yang

    2015-10-01

    The formation of protein-protein complexes is essential for proteins to perform their physiological functions in the cell. Mutations that prevent the proper formation of the correct complexes can have serious consequences for the associated cellular processes. Since experimental determination of protein-protein binding affinity remains difficult when performed on a large scale, computational methods for predicting the consequences of mutations on binding affinity are highly desirable. We show that a scoring function based on interface structure profiles collected from analogous protein-protein interactions in the PDB is a powerful predictor of protein binding affinity changes upon mutation. As a standalone feature, the differences between the interface profile score of the mutant and wild-type proteins has an accuracy equivalent to the best all-atom potentials, despite being two orders of magnitude faster once the profile has been constructed. Due to its unique sensitivity in collecting the evolutionary profiles of analogous binding interactions and the high speed of calculation, the interface profile score has additional advantages as a complementary feature to combine with physics-based potentials for improving the accuracy of composite scoring approaches. By incorporating the sequence-derived and residue-level coarse-grained potentials with the interface structure profile score, a composite model was constructed through the random forest training, which generates a Pearson correlation coefficient >0.8 between the predicted and observed binding free-energy changes upon mutation. This accuracy is comparable to, or outperforms in most cases, the current best methods, but does not require high-resolution full-atomic models of the mutant structures. The binding interface profiling approach should find useful application in human-disease mutation recognition and protein interface design studies.

  13. Mode of encapsulation of linezolid by β-cyclodextrin and its role in bovine serum albumin binding.

    Science.gov (United States)

    Natesan, Sudha; Sowrirajan, Chandrasekaran; Yousuf, Sameena; Enoch, Israel V M V

    2015-01-22

    We describe, in this article, the associative interaction between Linezolid and β-Cyclodextrin, and the influence of β-Cyclodextrin on Linezolid's binding to Bovine serum albumin. β-Cyclodextrin forms a 1:1 inclusion complex with Linezolid, with a binding constant value of 3.51×10(2)M(-1). The binding is studied using ultraviolet-visible absorption, fluorescence, nuclear magnetic resonance, and rotating-frame overhauser effect spectroscopic techniques. The amide substituent on the oxazolidinone ring of Linezolid is involved in its binding to β-Cyclodextrin. The binding of the Linezolid to bovine serum albumin, in the absence and the presence of β-Cyclodextrin, is studied by analyzing the fluorescence quenching and Förster resonance energy transfer. The Stern-Volmer quenching constant, the binding constant, and energy transfer occurring on the interaction of the Linezolid with BSA are found to be smaller in the presence of β-Cyclodextrin than in water.

  14. Flanking p10 contribution and sequence bias in matrix based epitope prediction: revisiting the assumption of independent binding pockets

    Directory of Open Access Journals (Sweden)

    Parry Christian S

    2008-10-01

    Full Text Available Abstract Background Eluted natural peptides from major histocompatibility molecules show patterns of conserved residues. Crystallographic structures show that the bound peptide in class II major histocompatibility complex adopts a near uniform polyproline II-like conformation. This way allele-specific favoured residues are able to anchor into pockets in the binding groove leaving other peptide side chains exposed for recognition by T cells. The anchor residues form a motif. This sequence pattern can be used to screen large sequences for potential epitopes. Quantitative matrices extend the motif idea to include the contribution of non-anchor peptide residues. This report examines two new matrices that extend the binding register to incorporate the polymorphic p10 pocket of human leukocyte antigen DR1. Their performance is quantified against experimental binding measurements and against the canonical nine-residue register matrix. Results One new matrix shows significant improvement over the base matrix; the other does not. The new matrices differ in the sequence of the peptide library. Conclusion One of the extended quantitative matrices showed significant improvement in prediction over the original nine residue matrix and over the other extended matrix. Proline in the sequence of the peptide library of the better performing matrix presumably stabilizes the peptide conformation through neighbour interactions. Such interactions may influence epitope prediction in this test of quantitative matrices. This calls into question the assumption of the independent contribution of individual binding pockets.

  15. Prediction of Peptide Binding to Major Histocompatibility II Receptors with Molecular Mechanics and Semi-Empirical Quantum Mechanics Methods

    Directory of Open Access Journals (Sweden)

    James A Platts

    2012-02-01

    Full Text Available Methods for prediction of the binding of peptides to major histocompatibility complex (MHC II receptors are examined, using literature values of IC50 as a benchmark. Two sets of IC50 data for closely structurally related peptides based on hen egg lysozyme (HEL and myelin basic protein (MBP are reported first. This shows that methods based on both molecular mechanics and semi-empirical quantum mechanics can predict binding with good-to-reasonable accuracy, as long as a suitable method for estimation of solvation effects is included. A more diverse set of 22 peptides bound to HLA-DR1 provides a tougher test of such methods, especially since no crystal structure is available for these peptide-MHC complexes. We therefore use sequence based methods such as SYFPEITHI and SVMHC to generate possible binding poses, using a consensus approach to determine the most likely anchor residues, which are then mapped onto the crystal structure of an unrelated peptide bound to the same receptor. This analysis shows that the MM/GBVI method performs particularly well, as does the AMBER94 forcefield with Born solvation model. Indeed, MM/GBVI can be used as an alternative to sequence based methods in generating binding poses, leading to still better accuracy.

  16. Love to win or hate to Lose? Asymmetry of dopamine D2 receptor binding predicts sensitivity to reward versus punishment.

    Science.gov (United States)

    Tomer, Rachel; Slagter, Heleen A; Christian, Bradley T; Fox, Andrew S; King, Carlye R; Murali, Dhanabalan; Gluck, Mark A; Davidson, Richard J

    2014-05-01

    Humans show consistent differences in the extent to which their behavior reflects a bias toward appetitive approach-related behavior or avoidance of aversive stimuli [Elliot, A. J. Approach and avoidance motivation. In A. J. Elliot (Ed.), Handbook of approach and avoidance motivation (pp. 3-14). New York: Psychology Press, 2008]. We examined the hypothesis that in healthy participants this motivational bias (assessed by self-report and by a probabilistic learning task that allows direct comparison of the relative sensitivity to reward and punishment) reflects lateralization of dopamine signaling. Using [F-18]fallypride to measure D2/D3 binding, we found that self-reported motivational bias was predicted by the asymmetry of frontal D2 binding. Similarly, striatal and frontal asymmetries in D2 dopamine receptor binding, rather than absolute binding levels, predicted individual differences in learning from reward versus punishment. These results suggest that normal variation in asymmetry of dopamine signaling may, in part, underlie human personality and cognition.

  17. Development of molecular docking-based binding energy to predict the joint effect of BPA and its analogs.

    Science.gov (United States)

    Zhang, Hong-Chang; Hu, Xia-Lin; Yin, Da-Qiang; Lin, Zhi-Fen

    2011-04-01

    A general proposal for predicting the joint effect of endocrine disrupting chemicals by examining binding energy models was developed in this study. 2,2-bis(4-hydroxyphenyl)propane (BPA) and 11 of its analogs were chosen, and the estrogenic activity of each compound was measured by determining its EC50 value using a recombinant gene yeast assay. Binding energies (BEs) were calculated using Surflex-Docking software. The analysis of the relationship between EC50 values and BEs showed that there is a linear correlation between the BEs and EC50 values. Furthermore, the analysis of the given binary and quaternary mixtures of BPA and three of its analogs showed that the joint effects of the mixtures were affected by the proportions of the chemicals in each mixture and their relative binding energy. The correlation between the joint effects of mixtures and the binding energy of the individual compounds has been described using one formula, which can be used to predict the joint effects of other mixtures.

  18. THUMP--a predicted RNA-binding domain shared by 4-thiouridine, pseudouridine synthases and RNA methylases.

    Science.gov (United States)

    Aravind, L; Koonin, E V

    2001-04-01

    Sequence profile searches were used to identify an ancient domain in ThiI-like thiouridine synthases, conserved RNA methylases, archaeal pseudouridine synthases and several uncharacterized proteins. We predict that this domain is an RNA-binding domain that adopts an alpha/beta fold similar to that found in the C-terminal domain of translation initiation factor 3 and ribosomal protein S8.

  19. Predictions of mixed mode interface crack growth using a cohesive zone model for ductile fracture

    DEFF Research Database (Denmark)

    Tvergaard, Viggo

    2004-01-01

    with the surrounding material in the tangential direction. Thus, the present interface description incorporates the important effect of stress triaxiality on damage evolution, which is not part of the usual cohesive zone models. The interface elements have been used previously for mode I loading conditions......, but are here extended to cover non-symmetric mixed mode loading conditions for crack growth along an interface between dissimilar elastic-plastic solids. Crack growth resistance curves are calculated, and the dependence of the interface fracture toughness on the degree of mode mixity is studied. (C) 2003...

  20. Comparisons of Predicted Plasma Performance in ITER H-mode Plasmas with Various Mixes of External He

    Energy Technology Data Exchange (ETDEWEB)

    R.V. Budny

    2009-03-20

    Performance in H-mode DT plasmas in ITER with various choices of heating systems are predicted and compared. Combinations of external heating by Negative Ion Neutral Beam Injection (NNBI), Ion Cyclotron Range of Frequencies (ICRF), and Electron Cyclotron Heating (ECH) are assumed. Scans with a range of physics assumptions about boundary temperatures in the edge pedestal, alpha ash transport, and toroidal momentum transport are used to indicate effects of uncertainties. Time-dependent integrated modeling with the PTRANSP code is used to predict profiles of heating, beam torque, and plasma profiles. The GLF23 model is used to predict temperature profiles. Either GLF23 or the assumption of a constant ratio for χø/χi is used to predict toroidal rotation profiles driven by the beam torques. Large differences for the core temperatures are predicted with different mixes of the external heating during the density and current ramp-up phase, but the profiles are similar during the flattop phase. With χø/χi = 0.5, the predicted toroidal rotation is relatively slow and the flow shear implied by the pressure, toroidal rotation, and neoclassical poloidal rotation are not sufficient to cause significant changes in the energy transport or steady state temperature profiles. The GLF23-predicted toroidal rotation is faster by a factor of six, and significant flow shear effects are predicted.

  1. Structural insight into mode of binding of Meropenem to CTX-M-15 type β-lactamase.

    Science.gov (United States)

    Maryam, Lubna; Khan, Asad U

    2017-03-01

    Among Enterobacteriaceae, CTX-M type extended spectrum beta lactamase confers potent hydrolytic activity against cephalosporin group of antibiotics. Strains producing CTX-M type beta lactamase enzymes, show high level of resistance against cefotaxime. Therefore carbapenem antibiotics are used against beta lactamase producing strains. Hence, this study was designed to understand an insight of molecular basis of CTX-M-15 interaction with meropenem, and its effect on CTX-M-15 efficiency. Clinical strain of Enterobacter cloacae (EC-15) was used to clone blaCTX-M-15 gene in E.coli BL21cells. The protein was then expressed and purified. Results showed that CTX-M-15 producing strains are susceptible to meropenem. It quenches the fluorescence of CTX-M-15 spontaneously with binding constant of the order of 10(3)M(-1). Meropenem binds on the active site of CTX-M-15, hydrogen bonded with four common amino acid residues of cefotaxime binding site, as revealed by molecular docking studies. Conformational change in the structure of CTX-M-15 was observed upon meropenem binding by CD spectroscopy. The catalytic efficiency of CTX-M-15 was decreased up to 4 times upon meropenem binding. Docking study shows that few amino acids of active site of enzyme are also involved in meropenem binding, hence substrate is difficult to bind on active site properly and does not get hydrolysed. Moreover, meropenem binding induces structural changes in CTX-M-15, making the enzyme less efficient.

  2. Quantitative genetics of CTCF binding reveal local sequence effects and different modes of X-chromosome association.

    Directory of Open Access Journals (Sweden)

    Zhihao Ding

    2014-11-01

    Full Text Available Associating genetic variation with quantitative measures of gene regulation offers a way to bridge the gap between genotype and complex phenotypes. In order to identify quantitative trait loci (QTLs that influence the binding of a transcription factor in humans, we measured binding of the multifunctional transcription and chromatin factor CTCF in 51 HapMap cell lines. We identified thousands of QTLs in which genotype differences were associated with differences in CTCF binding strength, hundreds of them confirmed by directly observable allele-specific binding bias. The majority of QTLs were either within 1 kb of the CTCF binding motif, or in linkage disequilibrium with a variant within 1 kb of the motif. On the X chromosome we observed three classes of binding sites: a minority class bound only to the active copy of the X chromosome, the majority class bound to both the active and inactive X, and a small set of female-specific CTCF sites associated with two non-coding RNA genes. In sum, our data reveal extensive genetic effects on CTCF binding, both direct and indirect, and identify a diversity of patterns of CTCF binding on the X chromosome.

  3. An analysis of the binding of repressor protein ModE to modABCD (molybdate transport) operator/promoter DNA of Escherichia coli.

    Science.gov (United States)

    Grunden, A M; Self, W T; Villain, M; Blalock, J E; Shanmugam, K T

    1999-08-20

    Expression of the modABCD operon in Escherichia coli, which codes for a molybdate-specific transporter, is repressed by ModE in vivo in a molybdate-dependent fashion. In vitro DNase I-footprinting experiments identified three distinct regions of protection by ModE-molybdate on the modA operator/promoter DNA, GTTATATT (-15 to -8; region 1), GCCTACAT (-4 to +4; region 2), and GTTACAT (+8 to +14; region 3). Within the three regions of the protected DNA, a pentamer sequence, TAYAT (Y = C or T), can be identified. DNA-electrophoretic mobility experiments showed that the protected regions 1 and 2 are essential for binding of ModE-molybdate to DNA, whereas the protected region 3 increases the affinity of the DNA to the repressor. The stoichiometry of this interaction was found to be two ModE-molybdate per modA operator DNA. ModE-molybdate at 5 nM completely protected the modABCD operator/promoter DNA from DNase I-catalyzed hydrolysis, whereas ModE alone failed to protect the DNA even at 100 nM. The apparent K(d) for the interaction between the modA operator DNA and ModE-molybdate was 0.3 nM, and the K(d) increased to 8 nM in the absence of molybdate. Among the various oxyanions tested, only tungstate replaced molybdate in the repression of modA by ModE, but the affinity of ModE-tungstate for modABCD operator DNA was 6 times lower than with ModE-molybdate. A mutant ModE(T125I) protein, which repressed modA-lac even in the absence of molybdate, protected the same region of modA operator DNA in the absence of molybdate. The apparent K(d) for the interaction between modA operator DNA and ModE(T125I) was 3 nM in the presence of molybdate and 4 nM without molybdate. The binding of molybdate to ModE resulted in a decrease in fluorescence emission, indicating a conformational change of the protein upon molybdate binding. The fluorescence emission spectra of mutant ModE proteins, ModE(T125I) and ModE(Q216*), were unaffected by molybdate. The molybdate-independent mutant ModE

  4. Asymmetry of /sup 3/H- imipramine binding may predict psychiatric illness

    Energy Technology Data Exchange (ETDEWEB)

    Demeter, E.; Tekes, K.; Majorossy, K.; Palkovits, M.; Soos, M.; Magyar, K.; Somogyl, E.

    1989-01-01

    The B/sub max/ and Kd values for /sup 3/H-imipramine binding were measured in post-mortem human brains from drug-free selected psychiatric subject homicide victims and normal controls. The two groups were comparable in age and gender. The number of imipramine binding sites in the frontal cortices of psychiatric subjects had significantly higher B/sub max/ values in the left hemisphere than in the right hemisphere. Inversely, the number of imipramine binding sites in the frontal cortices of normal controls were significantly higher in the right brain than in the left brain. It was postulated that the inhibiting effect of central serotonin has weakened in psychiatric cases, therefore the changes of presynaptic serotonergic activity might be associated with psychiatric illness in the left hemisphere of human brain.

  5. The Vα14 invariant natural killer T cell TCR forces microbial glycolipids and CD1d into a conserved binding mode

    Science.gov (United States)

    Li, Yali; Girardi, Enrico; Wang, Jing; Yu, Esther Dawen; Painter, Gavin F.; Kronenberg, Mitchell

    2010-01-01

    Invariant natural killer T cells (iNKT cells) rapidly produce effector cytokines. In this study, we report the first crystal structures of the iNKT cell T cell receptor (TCR) bound to two natural, microbial glycolipids presented by CD1d. Binding of the TCR induced CDR3-α–dependent structural changes in the F′ roof of CD1d; these changes resemble those occurring in the absence of TCR engagement when the highly potent synthetic antigen α-galactosylceramide (α-GalCer) binds CD1d. Furthermore, in the Borrelia burgdorferi α–galactosyl diacylglycerol–CD1d complex, TCR binding caused a marked repositioning of the galactose sugar into an orientation that closely resembles α-GalCer. The TCR-dependent reorientation of the sugar, together with the induced CD1d fit, may explain the weaker potency of the microbial antigens compared with α-GalCer. We propose that the TCR of iNKT cells binds with a conserved footprint onto CD1d, regardless of the bound glycolipid antigen, and that for microbial antigens this unique binding mode requires TCR-initiated conformational changes. PMID:20921281

  6. Computational Characterization and Prediction of Estrogen Receptor Coactivator Binding Site Inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Bennion, B J; Kulp, K S; Cosman, M; Lightstone, F C

    2005-08-26

    Many carcinogens have been shown to cause tissue specific tumors in animal models. The mechanism for this specificity has not been fully elucidated and is usually attributed to differences in organ metabolism. For heterocyclic amines, potent carcinogens that are formed in well-done meat, the ability to either bind to the estrogen receptor and activate or inhibit an estrogenic response will have a major impact on carcinogenicity. Here we describe our work with the human estrogen receptor alpha (hERa) and the mutagenic/carcinogenic heterocyclic amines PhIP, MeIQx, IFP, and the hydroxylated metabolite of PhIP, N2-hydroxy-PhIP. We found that PhIP, in contrast to the other heterocyclic amines, increased cell-proliferation in MCF-7 human breast cancer cells and activated the hERa receptor. We show mechanistic data supporting this activation both computationally by homology modeling and docking, and by NMR confirmation that PhIP binds with the ligand binding domain (LBD). This binding competes with estradiol (E2) in the native E2 binding cavity of the receptor. We also find that other heterocyclic amines and N2-hydroxy-PhIP inhibit ER activation presumably by binding into another cavity on the LBD. Moreover, molecular dynamics simulations of inhibitory heterocyclic amines reveal a disruption of the surface of the receptor protein involved with protein-protein signaling. We therefore propose that the mechanism for the tissue specific carcinogenicity seen in the rat breast tumors and the presumptive human breast cancer associated with the consumption of well-done meat maybe mediated by this receptor activation.

  7. A training method for locomotion mode prediction using powered lower limb prostheses.

    Science.gov (United States)

    Young, Aaron J; Simon, Ann M; Hargrove, Levi J

    2014-05-01

    Recently developed lower-limb prostheses are capable of actuating the knee and ankle joints, allowing amputees to perform advanced locomotion modes such as step-over-step stair ascent and walking on sloped surfaces. However, transitions between these locomotion modes and walking are neither automatic nor seamless. This study describes methods for construction and training of a high-level intent recognition system for a lower-limb prosthesis that provides natural transitions between walking, stair ascent, stair descent, ramp ascent, and ramp descent. Using mechanical sensors onboard a powered prosthesis, we collected steady-state and transition data from six transfemoral amputees while the five locomotion modes were performed. An intent recognition system built using only mechanical sensor data was 84.5% accurate using only steady-state training data. Including training data collected while amputees performed seamless transitions between locomotion modes improved the overall accuracy rate to 93.9%. Training using a single analysis window at heel contact and toe off provided higher recognition accuracy than training with multiple analysis windows. This study demonstrates the capability of an intent recognition system to provide automatic, natural, and seamless transitions between five locomotion modes for transfemoral amputees using powered lower limb prostheses.

  8. Differential interfacial and substrate binding modes of mammalian pancreatic phospholipases A2: a comparison among human, bovine, and porcine enzymes.

    Science.gov (United States)

    Snitko, Y; Han, S K; Lee, B I; Cho, W

    1999-06-15

    To identify the residues essential for interfacial binding and substrate binding of human pancreatic phospholipase A2 (hpPLA2), several ionic residues in the putative interfacial binding surface (R6E, K7E, K10E, and K116E) and substrate binding site (D53K and K56E) were mutated. Interfacial affinity of these mutants was measured using anionic polymerized liposomes, and their enzymatic activity was measured using various substrates including phospholipid monomers, zwitterionic and anionic micelles, and anionic polymerized mixed liposomes. Similar mutations (R6E, K10E, K56E, and K116E) were made to porcine pancreatic phospholipase A2 (ppPLA2), and the properties of mutants were measured by the same methods. Results indicate that hpPLA2 and ppPLA2 have similar interfacial binding mechanisms in which cationic residues in the amino terminus and Lys-116 in the carboxy terminus are involved in binding to anionic lipid surfaces. Small but definite differences between the two enzymes were observed in overall interfacial affinity and activity and the effects of the mutations on interfacial enzyme activity. The interfacial binding of hpPLA2 and ppPLA2 is distinct from that of bovine pancreatic phospholipase A2 in that Lys-56 is involved in the interfacial binding of the latter enzyme. The unique phospholipid headgroup specificity of hpPLA2 derives from the presence of Asp-53 in the substrate binding site. This residue appears to participate in stabilizing electrostatic interactions with the cationic ethanolamine headgroup, hence the phosphatidylethanolamine preference of hpPLA2. Taken together, these studies reveal the similarities and the differences in the mechanisms by which mammalian pancreatic phospholipases A2 interact with lipid aggregates and perform interfacial catalysis.

  9. Predicting the Strength of Anion-π Interactions of Substituted Benzenes: the Development of Anion-π Binding Substituent Constants.

    Science.gov (United States)

    Bagwill, Christina; Anderson, Christa; Sullivan, Elizabeth; Manohara, Varun; Murthy, Prithvi; Kirkpatrick, Charles C; Stalcup, Apryll; Lewis, Michael

    2016-11-23

    A computational study aimed at accurately predicting the strength of the anion-π binding of substituted benzenes is presented. The anion-π binding energies (Ebind) of 37 substituted benzenes and the parent benzene, with chloride or bromide were investigated at the MP2(full)/6-311++G** level of theory. In addition, energy decomposition analysis was performed on 27 selected chloride-arene complexes via symmetry adapted perturbation theory (SAPT), using the SAPT2+ approach. Initial efforts aimed to correlate the anion-π Ebind values with the sum of the Hammett constants σp (Σσp) or σm (Σσm), as done by others. This proved a decent approach for predicting the binding strength of aromatics with electron-withdrawing substituents. For the Cl(-)-substituted benzene Ebind values, the correlation with the Σσp and Σσm values of aromatics with electron-withdrawing groups had r(2) values of 0.89 and 0.87 respectively. For the Br(-)-substituted benzene Ebind values, the correlation with the Σσp and Σσm values of aromatics with electron-withdrawing groups had r(2) values of 0.90 and 0.87. However, adding aromatics with electron-donating substituents to the investigation caused the correlation to deteriorate. For the Cl(-)-substituted benzene complexes the correlation between Ebind values and the Hammett constants had r(2) = 0.81 for Σσp and r(2) = 0.84 for Σσm. For the Br(-)-substituted benzene complexes, the respective r(2) values were 0.71 for Σσp and 0.79 for Σσm. The deterioration in correlation upon consideration of substituted benzenes with electron-donating substituents is due to the anion-π binding energies becoming more attractive regardless of what type of substituent is added to the aromatic. A similar trend has been reported for parallel face-to-face substituted benzene-benzene binding. This is certainly counter to what electrostatic arguments would predict for trends in anion-π binding energies, and this discrepancy is further highlighted

  10. Search for β2 adrenergic receptor ligands by virtual screening via grid computing and investigation of binding modes by docking and molecular dynamics simulations.

    Directory of Open Access Journals (Sweden)

    Qifeng Bai

    Full Text Available We designed a program called MolGridCal that can be used to screen small molecule database in grid computing on basis of JPPF grid environment. Based on MolGridCal program, we proposed an integrated strategy for virtual screening and binding mode investigation by combining molecular docking, molecular dynamics (MD simulations and free energy calculations. To test the effectiveness of MolGridCal, we screened potential ligands for β2 adrenergic receptor (β2AR from a database containing 50,000 small molecules. MolGridCal can not only send tasks to the grid server automatically, but also can distribute tasks using the screensaver function. As for the results of virtual screening, the known agonist BI-167107 of β2AR is ranked among the top 2% of the screened candidates, indicating MolGridCal program can give reasonable results. To further study the binding mode and refine the results of MolGridCal, more accurate docking and scoring methods are used to estimate the binding affinity for the top three molecules (agonist BI-167107, neutral antagonist alprenolol and inverse agonist ICI 118,551. The results indicate agonist BI-167107 has the best binding affinity. MD simulation and free energy calculation are employed to investigate the dynamic interaction mechanism between the ligands and β2AR. The results show that the agonist BI-167107 also has the lowest binding free energy. This study can provide a new way to perform virtual screening effectively through integrating molecular docking based on grid computing, MD simulations and free energy calculations. The source codes of MolGridCal are freely available at http://molgridcal.codeplex.com.

  11. pkaPS: prediction of protein kinase A phosphorylation sites with the simplified kinase-substrate binding model

    Directory of Open Access Journals (Sweden)

    Schneider Georg

    2007-01-01

    Full Text Available Abstract Background Protein kinase A (cAMP-dependent kinase, PKA is a serine/threonine kinase, for which ca. 150 substrate proteins are known. Based on a refinement of the recognition motif using the available experimental data, we wished to apply the simplified substrate protein binding model for accurate prediction of PKA phosphorylation sites, an approach that was previously successful for the prediction of lipid posttranslational modifications and of the PTS1 peroxisomal translocation signal. Results Approximately 20 sequence positions flanking the phosphorylated residue on both sides have been found to be restricted in their sequence variability (region -18...+23 with the site at position 0. The conserved physical pattern can be rationalized in terms of a qualitative binding model with the catalytic cleft of the protein kinase A. Positions -6...+4 surrounding the phosphorylation site are influenced by direct interaction with the kinase in a varying degree. This sequence stretch is embedded in an intrinsically disordered region composed preferentially of hydrophilic residues with flexible backbone and small side chain. This knowledge has been incorporated into a simplified analytical model of productive binding of substrate proteins with PKA. Conclusion The scoring function of the pkaPS predictor can confidently discriminate PKA phosphorylation sites from serines/threonines with non-permissive sequence environments (sensitivity of ~96% at a specificity of ~94%. The tool "pkaPS" has been applied on the whole human proteome. Among new predicted PKA targets, there are entirely uncharacterized protein groups as well as apparently well-known families such as those of the ribosomal proteins L21e, L22 and L6. Availability The supplementary data as well as the prediction tool as WWW server are available at http://mendel.imp.univie.ac.at/sat/pkaPS. Reviewers Erik van Nimwegen (Biozentrum, University of Basel, Switzerland, Sandor Pongor (International

  12. Sex hormone-binding globulin levels predict insulin sensitivity, disposition index, and cardiovascular risk during puberty

    DEFF Research Database (Denmark)

    Sørensen, Kaspar; Aksglaede, Lise; Munch-Andersen, Thor;

    2009-01-01

    Early puberty is associated with increased risk of subsequent cardiovascular disease. Low sex hormone-binding globulin (SHBG) levels are a feature of early puberty and of conditions associated with increased cardiovascular risk. The aim of the present study was to evaluate SHBG as a predictor of ...

  13. Individual Differences in the Multisensory Temporal Binding Window Predict Susceptibility to Audiovisual Illusions

    Science.gov (United States)

    Stevenson, Ryan A.; Zemtsov, Raquel K.; Wallace, Mark T.

    2012-01-01

    Human multisensory systems are known to bind inputs from the different sensory modalities into a unified percept, a process that leads to measurable behavioral benefits. This integrative process can be observed through multisensory illusions, including the McGurk effect and the sound-induced flash illusion, both of which demonstrate the ability of…

  14. Unbound position II in MXCXXC metallochaperone model peptides impacts metal binding mode and reactivity: Distinct similarities to whole proteins.

    Science.gov (United States)

    Shoshan, Michal S; Dekel, Noa; Goch, Wojciech; Shalev, Deborah E; Danieli, Tsafi; Lebendiker, Mario; Bal, Wojciech; Tshuva, Edit Y

    2016-06-01

    The effect of position II in the binding sequence of copper metallochaperones, which varies between Thr and His, was investigated through structural analysis and affinity and oxidation kinetic studies of model peptides. A first Cys-Cu(I)-Cys model obtained for the His peptide at acidic and neutral pH, correlated with higher affinity and more rapid oxidation of its complex; in contrast, the Thr peptide with the Cys-Cu(I)-Met coordination under neutral conditions demonstrated weaker and pH dependent binding. Studies with human antioxidant protein 1 (Atox1) and three of its mutants where S residues were replaced with Ala suggested that (a) the binding affinity is influenced more by the binding sequence than by the protein fold (b) pH may play a role in binding reactivity, and (c) mutating the Met impacted the affinity and oxidation rate more drastically than did mutating one of the Cys, supporting its important role in protein function. Position II thus plays a dominant role in metal binding and transport.

  15. Improved model predictive control of resistive wall modes by error field estimator in EXTRAP T2R

    Science.gov (United States)

    Setiadi, A. C.; Brunsell, P. R.; Frassinetti, L.

    2016-12-01

    Many implementations of a model-based approach for toroidal plasma have shown better control performance compared to the conventional type of feedback controller. One prerequisite of model-based control is the availability of a control oriented model. This model can be obtained empirically through a systematic procedure called system identification. Such a model is used in this work to design a model predictive controller to stabilize multiple resistive wall modes in EXTRAP T2R reversed-field pinch. Model predictive control is an advanced control method that can optimize the future behaviour of a system. Furthermore, this paper will discuss an additional use of the empirical model which is to estimate the error field in EXTRAP T2R. Two potential methods are discussed that can estimate the error field. The error field estimator is then combined with the model predictive control and yields better radial magnetic field suppression.

  16. Prediction of aquatic toxicity mode of action using linear discriminant and random forest models

    Science.gov (United States)

    The ability to determine the mode of action (MOA) for a diverse group of chemicals is a critical part of ecological risk assessment and chemical regulation. However, existing MOA assignment approaches in ecotoxicology have been limited to a relatively few MOAs, have high uncertai...

  17. Predicting treatment response in schizophrenia: The role of striatal and frontal dopamine D2/D3 receptor binding potential

    DEFF Research Database (Denmark)

    Nørbak, Henrik; Wulff, Sanne; Nielsen, Mette Ødegaard

    Predicting treatment response in schizophrenia: the role of striatal and frontal dopamine D2/D3 receptor binding potential Authors: Henrik Nørbak-Emig, Sanne Wulff, Mette Ø. Nielsen, Hans Rasmussen, Egill Rostrup, Nikolaj Bak, Lars Pinborg, Claus Svarer, Lars Thorbjørn Jensen, Bjørn H. Ebdrup......, Birte Y. Glenthøj Background: One of the best validated findings in schizophrenia is an association between increased presynaptic striatal dopaminergic activity and psychotic symptoms. Preclinical studies suggest an inverse relationship between frontal and striatal dopamine activity. This activity can...... indirectly be expressed by the binding potential (BP) of dopamine receptors using Single Photon Emission Computed Tomography (SPECT) where low striatal BP is believed to reflect high dopamine availability. Aim to assess the association between D2 receptor BPs in antipsychotic-naïve first...

  18. Interplay between magnetism and energetics in Fe-Cr alloys from a predictive noncollinear magnetic tight-binding model

    DEFF Research Database (Denmark)

    Soulairol, R.; Barreteau, Cyrille; Fu, Chu-Chun

    2016-01-01

    Magnetism is a key driving force controlling several thermodynamic and kinetic properties of Fe-Cr systems. We present a tight-binding model for Fe-Cr, where magnetism is treated beyond the usual collinear approximation. A major advantage of this model consists in a rather simple fitting procedure....... In particular, no specific property of the binary system is explicitly required in the fitting database. The present model is proved to be accurate and highly transferable for electronic, magnetic, and energetic properties of a large variety of structural and chemical environments: surfaces, interfaces......, embedded clusters, and the whole compositional range of the binary alloy. The occurrence of noncollinear magnetic configurations caused by magnetic frustrations is successfully predicted. The present tight-binding approach can apply to other binary magnetic transition-metal alloys. It is expected...

  19. Development and Application of Benchmark Examples for Mixed-Mode I/II Quasi-Static Delamination Propagation Predictions

    Science.gov (United States)

    Krueger, Ronald

    2012-01-01

    The development of benchmark examples for quasi-static delamination propagation prediction is presented. The example is based on a finite element model of the Mixed-Mode Bending (MMB) specimen for 50% mode II. The benchmarking is demonstrated for Abaqus/Standard, however, the example is independent of the analysis software used and allows the assessment of the automated delamination propagation prediction capability in commercial finite element codes based on the virtual crack closure technique (VCCT). First, a quasi-static benchmark example was created for the specimen. Second, starting from an initially straight front, the delamination was allowed to propagate under quasi-static loading. Third, the load-displacement as well as delamination length versus applied load/displacement relationships from a propagation analysis and the benchmark results were compared, and good agreement could be achieved by selecting the appropriate input parameters. The benchmarking procedure proved valuable by highlighting the issues associated with choosing the input parameters of the particular implementation. Overall, the results are encouraging, but further assessment for mixed-mode delamination fatigue onset and growth is required.

  20. A new protein binding pocket similarity measure based on comparison of clouds of atoms in 3D: application to ligand prediction

    Directory of Open Access Journals (Sweden)

    Zaslavskiy Mikhail

    2010-02-01

    Full Text Available Abstract Background Predicting which molecules can bind to a given binding site of a protein with known 3D structure is important to decipher the protein function, and useful in drug design. A classical assumption in structural biology is that proteins with similar 3D structures have related molecular functions, and therefore may bind similar ligands. However, proteins that do not display any overall sequence or structure similarity may also bind similar ligands if they contain similar binding sites. Quantitatively assessing the similarity between binding sites may therefore be useful to propose new ligands for a given pocket, based on those known for similar pockets. Results We propose a new method to quantify the similarity between binding pockets, and explore its relevance for ligand prediction. We represent each pocket by a cloud of atoms, and assess the similarity between two pockets by aligning their atoms in the 3D space and comparing the resulting configurations with a convolution kernel. Pocket alignment and comparison is possible even when the corresponding proteins share no sequence or overall structure similarities. In order to predict ligands for a given target pocket, we compare it to an ensemble of pockets with known ligands to identify the most similar pockets. We discuss two criteria to evaluate the performance of a binding pocket similarity measure in the context of ligand prediction, namely, area under ROC curve (AUC scores and classification based scores. We show that the latter is better suited to evaluate the methods with respect to ligand prediction, and demonstrate the relevance of our new binding site similarity compared to existing similarity measures. Conclusions This study demonstrates the relevance of the proposed method to identify ligands binding to known binding pockets. We also provide a new benchmark for future work in this field. The new method and the benchmark are available at http://cbio.ensmp.fr/paris/.

  1. Immunohistochemical determination of calcium-calmodulin binding predicts neuronal damage after global ischemia.

    Science.gov (United States)

    Picone, C M; Grotta, J C; Earls, R; Strong, R; Dedman, J

    1989-12-01

    Since ionic Ca2+ binds with intracellular calmodulin (CaM) before activating proteases, kinases, and phospholipases, demonstration of persistent Ca2+-CaM binding in neurons destined to show ischemic cellular injury would support the concept that elevated intracellular Ca2+ plays a causative role in ischemic neuronal damage. In order to characterize Ca2+-CaM binding, we used a sheep anti-CaM antibody (CaM-Ab) which recognizes CaM that is not bound to Ca2+ or brain target proteins. Therefore, immunohistochemical staining of brain sections by labeled CaM-Ab represented only unbound CaM. Six normal rats were compared to 15 animals rendered ischemic for 30 min by a modification of the four-vessel occlusion model. Animals were killed immediately after ischemia, and after 2 and 24 h of reperfusion. Brain sections through hippocampus were incubated in CaM-Ab, and a diaminobenzadiene labeled anti-sheep secondary antibody was added to stain the CaM-Ab. Staining in the endal limb of dentate, dorsal CA1, lateral CA3, and parietal cortex was graded on a 4-point scale. All normal animals had grade 4 staining indicating the presence of unbound CaM in all four brain regions. Ischemic animals demonstrated reduced (grade 0 to 2) staining in the CA1 and CA3 regions immediately and 2 and 24 h after ischemia (p less than 0.01 for both regions at all three time intervals) indicating persistent binding of CaM with Ca2+ and target proteins in these regions. Staining decreased in dentate and cortex up to 2 h after ischemia (p = 0.02 for both regions) but returned toward normal by 24 h.(ABSTRACT TRUNCATED AT 250 WORDS)

  2. Individual Differences in the Multisensory Temporal Binding Window Predict Susceptibility to Audiovisual Illusions

    OpenAIRE

    Stevenson, Ryan A.; Raquel K Zemtsov; Wallace, Mark T.

    2012-01-01

    Human multisensory systems are known to bind inputs from the different sensory modalities into a unified percept, a process that leads to measurable behavioral benefits. This integrative process can be observed through multisensory illusions, including the McGurk effect and the sound-induced flash illusion, both of which demonstrate the ability of one sensory modality to modulate perception in a second modality. Such multisensory integration is highly dependent upon the temporal relationship ...

  3. Limitations of Ab Initio Predictions of Peptide Binding to MHC Class II Molecules

    DEFF Research Database (Denmark)

    Zhang, Hao; Lund, Ole; Nielsen, Morten;

    2010-01-01

    on the highly conserved 3D structure of peptide:MHC complexes. While several such methods have been described before, most are not publicly available and have not been independently tested for their performance. We here implemented and evaluated three prediction methods for MHC class II molecules: statistical...... methods prediction performance showed that these are significantly better than random, but still substantially lower than the best performing sequence based class II prediction methods available. While the approaches presented here were developed independently, we have chosen to present our results...

  4. Mode mixing in sub- and trans-critical flows over an obstacle: When should Hawking's predictions be recovered?

    CERN Document Server

    Michel, Florent

    2015-01-01

    We reexamine the scattering coefficients of shallow water waves blocked by a stationary counter current over an obstacle. By considering series of background flows, we show that the most relevant parameter is $F_{\\rm max}$, the maximal value of the ratio of the flow velocity over the speed of low frequency waves. For subcritical flows, i.e., $F_{\\rm max} < 1$, there is no analogue Killing horizon and the mode amplification is strongly suppressed. Instead, when $F_{\\rm max} \\gtrsim 1.1$, the amplification is enhanced at low frequency and the spectrum closely follows Hawking's prediction. We further study subcritical flows close to that used in the Vancouver experiment. Our numerical analysis suggests that their observation of the "thermal nature of the mode conversion" is due to the relatively steep slope on the upstream side and the narrowness of the obstacle.

  5. Numerical Predictions of Mode Reflections in an Open Circular Duct: Comparison with Theory

    Science.gov (United States)

    Dahl, Milo D.; Hixon, Ray

    2015-01-01

    The NASA Broadband Aeroacoustic Stator Simulation code was used to compute the acoustic field for higher-order modes in a circular duct geometry. To test the accuracy of the results computed by the code, the duct was terminated by an open end with an infinite flange or no flange. Both open end conditions have a theoretical solution that was used to compare with the computed results. Excellent comparison for reflection matrix values was achieved after suitable refinement of the grid at the open end. The study also revealed issues with the level of the mode amplitude introduced into the acoustic held from the source boundary and the amount of reflection that occurred at the source boundary when a general nonreflecting boundary condition was applied.

  6. Computational Immunology Meets Bioinformatics: The Use of Prediction Tools for Molecular Binding in the Simulation of the Immune System

    DEFF Research Database (Denmark)

    Rapin, N.; Lund, Ole; Bernaschi, M.

    2010-01-01

    -protein potential measurements, for assessing molecular binding in the context of immune complexes. We benchmark the resulting model by simulating a classical immunization experiment that reproduces the development of immune memory. We also investigate the role of major histocompatibility complex (MHC) haplotype......We present a new approach to the study of the immune system that combines techniques of systems biology with information provided by data-driven prediction methods. To this end, we have extended an agent-based simulator of the immune response, C-IMMSIM, such that it represents pathogens, as well...

  7. Predicting the right spacing between protein immobilization sites on self-assembled monolayers to optimize ligand binding.

    Science.gov (United States)

    Perez, Javier Batista; Tyagi, Deependra; Yang, Mo; Calvo, Loany; Perez, Rolando; Moreno, Ernesto; Zhu, Jinsong

    2015-09-01

    Self-assembled monolayers designed to immobilize capture antibodies are usually prepared using a mixture of functional and inactive linkers. Here, using low molar ratios (1:1 to 1:100) of the two linkers resulted in loss of binding capability of the anti-EGFR (epidermal growth factor receptor) antibody nimotuzumab, as assessed by surface plasmon resonance imaging. We then developed a simple theoretical model to predict the optimal surface density of the functional linker, taking into account the antibody size and linker diameter. A high (1:1000) dilution of the functional linker yielded the best results. As an advantage, this approach does not require chemical modification of the protein.

  8. Method for predicting whispering gallery mode spectra of active spherical microresonators

    CERN Document Server

    Hall, Jonathan M M; Henderson, Matthew R; Francois, Alexandre; Reynolds, Tess; Riesen, Nicolas; Monro, Tanya M

    2014-01-01

    A full three-dimensional Finite-Difference Time-Domain (FDTD)-based toolkit is developed to simulate the whispering gallery modes of a microsphere in the vicinity of a dipole source, placed on the surface. This provides a guide for experiments that rely on coupling to active microspheres. The resultant spectra are compared to those of analytic models used in the field. In contrast to the analytic models, the FDTD method is able to collect flux from an arbitrary collection region, such as a disk-shaped region, analogous to an optical fibre. The flux collection time may also be altered to access transient phenomena that may not appear at long collection times. The customisability of the technique allows one to consider a variety of mode excitation scenarios, such as refractive index inhomogeneity in the material, and different resonator shapes, such as shells and ellipsoids. The coupling efficiency to specific modes within wavelength regions can thus be optimized, preselecting the desired optical properties pri...

  9. Characterization of the differences in the cyclopiazonic acid binding mode to mammalian and P. Falciparum Ca2+ pumps: a computational study.

    KAUST Repository

    Di Marino, Daniele

    2015-03-01

    Despite the investments in malaria research, an effective vaccine has not yet been developed and the causative parasites are becoming increasingly resistant to most of the available drugs. PfATP6, the sarco/endoplasmic reticulum Ca2+ pump (SERCA) of P. falciparum, has been recently genetically validated as a potential antimalarial target and cyclopiazonic acid (CPA) has been found to be a potent inhibitor of SERCAs in several organisms, including P. falciparum. In position 263, PfATP6 displays a leucine residue, whilst the corresponding position in the mammalian SERCA is occupied by a glutamic acid. The PfATP6 L263E mutation has been studied in relation to the artemisinin inhibitory effect on P. falciparum and recent studies have provided evidence that the parasite with this mutation is more susceptible to CPA. Here, we characterized, for the first time, the interaction of CPA with PfATP6 and its mammalian counterpart to understand similarities and differences in the mode of binding of the inhibitor to the two Ca2+ pumps. We found that, even though CPA does not directly interact with the residue in position 263, the presence of a hydrophobic residue in this position in PfATP6 rather than a negatively charged one, as in the mammalian SERCA, entails a conformational arrangement of the binding pocket which, in turn, determines a relaxation of CPA leading to a different binding mode of the compound. Our findings highlight differences between the plasmodial and human SERCA CPA-binding pockets that may be exploited to design CPA derivatives more selective toward PfATP6.

  10. Prediction of major histocompatibility complex binding regions of protein antigens by sequence pattern analysis

    DEFF Research Database (Denmark)

    Sette, A; Buus, S; Appella, E;

    1989-01-01

    We have previously experimentally analyzed the structural requirements for interaction between peptide antigens and mouse major histocompatibility complex (MHC) molecules of the d haplotype. We describe here two procedures devised to predict specifically the capacity of peptide molecules to inter......We have previously experimentally analyzed the structural requirements for interaction between peptide antigens and mouse major histocompatibility complex (MHC) molecules of the d haplotype. We describe here two procedures devised to predict specifically the capacity of peptide molecules...

  11. The distal pocket histidine residue in horse heart myoglobin directs the O-binding mode of nitrite to the heme iron.

    Science.gov (United States)

    Yi, Jun; Heinecke, Julie; Tan, Hui; Ford, Peter C; Richter-Addo, George B

    2009-12-23

    It is now well-established that mammalian heme proteins are reactive with various nitrogen oxide species and that these reactions may play significant roles in mammalian physiology. For example, the ferrous heme protein myoglobin (Mb) has been shown to reduce nitrite (NO(2)(-)) to nitric oxide (NO) under hypoxic conditions. We demonstrate here that the distal pocket histidine residue (His64) of horse heart metMb(III) (i.e., ferric Mb(III)) has marked effects on the mode of nitrite ion coordination to the iron center. X-ray crystal structures were determined for the mutant proteins metMb(III) H64V (2.0 A resolution) and its nitrite ion adduct metMb(III) H64V-nitrite (1.95 A resolution), and metMb(III) H64V/V67R (1.9 A resolution) and its nitrite ion adduct metMb(III) H64V/V67R-nitrite (2.0 A resolution). These are compared to the known structures of wild-type (wt) hh metMb(III) and its nitrite ion adduct hh metMb(III)-nitrite, which binds NO(2)(-) via an O-atom in a trans-FeONO configuration. Unlike wt metMb(III), no axial H(2)O is evident in either of the metMb(III) mutant structures. In the ferric H64V-nitrite structure, replacement of the distal His residue with Val alters the binding mode of nitrite from the nitrito (O-binding) form in the wild-type protein to a weakly bound nitro (N-binding) form. Reintroducing a H-bonding residue in the H64V/V67R double mutant restores the O-binding mode of nitrite. We have also examined the effects of these mutations on reactivities of the metMb(III)s with cysteine as a reducing agent and of the (ferrous) Mb(II)s with nitrite ion under anaerobic conditions. The Mb(II)s were generated by reduction of the Mb(III) precursors in a second-order reaction with cysteine, the rate constants for this step following the order H64V/V67R > H64V > wt. The rate constants for the oxidation of the Mb(II)s by nitrite (giving NO as the other product) follow the order wt > H64V/V67R > H64V and suggest a significant role of the distal pocket H

  12. A Conserved Mode of Protein Recognition and Binding in a ParD−ParE Toxin−Antitoxin Complex

    Energy Technology Data Exchange (ETDEWEB)

    Dalton, Kevin M.; Crosson, Sean (UC)

    2010-05-06

    Toxin-antitoxin (TA) systems form a ubiquitous class of prokaryotic proteins with functional roles in plasmid inheritance, environmental stress response, and cell development. ParDE family TA systems are broadly conserved on plasmids and bacterial chromosomes and have been well characterized as genetic elements that promote stable plasmid inheritance. We present a crystal structure of a chromosomally encoded ParD-ParE complex from Caulobacter crescentus at 2.6 {angstrom} resolution. This TA system forms an {alpha}{sub 2}{beta}{sub 2} heterotetramer in the crystal and in solution. The toxin-antitoxin binding interface reveals extensive polar and hydrophobic contacts of ParD antitoxin helices with a conserved recognition and binding groove on the ParE toxin. A cross-species comparison of this complex structure with related toxin structures identified an antitoxin recognition and binding subdomain that is conserved between distantly related members of the RelE/ParE toxin superfamily despite a low level of overall primary sequence identity. We further demonstrate that ParD antitoxin is dimeric, stably folded, and largely helical when not bound to ParE toxin. Thus, the paradigmatic model in which antitoxin undergoes a disorder-to-order transition upon toxin binding does not apply to this chromosomal ParD-ParE TA system.

  13. A unique binding mode enables MCM2 to chaperone histones H3-H4 at replication forks

    DEFF Research Database (Denmark)

    Huang, Hongda; Strømme, Caroline B; Saredi, Giulia;

    2015-01-01

    , chaperones histones H3-H4. Our first structure shows an H3-H4 tetramer bound by two MCM2 histone-binding domains (HBDs), which hijack interaction sites used by nucleosomal DNA. Our second structure reveals MCM2 and ASF1 cochaperoning an H3-H4 dimer. Mutational analyses show that the MCM2 HBD is required...

  14. Inhibition and Larvicidal Activity of Phenylpropanoids from Piper sarmentosum on Acetylcholinesterase against Mosquito Vectors and Their Binding Mode of Interaction.

    Science.gov (United States)

    Hematpoor, Arshia; Liew, Sook Yee; Chong, Wei Lim; Azirun, Mohd Sofian; Lee, Vannajan Sanghiran; Awang, Khalijah

    2016-01-01

    Aedes aegypti, Aedes albopictus and Culex quinquefasciatus are vectors of dengue fever and West Nile virus diseases. This study was conducted to determine the toxicity, mechanism of action and the binding interaction of three active phenylpropanoids from Piper sarmentosum (Piperaceae) toward late 3rd or early 4th larvae of above vectors. A bioassay guided-fractionation on the hexane extract from the roots of Piper sarmentosum led to the isolation and identification of three active phenylpropanoids; asaricin 1, isoasarone 2 and trans-asarone 3. The current study involved evaluation of the toxicity and acetylcholinesterase (AChE) inhibition of these compounds against Aedes aegypti, Aedes albopictus and Culex quinquefasciatus larvae. Asaricin 1 and isoasarone 2 were highly potent against Aedes aegypti, Aedes albopictus and Culex quinquefasciatus larvae causing up to 100% mortality at ≤ 15 μg/mL concentration. The ovicidal activity of asaricin 1, isoasarone 2 and trans-asarone 3 were evaluated through egg hatching. Asaricin 1 and isoasarone 2 showed potent ovicidal activity. Ovicidal activity for both compounds was up to 95% at 25μg/mL. Asaricin 1 and isoasarone 2 showed strong inhibition on acetylcholinesterase with relative IC50 values of 0.73 to 1.87 μg/mL respectively. These findings coupled with the high AChE inhibition may suggest that asaricin 1 and isoasarone 2 are neuron toxic compounds toward Aedes aegypti, Aedes albopictus and Culex quinquefasciatus. Further computational docking with Autodock Vina elaborates the possible interaction of asaricin 1 and isoasarone 2 with three possible binding sites of AChE which includes catalytic triads (CAS: S238, E367, H480), the peripheral sites (PAS: E72, W271) and anionic binding site (W83). The binding affinity of asaricin 1 and isoasarone 2 were relatively strong with asaricin 1 showed a higher binding affinity in the anionic pocket.

  15. Inhibition and Larvicidal Activity of Phenylpropanoids from Piper sarmentosum on Acetylcholinesterase against Mosquito Vectors and Their Binding Mode of Interaction

    Science.gov (United States)

    Hematpoor, Arshia; Liew, Sook Yee; Chong, Wei Lim; Azirun, Mohd Sofian; Lee, Vannajan Sanghiran; Awang, Khalijah

    2016-01-01

    Aedes aegypti, Aedes albopictus and Culex quinquefasciatus are vectors of dengue fever and West Nile virus diseases. This study was conducted to determine the toxicity, mechanism of action and the binding interaction of three active phenylpropanoids from Piper sarmentosum (Piperaceae) toward late 3rd or early 4th larvae of above vectors. A bioassay guided-fractionation on the hexane extract from the roots of Piper sarmentosum led to the isolation and identification of three active phenylpropanoids; asaricin 1, isoasarone 2 and trans-asarone 3. The current study involved evaluation of the toxicity and acetylcholinesterase (AChE) inhibition of these compounds against Aedes aegypti, Aedes albopictus and Culex quinquefasciatus larvae. Asaricin 1 and isoasarone 2 were highly potent against Aedes aegypti, Aedes albopictus and Culex quinquefasciatus larvae causing up to 100% mortality at ≤ 15 μg/mL concentration. The ovicidal activity of asaricin 1, isoasarone 2 and trans-asarone 3 were evaluated through egg hatching. Asaricin 1 and isoasarone 2 showed potent ovicidal activity. Ovicidal activity for both compounds was up to 95% at 25μg/mL. Asaricin 1 and isoasarone 2 showed strong inhibition on acetylcholinesterase with relative IC50 values of 0.73 to 1.87 μg/mL respectively. These findings coupled with the high AChE inhibition may suggest that asaricin 1 and isoasarone 2 are neuron toxic compounds toward Aedes aegypti, Aedes albopictus and Culex quinquefasciatus. Further computational docking with Autodock Vina elaborates the possible interaction of asaricin 1 and isoasarone 2 with three possible binding sites of AChE which includes catalytic triads (CAS: S238, E367, H480), the peripheral sites (PAS: E72, W271) and anionic binding site (W83). The binding affinity of asaricin 1 and isoasarone 2 were relatively strong with asaricin 1 showed a higher binding affinity in the anionic pocket. PMID:27152416

  16. Inhibition and Larvicidal Activity of Phenylpropanoids from Piper sarmentosum on Acetylcholinesterase against Mosquito Vectors and Their Binding Mode of Interaction.

    Directory of Open Access Journals (Sweden)

    Arshia Hematpoor

    Full Text Available Aedes aegypti, Aedes albopictus and Culex quinquefasciatus are vectors of dengue fever and West Nile virus diseases. This study was conducted to determine the toxicity, mechanism of action and the binding interaction of three active phenylpropanoids from Piper sarmentosum (Piperaceae toward late 3rd or early 4th larvae of above vectors. A bioassay guided-fractionation on the hexane extract from the roots of Piper sarmentosum led to the isolation and identification of three active phenylpropanoids; asaricin 1, isoasarone 2 and trans-asarone 3. The current study involved evaluation of the toxicity and acetylcholinesterase (AChE inhibition of these compounds against Aedes aegypti, Aedes albopictus and Culex quinquefasciatus larvae. Asaricin 1 and isoasarone 2 were highly potent against Aedes aegypti, Aedes albopictus and Culex quinquefasciatus larvae causing up to 100% mortality at ≤ 15 μg/mL concentration. The ovicidal activity of asaricin 1, isoasarone 2 and trans-asarone 3 were evaluated through egg hatching. Asaricin 1 and isoasarone 2 showed potent ovicidal activity. Ovicidal activity for both compounds was up to 95% at 25μg/mL. Asaricin 1 and isoasarone 2 showed strong inhibition on acetylcholinesterase with relative IC50 values of 0.73 to 1.87 μg/mL respectively. These findings coupled with the high AChE inhibition may suggest that asaricin 1 and isoasarone 2 are neuron toxic compounds toward Aedes aegypti, Aedes albopictus and Culex quinquefasciatus. Further computational docking with Autodock Vina elaborates the possible interaction of asaricin 1 and isoasarone 2 with three possible binding sites of AChE which includes catalytic triads (CAS: S238, E367, H480, the peripheral sites (PAS: E72, W271 and anionic binding site (W83. The binding affinity of asaricin 1 and isoasarone 2 were relatively strong with asaricin 1 showed a higher binding affinity in the anionic pocket.

  17. Prediction of DtxR regulon: Identification of binding sites and operons controlled by Diphtheria toxin repressor in Corynebacterium diphtheriae

    Directory of Open Access Journals (Sweden)

    Hasnain Seyed

    2004-09-01

    Full Text Available Abstract Background The diphtheria toxin repressor, DtxR, of Corynebacterium diphtheriae has been shown to be an iron-activated transcription regulator that controls not only the expression of diphtheria toxin but also of iron uptake genes. This study aims to identify putative binding sites and operons controlled by DtxR to understand the role of DtxR in patho-physiology of Corynebacterium diphtheriae. Result Positional Shannon relative entropy method was used to build the DtxR-binding site recognition profile and the later was used to identify putative regulatory sites of DtxR within C. diphtheriae genome. In addition, DtxR-regulated operons were also identified taking into account the predicted DtxR regulatory sites and genome annotation. Few of the predicted motifs were experimentally validated by electrophoretic mobility shift assay. The analysis identifies motifs upstream to the novel iron-regulated genes that code for Formamidopyrimidine-DNA glycosylase (FpG, an enzyme involved in DNA-repair and starvation inducible DNA-binding protein (Dps which is involved in iron storage and oxidative stress defense. In addition, we have found the DtxR motifs upstream to the genes that code for sortase which catalyzes anchoring of host-interacting proteins to the cell wall of pathogenic bacteria and the proteins of secretory system which could be involved in translocation of various iron-regulated virulence factors including diphtheria toxin. Conclusions We have used an in silico approach to identify the putative binding sites and genes controlled by DtxR in Corynebacterium diphtheriae. Our analysis shows that DtxR could provide a molecular link between Fe+2-induced Fenton's reaction and protection of DNA from oxidative damage. DtxR-regulated Dps prevents lethal combination of Fe+2 and H2O2 and also protects DNA by nonspecific DNA-binding. In addition DtxR could play an important role in host interaction and virulence by regulating the levels of sortase

  18. Prediction of binding affinity and efficacy of thyroid hormone receptor ligands using QSAR and structure-based modeling methods

    Energy Technology Data Exchange (ETDEWEB)

    Politi, Regina [Laboratory for Molecular Modeling, Division of Chemical Biology and Medicinal Chemistry, University of North Carolina, Chapel Hill, NC 27599 (United States); Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, NC 27599 (United States); Rusyn, Ivan, E-mail: iir@unc.edu [Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, NC 27599 (United States); Tropsha, Alexander, E-mail: alex_tropsha@unc.edu [Laboratory for Molecular Modeling, Division of Chemical Biology and Medicinal Chemistry, University of North Carolina, Chapel Hill, NC 27599 (United States)

    2014-10-01

    The thyroid hormone receptor (THR) is an important member of the nuclear receptor family that can be activated by endocrine disrupting chemicals (EDC). Quantitative Structure–Activity Relationship (QSAR) models have been developed to facilitate the prioritization of THR-mediated EDC for the experimental validation. The largest database of binding affinities available at the time of the study for ligand binding domain (LBD) of THRβ was assembled to generate both continuous and classification QSAR models with an external accuracy of R{sup 2} = 0.55 and CCR = 0.76, respectively. In addition, for the first time a QSAR model was developed to predict binding affinities of antagonists inhibiting the interaction of coactivators with the AF-2 domain of THRβ (R{sup 2} = 0.70). Furthermore, molecular docking studies were performed for a set of THRβ ligands (57 agonists and 15 antagonists of LBD, 210 antagonists of the AF-2 domain, supplemented by putative decoys/non-binders) using several THRβ structures retrieved from the Protein Data Bank. We found that two agonist-bound THRβ conformations could effectively discriminate their corresponding ligands from presumed non-binders. Moreover, one of the agonist conformations could discriminate agonists from antagonists. Finally, we have conducted virtual screening of a chemical library compiled by the EPA as part of the Tox21 program to identify potential THRβ-mediated EDCs using both QSAR models and docking. We concluded that the library is unlikely to have any EDC that would bind to the THRβ. Models developed in this study can be employed either to identify environmental chemicals interacting with the THR or, conversely, to eliminate the THR-mediated mechanism of action for chemicals of concern. - Highlights: • This is the largest curated dataset for ligand binding domain (LBD) of the THRβ. • We report the first QSAR model for antagonists of AF-2 domain of THRβ. • A combination of QSAR and docking enables

  19. Predicting the occurrence of mixed mode failure associated with hydraulic fracturing, part 2 water saturated tests

    Energy Technology Data Exchange (ETDEWEB)

    Bauer, Stephen J. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Broome, Scott Thomas [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Choens, Charles [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Barrow, Perry Carl [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)

    2015-09-14

    Seven water-saturated triaxial extension experiments were conducted on four sedimentary rocks. This experimental condition was hypothesized more representative of that existing for downhole hydrofracture and thus it may improve our understanding of the phenomena. In all tests the pore pressure was 10 MPa and confirming pressure was adjusted to achieve tensile and transitional failure mode conditions. Using previous work in this LDRD for comparison, the law of effective stress is demonstrated in extension using this sample geometry. In three of the four lithologies, no apparent chemo-mechanical effect of water is apparent, and in the fourth lithology test results indicate some chemo-mechanical effect of water.

  20. Higher-order Mode Calculations, predictions and Overview of Damping Schemes for ERLs

    Energy Technology Data Exchange (ETDEWEB)

    Robert Rimmer

    2005-03-19

    This paper gives a brief review of computational methods for calculating higher-order mode (HOM) impedances for RF structures, the cases for which they are appropriate and some comparisons with measurements. An overview of damping schemes suitable for moderate to high current energy recovered linacs (ERL's), is presented, with a discussion of the pro's and con's of each. The influence of number of cells per cavity, cell shape and cell-to-cell coupling are described. The Jefferson Lab Ampere-class cryomodule concept is presented as an example and the issue of HOM power is highlighted.

  1. Higher-order mode calculations, predictions and overview of damping schemes for energy recovering linacs

    Energy Technology Data Exchange (ETDEWEB)

    Rimmer, R.A. [Jefferson Laboratory, 12000 Jefferson Avenue, Newport News, VA 23606 (United States)]. E-mail: rarimmer@jlab.org

    2006-02-01

    This paper gives a brief review of computational methods for calculating higher-order mode (HOM) impedances for RF structures, the cases for which they are appropriate and some comparisons with measurements. An overview of damping schemes suitable for moderate to high current energy recovered linacs (ERLs), is presented, with a discussion of the pro's and con's of each. The influence of number of cells per cavity, cell shape and cell-to-cell coupling are described. The Jefferson Lab Ampere-class cryomodule concept is presented as an example and the issue of HOM power is highlighted.

  2. Markov Chain Modelling of Reliability Analysis and Prediction under Mixed Mode Loading

    Institute of Scientific and Technical Information of China (English)

    SINGH Salvinder; ABDULLAH Shahrum; NIK MOHAMED Nik Abdullah; MOHD NOORANI Mohd Salmi

    2015-01-01

    The reliability assessment for an automobile crankshaft provides an important understanding in dealing with the design life of the component in order to eliminate or reduce the likelihood of failure and safety risks. The failures of the crankshafts are considered as a catastrophic failure that leads towards a severe failure of the engine block and its other connecting subcomponents. The reliability of an automotive crankshaft under mixed mode loading using the Markov Chain Model is studied. The Markov Chain is modelled by using a two-state condition to represent the bending and torsion loads that would occur on the crankshaft. The automotive crankshaft represents a good case study of a component under mixed mode loading due to the rotating bending and torsion stresses. An estimation of the Weibull shape parameter is used to obtain the probability density function, cumulative distribution function, hazard and reliability rate functions, the bathtub curve and the mean time to failure. The various properties of the shape parameter is used to model the failure characteristic through the bathtub curve is shown. Likewise, an understanding of the patterns posed by the hazard rate onto the component can be used to improve the design and increase the life cycle based on the reliability and dependability of the component. The proposed reliability assessment provides an accurate, efficient, fast and cost effective reliability analysis in contrast to costly and lengthy experimental techniques.

  3. Alternative binding modes of l-histidine guided by metal ions for the activation of the antiterminator protein HutP of Bacillus subtilis.

    Science.gov (United States)

    Dhakshnamoorthy, Balasundaresan; Mizuno, Hiroshi; Kumar, Penmetcha K R

    2013-09-01

    Anti-terminator proteins control gene expression by recognizing control signals within cognate transcripts and then preventing transcription termination. HutP is such a regulatory protein that regulates the expression of the histidine utilization (hut) operon in Bacillus subtilis by binding to cis-acting regulatory sequences in hut mRNAs. During the anti-termination process, l-histidine and a divalent ion are required for hutP to bind to the specific sequence within the hut mRNA. Our previous crystal structure of the HutP-l-histidine-Mg(2+)-RNA ternary complex demonstrated that the l-histidine ligand and Mg(2+) bind together such that the backbone nitrogen and carboxyl oxygen of l-histidine coordinate with Mg(2+). In addition to the Mg(2+), other divalent ions are also known to efficiently support the l-histidine-dependent anti-termination of the hut operon, and the best divalent ion is Zn(2+). In this study, we determined the crystal structure of the HutP-l-histidine-Zn(2+) complex and found that the orientation of l-histidine coordinated to Zn(2+) is reversed relative to that of l-histidine coordinated to Mg(2+), i.e., the imidazole side chain nitrogen of l-histidine coordinates to Zn(2+). This alternative binding mode of the l-histidine ligand to a divalent ion provides further insight into the mechanisms responsible for the activation of RNA binding during the hut anti-termination process.

  4. Preterm birth and cerebral palsy. Predictive value of pregnancy complications, mode of delivery, and Apgar scores

    DEFF Research Database (Denmark)

    Topp, Monica Wedell; Langhoff-Roos, J; Uldall, P

    1997-01-01

    .01), and low Apgar scores at 1 minute (45% vs. 36%, p or = 3 (adjusted OR = 1.53 (95% CI 1.00-2.34), p ... complications preceding preterm birth did not imply a higher risk of cerebral palsy. Delivery by Cesarean section was a prognostic factor for developing cerebral palsy, and the predictive value of Apgar scores was highly limited....

  5. Probing Structural Features and Binding Mode of 3-Arylpyrimidin-2,4-diones within Housefly γ-Aminobutyric Acid (GABA Receptor

    Directory of Open Access Journals (Sweden)

    Xiangya Kong

    2011-09-01

    Full Text Available In order to obtain structural features of 3-arylpyrimidin-2,4-diones emerged as promising inhibitors of insect γ-aminobutyric acid (GABA receptor, a set of ligand-/receptor-based 3D-QSAR models for 60 derivatives are generated using Comparative Molecular Field Analysis (CoMFA and Comparative Molecular Similarity Index Analysis (CoMSIA. The statistically optimal CoMSIA model is produced with highest q2 of 0.62, r2ncv of 0.97, and r2pred of 0.95. A minor/bulky electronegative hydrophilic polar substituent at the 1-/6-postion of the uracil ring, and bulky substituents at the 3'-, 4'- and 5'-positions of the benzene ring are beneficial for the enhanced potency of the inhibitors as revealed by the obtained 3D-contour maps. Furthermore, homology modeling, molecular dynamics (MD simulation and molecular docking are also carried out to gain a better understanding of the probable binding modes of these inhibitors, and the results show that residues Ala-183(C, Thr-187(B, Thr-187(D and Thr-187(E in the second transmembrane domains of GABA receptor are responsible for the H-bonding interactions with the inhibitor. The good correlation between docking observations and 3D-QSAR analyses further proves the model reasonability in probing the structural features and the binding mode of 3-arylpyrimidin-2,4-dione derivatives within the housefly GABA receptor.

  6. Binding of the auxiliary subunit TRIP8b to HCN channels shifts the mode of action of cAMP.

    Science.gov (United States)

    Hu, Lei; Santoro, Bina; Saponaro, Andrea; Liu, Haiying; Moroni, Anna; Siegelbaum, Steven

    2013-12-01

    Hyperpolarization-activated cyclic nucleotide-regulated cation (HCN) channels generate the hyperpolarization-activated cation current Ih present in many neurons. These channels are directly regulated by the binding of cAMP, which both shifts the voltage dependence of HCN channel opening to more positive potentials and increases maximal Ih at extreme negative voltages where voltage gating is complete. Here we report that the HCN channel brain-specific auxiliary subunit TRIP8b produces opposing actions on these two effects of cAMP. In the first action, TRIP8b inhibits the effect of cAMP to shift voltage gating, decreasing both the sensitivity of the channel to cAMP (K1/2) and the efficacy of cAMP (maximal voltage shift); conversely, cAMP binding inhibits these actions of TRIP8b. These mutually antagonistic actions are well described by a cyclic allosteric mechanism in which TRIP8b binding reduces the affinity of the channel for cAMP, with the affinity of the open state for cAMP being reduced to a greater extent than the cAMP affinity of the closed state. In a second apparently independent action, TRIP8b enhances the action of cAMP to increase maximal Ih. This latter effect cannot be explained by the cyclic allosteric model but results from a previously uncharacterized action of TRIP8b to reduce maximal current through the channel in the absence of cAMP. Because the binding of cAMP also antagonizes this second effect of TRIP8b, application of cAMP produces a larger increase in maximal Ih in the presence of TRIP8b than in its absence. These findings may provide a mechanistic explanation for the wide variability in the effects of modulatory transmitters on the voltage gating and maximal amplitude of Ih reported for different neurons in the brain.

  7. Identification of the Zn2+ binding site and mode of operation of a mammalian Zn2+ transporter.

    Science.gov (United States)

    Ohana, Ehud; Hoch, Eitan; Keasar, Chen; Kambe, Taiho; Yifrach, Ofer; Hershfinkel, Michal; Sekler, Israel

    2009-06-26

    Vesicular zinc transporters (ZnTs) play a critical role in regulating Zn2+ homeostasis in various cellular compartments and are linked to major diseases ranging from Alzheimer disease to diabetes. Despite their importance, the intracellular localization of ZnTs poses a major challenge for establishing the mechanisms by which they function and the identity of their ion binding sites. Here, we combine fluorescence-based functional analysis and structural modeling aimed at elucidating these functional aspects. Expression of ZnT5 was followed by both accelerated removal of Zn2+ from the cytoplasm and its increased vesicular sequestration. Further, activity of this zinc transport was coupled to alkalinization of the trans-Golgi network. Finally, structural modeling of ZnT5, based on the x-ray structure of the bacterial metal transporter YiiP, identified four residues that can potentially form the zinc binding site on ZnT5. Consistent with this model, replacement of these residues, Asp599 and His451, with alanine was sufficient to block Zn2+ transport. These findings indicate, for the first time, that Zn2+ transport mediated by a mammalian ZnT is catalyzed by H+/Zn2+ exchange and identify the zinc binding site of ZnT proteins essential for zinc transport.

  8. Life Prediction and Classification of Failure Modes in Solid State Luminaires Using Bayesian Probabilistic Models

    Energy Technology Data Exchange (ETDEWEB)

    Lall, Pradeep; Wei, Junchao; Sakalaukus, Peter

    2014-05-27

    A new method has been developed for assessment of the onset of degradation in solid state luminaires to classify failure mechanisms by using metrics beyond lumen degradation that are currently used for identification of failure. Luminous Flux output, Correlated Color Temperature Data on Philips LED Lamps has been gathered under 85°C/85%RH till lamp failure. The acquired data has been used in conjunction with Bayesian Probabilistic Models to identify luminaires with onset of degradation much prior to failure through identification of decision boundaries between lamps with accrued damage and lamps beyond the failure threshold in the feature space. In addition luminaires with different failure modes have been classified separately from healthy pristine luminaires. It is expected that, the new test technique will allow the development of failure distributions without testing till L70 life for the manifestation of failure.

  9. Bayesian Models for Life Prediction and Fault-Mode Classification in Solid State Lamps

    Energy Technology Data Exchange (ETDEWEB)

    Lall, Pradeep; Wei, Junchao; Sakalaukus, Peter

    2015-04-19

    A new method has been developed for assessment of the onset of degradation in solid state luminaires to classifY failure mechanisms by using metrics beyond lumen degradation that are currently used for identification of failure. Luminous Flux output, Correlated Color Temperature Data on Philips LED Lamps has been gathered under 85°C/85%RH till lamp failure. The acquired data has been used in conjunction with Bayesian Probabilistic Models to identifY luminaires with onset of degradation much prior to failure through identification of decision boundaries between lamps with accrued damage and lamps beyond the failure threshold in the feature space. In addition luminaires with different failure modes have been classified separately from healthy pristine luminaires. It is expected that, the new test technique will allow the development of failure distributions without testing till L 70 life for the manifestation of failure.

  10. Agrobacterium uses a unique ligand-binding mode for trapping opines and acquiring a competitive advantage in the niche construction on plant host.

    Directory of Open Access Journals (Sweden)

    Julien Lang

    2014-10-01

    Full Text Available By modifying the nuclear genome of its host, the plant pathogen Agrobacterium tumefaciens induces the development of plant tumours in which it proliferates. The transformed plant tissues accumulate uncommon low molecular weight compounds called opines that are growth substrates for A. tumefaciens. In the pathogen-induced niche (the plant tumour, a selective advantage conferred by opine assimilation has been hypothesized, but not experimentally demonstrated. Here, using genetics and structural biology, we deciphered how the pathogen is able to bind opines and use them to efficiently compete in the plant tumour. We report high resolution X-ray structures of the periplasmic binding protein (PBP NocT unliganded and liganded with the opine nopaline (a condensation product of arginine and α-ketoglurate and its lactam derivative pyronopaline. NocT exhibited an affinity for pyronopaline (K(D of 0.6 µM greater than that for nopaline (KD of 3.7 µM. Although the binding-mode of the arginine part of nopaline/pyronopaline in NocT resembled that of arginine in other PBPs, affinity measurement by two different techniques showed that NocT did not bind arginine. In contrast, NocT presented specific residues such as M117 to stabilize the bound opines. NocT relatives that exhibit the nopaline/pyronopaline-binding mode were only found in genomes of the genus Agrobacterium. Transcriptomics and reverse genetics revealed that A. tumefaciens uses the same pathway for assimilating nopaline and pyronopaline. Fitness measurements showed that NocT is required for a competitive colonization of the plant tumour by A. tumefaciens. Moreover, even though the Ti-plasmid conjugal transfer was not regulated by nopaline, the competitive advantage gained by the nopaline-assimilating Ti-plasmid donors led to a preferential horizontal propagation of this Ti-plasmid amongst the agrobacteria colonizing the plant-tumour niche. This work provided structural and genetic evidences to

  11. Agrobacterium Uses a Unique Ligand-Binding Mode for Trapping Opines and Acquiring A Competitive Advantage in the Niche Construction on Plant Host

    Science.gov (United States)

    Planamente, Sara; El Sahili, Abbas; Blin, Pauline; Aumont-Nicaise, Magali; Dessaux, Yves; Moréra, Solange; Faure, Denis

    2014-01-01

    By modifying the nuclear genome of its host, the plant pathogen Agrobacterium tumefaciens induces the development of plant tumours in which it proliferates. The transformed plant tissues accumulate uncommon low molecular weight compounds called opines that are growth substrates for A. tumefaciens. In the pathogen-induced niche (the plant tumour), a selective advantage conferred by opine assimilation has been hypothesized, but not experimentally demonstrated. Here, using genetics and structural biology, we deciphered how the pathogen is able to bind opines and use them to efficiently compete in the plant tumour. We report high resolution X-ray structures of the periplasmic binding protein (PBP) NocT unliganded and liganded with the opine nopaline (a condensation product of arginine and α-ketoglurate) and its lactam derivative pyronopaline. NocT exhibited an affinity for pyronopaline (KD of 0.6 µM) greater than that for nopaline (KD of 3.7 µM). Although the binding-mode of the arginine part of nopaline/pyronopaline in NocT resembled that of arginine in other PBPs, affinity measurement by two different techniques showed that NocT did not bind arginine. In contrast, NocT presented specific residues such as M117 to stabilize the bound opines. NocT relatives that exhibit the nopaline/pyronopaline-binding mode were only found in genomes of the genus Agrobacterium. Transcriptomics and reverse genetics revealed that A. tumefaciens uses the same pathway for assimilating nopaline and pyronopaline. Fitness measurements showed that NocT is required for a competitive colonization of the plant tumour by A. tumefaciens. Moreover, even though the Ti-plasmid conjugal transfer was not regulated by nopaline, the competitive advantage gained by the nopaline-assimilating Ti-plasmid donors led to a preferential horizontal propagation of this Ti-plasmid amongst the agrobacteria colonizing the plant-tumour niche. This work provided structural and genetic evidences to support the niche

  12. Crystal structures of antibiotic-bound complexes of aminoglycoside 2''-phosphotransferase IVa highlight the diversity in substrate binding modes among aminoglycoside kinases.

    Science.gov (United States)

    Shi, Kun; Houston, Douglas R; Berghuis, Albert M

    2011-07-19

    Aminoglycoside 2''-phosphotransferase IVa [APH(2'')-IVa] is a member of a family of bacterial enzymes responsible for medically relevant resistance to antibiotics. APH(2'')-IVa confers high-level resistance against several clinically used aminoglycoside antibiotics in various pathogenic Enterococcus species by phosphorylating the drug, thereby preventing it from binding to its ribosomal target and producing a bactericidal effect. We describe here three crystal structures of APH(2'')-IVa, one in its apo form and two in complex with a bound antibiotic, tobramycin and kanamycin A. The apo structure was refined to a resolution of 2.05 Å, and the APH(2'')-IVa structures with tobramycin and kanamycin A bound were refined to resolutions of 1.80 and 2.15 Å, respectively. Comparison among the structures provides insight concerning the substrate selectivity of this enzyme. In particular, conformational changes upon substrate binding, involving rotational shifts of two distinct segments of the enzyme, are observed. These substrate-induced shifts may also rationalize the altered substrate preference of APH(2'')-IVa in comparison to those of other members of the APH(2'') subfamily, which are structurally closely related. Finally, analysis of the interactions between the enzyme and aminoglycoside reveals a distinct binding mode as compared to the intended ribosomal target. The differences in the pattern of interactions can be utilized as a structural basis for the development of improved aminoglycosides that are not susceptible to these resistance factors.

  13. A highly tilted binding mode by a self-reactive T cell receptor results in altered engagement of peptide and MHC

    Energy Technology Data Exchange (ETDEWEB)

    Sethi, D.K.; Heroux, A.; Schubert, D. A.; Anders, A.-K.; Bonsor, D. A.; Thomas, C. P.; Sundberg, E. J.; Pyrdol, J.; Wucherpfennig, K. W.

    2011-01-17

    Self-reactive T cells that escape elimination in the thymus can cause autoimmune pathology, and it is therefore important to understand the structural mechanisms of self-antigen recognition. We report the crystal structure of a T cell receptor (TCR) from a patient with relapsing-remitting multiple sclerosis that engages its self-peptide-major histocompatibility complex (pMHC) ligand in an unusual manner. The TCR is bound in a highly tilted orientation that prevents interaction of the TCR-{alpha} chain with the MHC class II {beta} chain helix. In this structure, only a single germline-encoded TCR loop engages the MHC protein, whereas in most other TCR-pMHC structures all four germline-encoded TCR loops bind to the MHC helices. The tilted binding mode also prevents peptide contacts by the short complementarity-determining region (CDR) 3{beta} loop, and interactions that contribute to peptide side chain specificity are focused on the CDR3{alpha} loop. This structure is the first example in which only a single germline-encoded TCR loop contacts the MHC helices. Furthermore, the reduced interaction surface with the peptide may facilitate TCR cross-reactivity. The structural alterations in the trimolecular complex are distinct from previously characterized self-reactive TCRs, indicating that there are multiple unusual ways for self-reactive TCRs to bind their pMHC ligand.

  14. A Highly Tilted Binding Mode by a Self-Reactive T Cell Receptor Results in Altered Engagement of Peptide and MHC

    Energy Technology Data Exchange (ETDEWEB)

    D Sethi; D Schubert; A Anders; A Heroux; D Bonsor; C Thomas; E Sundberg; J Pyrdol; K Wucherpfennig

    2011-12-31

    Self-reactive T cells that escape elimination in the thymus can cause autoimmune pathology, and it is therefore important to understand the structural mechanisms of self-antigen recognition. We report the crystal structure of a T cell receptor (TCR) from a patient with relapsing-remitting multiple sclerosis that engages its self-peptide-major histocompatibility complex (pMHC) ligand in an unusual manner. The TCR is bound in a highly tilted orientation that prevents interaction of the TCR-{alpha} chain with the MHC class II {beta} chain helix. In this structure, only a single germline-encoded TCR loop engages the MHC protein, whereas in most other TCR-pMHC structures all four germline-encoded TCR loops bind to the MHC helices. The tilted binding mode also prevents peptide contacts by the short complementarity-determining region (CDR) 3{beta} loop, and interactions that contribute to peptide side chain specificity are focused on the CDR3{alpha} loop. This structure is the first example in which only a single germline-encoded TCR loop contacts the MHC helices. Furthermore, the reduced interaction surface with the peptide may facilitate TCR cross-reactivity. The structural alterations in the trimolecular complex are distinct from previously characterized self-reactive TCRs, indicating that there are multiple unusual ways for self-reactive TCRs to bind their pMHC ligand.

  15. Predicting protein-binding RNA nucleotides using the feature-based removal of data redundancy and the interaction propensity of nucleotide triplets.

    Science.gov (United States)

    Choi, Sungwook; Han, Kyungsook

    2013-11-01

    Several learning approaches have been used to predict RNA-binding amino acids in a protein sequence, but there has been little attempt to predict protein-binding nucleotides in an RNA sequence. One of the reasons is that the differences between nucleotides in their interaction propensity are much smaller than those between amino acids. Another reason is that RNA exhibits less diverse sequence patterns than protein. Therefore, predicting protein-binding RNA nucleotides is much harder than predicting RNA-binding amino acids. We developed a new method that removes data redundancy in a training set of sequences based on their features. The new method constructs a larger and more informative training set than the standard redundancy removal method based on sequence similarity, and the constructed dataset is guaranteed to be redundancy-free. We computed the interaction propensity (IP) of nucleotide triplets by applying a new definition of IP to an extensive dataset of protein-RNA complexes, and developed a support vector machine (SVM) model to predict protein binding sites in RNA sequences. In a 5-fold cross-validation with 812 RNA sequences, the SVM model predicted protein-binding nucleotides with an accuracy of 86.4%, an F-measure of 84.8%, and a Matthews correlation coefficient of 0.66. With an independent dataset of 56 RNA sequences that were not used in training, the resulting accuracy was 68.1% with an F-measure of 71.7% and a Matthews correlation coefficient of 0.35. To the best of our knowledge, this is the first attempt to predict protein-binding RNA nucleotides in a given RNA sequence from the sequence data alone. The SVM model and datasets are freely available for academics at http://bclab.inha.ac.kr/primer.

  16. Accurate microRNA target prediction using detailed binding site accessibility and machine learning on proteomics data

    Directory of Open Access Journals (Sweden)

    Martin eReczko

    2012-01-01

    Full Text Available MicroRNAs (miRNAs are a class of small regulatory genes regulating gene expression by targetingmessenger RNA. Though computational methods for miRNA target prediction are the prevailingmeans to analyze their function, they still miss a large fraction of the targeted genes and additionallypredict a large number of false positives. Here we introduce a novel algorithm called DIANAmicroT-ANN which combines multiple novel target site features through an artificial neural network(ANN and is trained using recently published high-throughput data measuring the change of proteinlevels after miRNA overexpression, providing positive and negative targeting examples. The featurescharacterizing each miRNA recognition element include binding structure, conservation level and aspecific profile of structural accessibility. The ANN is trained to integrate the features of eachrecognition element along the 3’ untranslated region into a targeting score, reproducing the relativerepression fold change of the protein. Tested on two different sets the algorithm outperforms otherwidely used algorithms and also predicts a significant number of unique and reliable targets notpredicted by the other methods. For 542 human miRNAs DIANA-microT-ANN predicts 120,000targets not provided by TargetScan 5.0. The algorithm is freely available athttp://microrna.gr/microT-ANN.

  17. Intrinsic default mode network connectivity predicts spontaneous verbal descriptions of autobiographical memories during social processing

    Directory of Open Access Journals (Sweden)

    Xiao-Fei eYang

    2013-01-01

    Full Text Available Neural systems activated in a coordinated way during rest, known as the default mode network (DMN, also support autobiographical memory (AM retrieval and social processing/mentalizing. However, little is known about how individual variability in reliance on personal memories during social processing relates to individual differences in DMN functioning during rest (intrinsic functional connectivity. Here we examined 18 participants’ spontaneous descriptions of autobiographical memories during a two-hour, private, open-ended interview in which they reacted to a series of true stories about real people’s social situations and responded to the prompt, how does this person’s story make you feel? We classified these descriptions as either containing factual information (semantic AMs or more elaborate descriptions of emotionally meaningful events (episodic AMs. We also collected resting state fMRI scans from the participants and related individual differences in frequency of described AMs to participants’ intrinsic functional connectivity within regions of the DMN. We found that producing more descriptions of either memory type correlated with stronger intrinsic connectivity in the parahippocampal and middle temporal gyri. Additionally, episodic AM descriptions correlated with connectivity in the bilateral hippocampi and medial prefrontal cortex, and semantic memory descriptions correlated with connectivity in right inferior lateral parietal cortex. These findings suggest that in individuals who naturally invoke more memories during social processing, brain regions involved in memory retrieval and self/social processing are more strongly coupled to the DMN during rest.

  18. Time-perception network and default mode network are associated with temporal prediction in a periodic motion task

    Directory of Open Access Journals (Sweden)

    Fabiana Mesquita Carvalho

    2016-06-01

    Full Text Available The updating of prospective internal models is necessary to accurately predict future observations. Uncertainty-driven internal model updating has been studied using a variety of perceptual paradigms, and have revealed engagement of frontal and parietal areas. In a distinct literature, studies on temporal expectations have also characterized a time-perception network, which relies on temporal orienting of attention. However, the updating of prospective internal models is highly dependent on temporal attention, since temporal attention must be reoriented according to the current environmental demands. In this study we used fMRI to evaluate to what extend the continuous manipulation of temporal prediction would recruit update-related areas and the time-perception network areas. We developed an exogenous temporal task that combines rhythm cueing and time-to-contact principles to generate implicit temporal expectation. Two patterns of motion were created: periodic (simple harmonic oscillation and non-periodic (harmonic oscillation with variable acceleration. We found that non-periodic motion engaged the exogenous temporal orienting network, which includes the ventral premotor and inferior parietal cortices, and the cerebellum, as well as the presupplementary motor area, which has previously been implicated in internal model updating, and the motion-sensitive area MT+. Interestingly, we found a right-hemisphere preponderance suggesting the engagement of explicit timing mechanisms. We also show that the periodic motion condition, when compared to the non-periodic motion, activated a particular subset of the default-mode network (DMN midline areas, including the left dorsomedial prefrontal cortex, anterior cingulate cortex, and bilateral posterior cingulate cortex/precuneus. It suggests that the DMN plays a role in processing contextually expected information and supports recent evidence that the DMN may reflect the validation of prospective internal

  19. Structure of the human angiotensin II type 1 (AT1) receptor bound to angiotensin II from multiple chemoselective photoprobe contacts reveals a unique peptide binding mode.

    Science.gov (United States)

    Fillion, Dany; Cabana, Jérôme; Guillemette, Gaétan; Leduc, Richard; Lavigne, Pierre; Escher, Emanuel

    2013-03-22

    Breakthroughs in G protein-coupled receptor structure determination based on crystallography have been mainly obtained from receptors occupied in their transmembrane domain core by low molecular weight ligands, and we have only recently begun to elucidate how the extracellular surface of G protein-coupled receptors (GPCRs) allows for the binding of larger peptide molecules. In the present study, we used a unique chemoselective photoaffinity labeling strategy, the methionine proximity assay, to directly identify at physiological conditions a total of 38 discrete ligand/receptor contact residues that form the extracellular peptide-binding site of an activated GPCR, the angiotensin II type 1 receptor. This experimental data set was used in homology modeling to guide the positioning of the angiotensin II (AngII) peptide within several GPCR crystal structure templates. We found that the CXC chemokine receptor type 4 accommodated the results better than the other templates evaluated; ligand/receptor contact residues were spatially grouped into defined interaction clusters with AngII. In the resulting receptor structure, a β-hairpin fold in extracellular loop 2 in conjunction with two extracellular disulfide bridges appeared to open and shape the entrance of the ligand-binding site. The bound AngII adopted a somewhat vertical binding mode, allowing concomitant contacts across the extracellular surface and deep within the transmembrane domain core of the receptor. We propose that such a dualistic nature of GPCR interaction could be well suited for diffusible linear peptide ligands and a common feature of other peptidergic class A GPCRs.

  20. Anti-adaptors use distinct modes of binding to inhibit the RssB-dependent turnover of RpoS (σS by ClpXP.

    Directory of Open Access Journals (Sweden)

    Dimce eMicevski

    2015-04-01

    Full Text Available In Escherichia coli, σS is the master regulator of the general stress response. The level of σS changes in response to multiple stress conditions and it is regulated at many levels including protein turnover. In the absence of stress, σS is rapidly degraded by the AAA+ protease, ClpXP in a regulated manner that depends on the adaptor protein RssB. This two-component response regulator mediates the recognition of σS and its delivery to ClpXP. The turnover of σS however, can be inhibited in a stress specific manner, by one of three anti-adaptor proteins. Each anti-adaptor binds to RssB and inhibits its activity, but how this is achieved is not fully understood at a molecular level. Here we describe details of the interaction between each anti-adaptor and RssB that leads to the stabilization of σS. By defining the domains of RssB using partial proteolysis we demonstrate that each anti-adaptor uses a distinct mode of binding to inhibit RssB activity. IraD docks specifically to the N-terminal domain of RssB, IraP interacts primarily with the C-terminal domain, while IraM interacts with both domains. Despite these differences in binding, we propose that docking of each anti-adaptor induces a conformational change in RssB, which resembles the inactive dimer of RssB. This dimer-like state of RssB not only prevents substrate binding but also triggers substrate release from a pre-bound complex.

  1. Physics-based enzyme design: predicting binding affinity and catalytic activity.

    Science.gov (United States)

    Sirin, Sarah; Pearlman, David A; Sherman, Woody

    2014-12-01

    Computational enzyme design is an emerging field that has yielded promising success stories, but where numerous challenges remain. Accurate methods to rapidly evaluate possible enzyme design variants could provide significant value when combined with experimental efforts by reducing the number of variants needed to be synthesized and speeding the time to reach the desired endpoint of the design. To that end, extending our computational methods to model the fundamental physical-chemical principles that regulate activity in a protocol that is automated and accessible to a broad population of enzyme design researchers is essential. Here, we apply a physics-based implicit solvent MM-GBSA scoring approach to enzyme design and benchmark the computational predictions against experimentally determined activities. Specifically, we evaluate the ability of MM-GBSA to predict changes in affinity for a steroid binder protein, catalytic turnover for a Kemp eliminase, and catalytic activity for α-Gliadin peptidase variants. Using the enzyme design framework developed here, we accurately rank the most experimentally active enzyme variants, suggesting that this approach could provide enrichment of active variants in real-world enzyme design applications.

  2. Determination of the binding mode for anti-inflammatory natural product xanthohumol with myeloid differentiation protein 2.

    Science.gov (United States)

    Fu, Weitao; Chen, Lingfeng; Wang, Zhe; Zhao, Chengwei; Chen, Gaozhi; Liu, Xing; Dai, Yuanrong; Cai, Yuepiao; Li, Chenglong; Zhou, Jianmin; Liang, Guang

    2016-01-01

    It is recognized that myeloid differentiation protein 2 (MD-2), a coreceptor of toll-like receptor 4 (TLR4) for innate immunity, plays an essential role in activation of the lipopolysaccharide signaling pathway. MD-2 is known as a neoteric and suitable therapeutical target. Therefore, there is great interest in the development of a potent MD-2 inhibitor for anti-inflammatory therapeutics. Several studies have reported that xanthohumol (XN), an anti-inflammatory natural product from hops and beer, can block the TLR4 signaling by binding to MD-2 directly. However, the interaction between MD-2 and XN remains unknown. Herein, our work aims at characterizing interactions between MD-2 and XN. Using a combination of experimental and theoretical modeling analysis, we found that XN can embed into the hydrophobic pocket of MD-2 and form two stable hydrogen bonds with residues ARG-90 and TYR-102 of MD-2. Moreover, we confirmed that ARG-90 and TYR-102 were two necessary residues during the recognition process of XN binding to MD-2. Results from this study identified the atomic interactions between the MD-2 and XN, which will contribute to future structural design of novel MD-2-targeting molecules for the treatment of inflammatory diseases.

  3. Kinetic and structural studies reveal a unique binding mode of sulfite to the nickel center in urease.

    Science.gov (United States)

    Mazzei, Luca; Cianci, Michele; Benini, Stefano; Bertini, Leonardo; Musiani, Francesco; Ciurli, Stefano

    2016-01-01

    Urease is the most efficient enzyme known to date, and catalyzes the hydrolysis of urea using two Ni(II) ions in the active site. Urease is a virulence factor in several human pathogens, while causing severe environmental and agronomic problems. Sporosarcina pasteurii urease has been used extensively in the structural characterization of the enzyme. Sodium sulfite has been widely used as a preservative in urease solutions to prevent oxygen-induced oxidation, but its role as an inhibitor has also been suggested. In the present study, isothermal titration microcalorimetry was used to establish sulfite as a competitive inhibitor for S. pasteurii urease, with an inhibition constant of 0.19mM at pH7. The structure of the urease-sulfite complex, determined at 1.65Å resolution, shows the inhibitor bound to the dinuclear Ni(II) center of urease in a tridentate mode involving bonds between the two Ni(II) ions in the active site and all three oxygen atoms of the inhibitor, supporting the observed competitive inhibition kinetics. This coordination mode of sulfite has never been observed, either in proteins or in small molecule complexes, and could inspire synthetic coordination chemists as well as biochemists to develop urease inhibitors based on this chemical moiety.

  4. Discovery, SAR, and X-ray Binding Mode Study of BCATm Inhibitors from a Novel DNA-Encoded Library.

    Science.gov (United States)

    Deng, Hongfeng; Zhou, Jingye; Sundersingh, Flora S; Summerfield, Jennifer; Somers, Don; Messer, Jeffrey A; Satz, Alexander L; Ancellin, Nicolas; Arico-Muendel, Christopher C; Sargent Bedard, Katie L; Beljean, Arthur; Belyanskaya, Svetlana L; Bingham, Ryan; Smith, Sarah E; Boursier, Eric; Carter, Paul; Centrella, Paolo A; Clark, Matthew A; Chung, Chun-Wa; Davie, Christopher P; Delorey, Jennifer L; Ding, Yun; Franklin, G Joseph; Grady, LaShadric C; Herry, Kenny; Hobbs, Clare; Kollmann, Christopher S; Morgan, Barry A; Pothier Kaushansky, Laura J; Zhou, Quan

    2015-08-13

    As a potential target for obesity, human BCATm was screened against more than 14 billion DNA encoded compounds of distinct scaffolds followed by off-DNA synthesis and activity confirmation. As a consequence, several series of BCATm inhibitors were discovered. One representative compound (R)-3-((1-(5-bromothiophene-2-carbonyl)pyrrolidin-3-yl)oxy)-N-methyl-2'-(methylsulfonamido)-[1,1'-biphenyl]-4-carboxamide (15e) from a novel compound library synthesized via on-DNA Suzuki-Miyaura cross-coupling showed BCATm inhibitory activity with IC50 = 2.0 μM. A protein crystal structure of 15e revealed that it binds to BCATm within the catalytic site adjacent to the PLP cofactor. The identification of this novel inhibitor series plus the establishment of a BCATm protein structure provided a good starting point for future structure-based discovery of BCATm inhibitors.

  5. Penicillin-Binding Protein Transpeptidase Signatures for Tracking and Predicting β-Lactam Resistance Levels in Streptococcus pneumoniae

    Directory of Open Access Journals (Sweden)

    Yuan Li

    2016-06-01

    Full Text Available β-Lactam antibiotics are the drugs of choice to treat pneumococcal infections. The spread of β-lactam-resistant pneumococci is a major concern in choosing an effective therapy for patients. Systematically tracking β-lactam resistance could benefit disease surveillance. Here we developed a classification system in which a pneumococcal isolate is assigned to a “PBP type” based on sequence signatures in the transpeptidase domains (TPDs of the three critical penicillin-binding proteins (PBPs, PBP1a, PBP2b, and PBP2x. We identified 307 unique PBP types from 2,528 invasive pneumococcal isolates, which had known MICs to six β-lactams based on broth microdilution. We found that increased β-lactam MICs strongly correlated with PBP types containing divergent TPD sequences. The PBP type explained 94 to 99% of variation in MICs both before and after accounting for genomic backgrounds defined by multilocus sequence typing, indicating that genomic backgrounds made little independent contribution to β-lactam MICs at the population level. We further developed and evaluated predictive models of MICs based on PBP type. Compared to microdilution MICs, MICs predicted by PBP type showed essential agreement (MICs agree within 1 dilution of >98%, category agreement (interpretive results agree of >94%, a major discrepancy (sensitive isolate predicted as resistant rate of <3%, and a very major discrepancy (resistant isolate predicted as sensitive rate of <2% for all six β-lactams. Thus, the PBP transpeptidase signatures are robust indicators of MICs to different β-lactam antibiotics in clinical pneumococcal isolates and serve as an accurate alternative to phenotypic susceptibility testing.

  6. An Entropy-Based Upper Bound Methodology for Robust Predictive Multi-Mode RCPSP Schedules

    Directory of Open Access Journals (Sweden)

    Angela Hsiang-Ling Chen

    2014-09-01

    Full Text Available Projects are an important part of our activities and regardless of their magnitude, scheduling is at the very core of every project. In an ideal world makespan minimization, which is the most commonly sought objective, would give us an advantage. However, every time we execute a project we have to deal with uncertainty; part of it coming from known sources and part remaining unknown until it affects us. For this reason, it is much more practical to focus on making our schedules robust, capable of handling uncertainty, and even to determine a range in which the project could be completed. In this paper we focus on an approach to determine such a range for the Multi-mode Resource Constrained Project Scheduling Problem (MRCPSP, a widely researched, NP-complete problem, but without adding any subjective considerations to its estimation. We do this by using a concept well known in the domain of thermodynamics, entropy and a three-stage approach. First we use Artificial Bee Colony (ABC—an effective and powerful meta-heuristic—to determine a schedule with minimized makespan which serves as a lower bound. The second stage defines buffer times and creates an upper bound makespan using an entropy function, with the advantage over other methods that it only considers elements which are inherent to the schedule itself and does not introduce any subjectivity to the buffer time generation. In the last stage, we use the ABC algorithm with an objective function that seeks to maximize robustness while staying within the makespan boundaries defined previously and in some cases even below the lower boundary. We evaluate our approach with two different benchmarks sets: when using the PSPLIB for the MRCPSP benchmark set, the computational results indicate that it is possible to generate robust schedules which generally result in an increase of less than 10% of the best known solutions while increasing the robustness in at least 20% for practically every

  7. RBscore&NBench: a high-level web server for nucleic acid binding residues prediction with a large-scale benchmarking database.

    Science.gov (United States)

    Miao, Zhichao; Westhof, Eric

    2016-07-08

    RBscore&NBench combines a web server, RBscore and a database, NBench. RBscore predicts RNA-/DNA-binding residues in proteins and visualizes the prediction scores and features on protein structures. The scoring scheme of RBscore directly links feature values to nucleic acid binding probabilities and illustrates the nucleic acid binding energy funnel on the protein surface. To avoid dataset, binding site definition and assessment metric biases, we compared RBscore with 18 web servers and 3 stand-alone programs on 41 datasets, which demonstrated the high and stable accuracy of RBscore. A comprehensive comparison led us to develop a benchmark database named NBench. The web server is available on: http://ahsoka.u-strasbg.fr/rbscorenbench/.

  8. Unusual mode of protein binding by a cytotoxic π-arene ruthenium(ii) piano-stool compound containing an O,S-chelating ligand.

    Science.gov (United States)

    Hildebrandt, Jana; Görls, Helmar; Häfner, Norman; Ferraro, Giarita; Dürst, Matthias; Runnebaum, Ingo B; Weigand, Wolfgang; Merlino, Antonello

    2016-08-02

    A new pseudo-octahedral π-arene ruthenium(ii) piano-stool compound, containing an O,S-bidentate ligand (compound 1) and showing significant cytotoxic activity in vitro, was synthesized and characterized. In solution stability and interaction with the model protein bovine pancreatic ribonuclease (RNase A) were investigated by using UV-Vis absorption spectroscopy. Its crystal structure and that of the adduct formed upon reaction with RNase A were obtained by X-ray crystallography. The comparison between the structure of purified compound 1 and that of the fragment bound to RNase A reveals an unusual mode of protein binding that includes ligand exchange and alteration of coordination sphere geometry.

  9. Protein-DNA binding dynamics predict transcriptional response to nutrients in archaea.

    Science.gov (United States)

    Todor, Horia; Sharma, Kriti; Pittman, Adrianne M C; Schmid, Amy K

    2013-10-01

    Organisms across all three domains of life use gene regulatory networks (GRNs) to integrate varied stimuli into coherent transcriptional responses to environmental pressures. However, inferring GRN topology and regulatory causality remains a central challenge in systems biology. Previous work characterized TrmB as a global metabolic transcription factor in archaeal extremophiles. However, it remains unclear how TrmB dynamically regulates its ∼100 metabolic enzyme-coding gene targets. Using a dynamic perturbation approach, we elucidate the topology of the TrmB metabolic GRN in the model archaeon Halobacterium salinarum. Clustering of dynamic gene expression patterns reveals that TrmB functions alone to regulate central metabolic enzyme-coding genes but cooperates with various regulators to control peripheral metabolic pathways. Using a dynamical model, we predict gene expression patterns for some TrmB-dependent promoters and infer secondary regulators for others. Our data suggest feed-forward gene regulatory topology for cobalamin biosynthesis. In contrast, purine biosynthesis appears to require TrmB-independent regulators. We conclude that TrmB is an important component for mediating metabolic modularity, integrating nutrient status and regulating gene expression dynamics alone and in concert with secondary regulators.

  10. Protein–DNA binding dynamics predict transcriptional response to nutrients in archaea

    Science.gov (United States)

    Todor, Horia; Sharma, Kriti; Pittman, Adrianne M. C.; Schmid, Amy K.

    2013-01-01

    Organisms across all three domains of life use gene regulatory networks (GRNs) to integrate varied stimuli into coherent transcriptional responses to environmental pressures. However, inferring GRN topology and regulatory causality remains a central challenge in systems biology. Previous work characterized TrmB as a global metabolic transcription factor in archaeal extremophiles. However, it remains unclear how TrmB dynamically regulates its ∼100 metabolic enzyme-coding gene targets. Using a dynamic perturbation approach, we elucidate the topology of the TrmB metabolic GRN in the model archaeon Halobacterium salinarum. Clustering of dynamic gene expression patterns reveals that TrmB functions alone to regulate central metabolic enzyme-coding genes but cooperates with various regulators to control peripheral metabolic pathways. Using a dynamical model, we predict gene expression patterns for some TrmB-dependent promoters and infer secondary regulators for others. Our data suggest feed-forward gene regulatory topology for cobalamin biosynthesis. In contrast, purine biosynthesis appears to require TrmB-independent regulators. We conclude that TrmB is an important component for mediating metabolic modularity, integrating nutrient status and regulating gene expression dynamics alone and in concert with secondary regulators. PMID:23892291

  11. The timing of associative memory formation: frontal lobe and anterior medial temporal lobe activity at associative binding predicts memory.

    Science.gov (United States)

    Hales, J B; Brewer, J B

    2011-04-01

    The process of associating items encountered over time and across variable time delays is fundamental for creating memories in daily life, such as for stories and episodes. Forming associative memory for temporally discontiguous items involves medial temporal lobe structures and additional neocortical processing regions, including prefrontal cortex, parietal lobe, and lateral occipital regions. However, most prior memory studies, using concurrently presented stimuli, have failed to examine the temporal aspect of successful associative memory formation to identify when activity in these brain regions is predictive of associative memory formation. In the current study, functional MRI data were acquired while subjects were shown pairs of sequentially presented visual images with a fixed interitem delay within pairs. This design allowed the entire time course of the trial to be analyzed, starting from onset of the first item, across the 5.5-s delay period, and through offset of the second item. Subjects then completed a postscan recognition test for the items and associations they encoded during the scan and their confidence for each. After controlling for item-memory strength, we isolated brain regions selectively involved in associative encoding. Consistent with prior findings, increased regional activity predicting subsequent associative memory success was found in anterior medial temporal lobe regions of left perirhinal and entorhinal cortices and in left prefrontal cortex and lateral occipital regions. The temporal separation within each pair, however, allowed extension of these findings by isolating the timing of regional involvement, showing that increased response in these regions occurs during binding but not during maintenance.

  12. Predicting the effects of amino acid replacements in peptide hormones on their binding affinities for class B GPCRs and application to the design of secretin receptor antagonists

    Science.gov (United States)

    Te, Jerez A.; Dong, Maoqing; Miller, Laurence J.; Bordner, Andrew J.

    2012-07-01

    Computational prediction of the effects of residue changes on peptide-protein binding affinities, followed by experimental testing of the top predicted binders, is an efficient strategy for the rational structure-based design of peptide inhibitors. In this study we apply this approach to the discovery of competitive antagonists for the secretin receptor, the prototypical member of class B G protein-coupled receptors (GPCRs). Proteins in this family are involved in peptide hormone-stimulated signaling and are implicated in several human diseases, making them potential therapeutic targets. We first validated our computational method by predicting changes in the binding affinities of several peptides to their cognate class B GPCRs due to alanine replacement and compared the results with previously published experimental values. Overall, the results showed a significant correlation between the predicted and experimental ΔΔG values. Next, we identified candidate inhibitors by applying this method to a homology model of the secretin receptor bound to an N-terminal truncated secretin peptide. Predictions were made for single residue replacements to each of the other nineteen naturally occurring amino acids at peptide residues within the segment binding the receptor N-terminal domain. Amino acid replacements predicted to most enhance receptor binding were then experimentally tested by competition-binding assays. We found two residue changes that improved binding affinities by almost one log unit. Furthermore, a peptide combining both of these favorable modifications resulted in an almost two log unit improvement in binding affinity, demonstrating the approximately additive effect of these changes on binding. In order to further investigate possible physical effects of these residue changes on receptor binding affinity, molecular dynamics simulations were performed on representatives of the successful peptide analogues (namely A17I, G25R, and A17I/G25R) in bound and

  13. Binding mode of CA074, a specific irreversible inhibitor, to bovine cathepsin B as determined by X-ray crystal analysis of the complex.

    Science.gov (United States)

    Yamamoto, A; Hara, T; Tomoo, K; Ishida, T; Fujii, T; Hata, Y; Murata, M; Kitamura, K

    1997-05-01

    The binding mode of CA074 [N-(L-3-trans-propylcarbamoyl-oxirane-2-carbonyl)-L-isoleucyl-L-pr oline], a specific irreversible inhibitor, to bovine spleen cathepsin B was elucidated by X-ray crystal structure analysis of the complex at 2.2 A resolution (conventional R=0.185). Inconsistently with our model used for the development of CA074, the L-isoleucyl-L-proline and propylcarbamoyl moieties are located at the S' and S subsites, respectively. This unexpected binding is primarily due to (i) similar extended chain conformations (due to the same S configurations) at the oxirane C2 and C3 atoms of CA074 and (ii) the just fit formation of double hydrogen bonds between the carboxyl oxygens of L-proline and the imidazole nitrogens of His-110 and His-111 residues (these residues are missing in papain, the tertiary structure of which was used for the design of CA074). The oxirane C3 atom possessing the P' substituent is covalently bound to the Cys-29 Sgamma atom (C3-Sgamma=1.79 A) and the S configuration is maintained. The present result will provide useful information for characterizing the substrate-specificity of cathepsin B.

  14. Interaction pattern of Arg 62 in the A-pocket of differentially disease-associated HLA-B27 subtypes suggests distinct TCR binding modes.

    Directory of Open Access Journals (Sweden)

    Elisa Nurzia

    Full Text Available The single amino acid replacement Asp116His distinguishes the two subtypes HLA-B*2705 and HLA-B*2709 which are, respectively, associated and non-associated with Ankylosing Spondylitis, an autoimmune chronic inflammatory disease. The reason for this differential association is so far poorly understood and might be related to subtype-specific HLA:peptide conformations as well as to subtype/peptide-dependent dynamical properties on the nanoscale. Here, we combine functional experiments with extensive molecular dynamics simulations to investigate the molecular dynamics and function of the conserved Arg62 of the α1-helix for both B27 subtypes in complex with the self-peptides pVIPR (RRKWRRWHL and TIS (RRLPIFSRL, and the viral peptides pLMP2 (RRRWRRLTV and NPflu (SRYWAIRTR. Simulations of HLA:peptide systems suggest that peptide-stabilizing interactions of the Arg62 residue observed in crystal structures are metastable for both B27 subtypes under physiological conditions, rendering this arginine solvent-exposed and, probably, a key residue for TCR interaction more than peptide-binding. This view is supported by functional experiments with conservative (R62K and non-conservative (R62A B*2705 and B*2709 mutants that showed an overall reduction in their capability to present peptides to CD8+ T cells. Moreover, major subtype-dependent differences in the peptide recognition suggest distinct TCR binding modes for the B*2705 versus the B*2709 subtype.

  15. Binding modes of phosphotriesterase-like lactonase complexed with δ-nonanoic lactone and paraoxon using molecular dynamics simulations.

    Science.gov (United States)

    Guan, Shanshan; Zhao, Li; Jin, Hanyong; Shan, Ning; Han, Weiwei; Wang, Song; Shan, Yaming

    2017-02-01

    Phosphotriesterase-like lactonases (PLLs) have received much attention because of their physical and chemical properties. They may have widespread applications in various fields. For example, they show potential for quorum-sensing signaling pathways and organophosphorus (OP) detoxification in agricultural science. However, the mechanism by which PLLs hydrolyze, which involves OP compounds and lactones and a variety of distinct catalytic efficiencies, has only rarely been explored. In the present study, molecular dynamics (MD) simulations were performed to characterize and contrast the structural dynamics of DrPLL, a member of the PLL superfamily in Deinococcus radiodurans, bound to two substrates, δ-nonanoic lactone and paraoxon. It has been observed that there is a 16-fold increase in the catalytic efficiency of the two mutant strains of DrPLL (F26G/C72I) vs. the wild-type enzyme toward the hydrolysis of paraoxon, but an explanation for this behavior is currently lacking. The analysis of the molecular trajectories of DrPLL bound to δ-nonanoic lactone indicated that lactone-induced conformational changes take place in loop 8, which is near the active site. Binding to paraoxon may lead to conformational displacement of loop 1 residues, which could lead to the deformation of the active site and so trigger the entry of the paraoxon into the active site. The efficiency of the F26G/C72I mutant was increased by decreasing the displacement of loop 1 residues and increasing the flexibility of loop 8 residues. These results provide a molecular-level explanation for the experimental behavior.

  16. Prediction of daily modes of South Asian monsoon variability and its association with Indian and Pacific Ocean SST in the NCEP CFS V2

    Science.gov (United States)

    Shahi, Namendra Kumar; Rai, Shailendra; Pandey, D. K.

    2016-02-01

    The prediction capability of daily modes of variability for South Asian monsoon from climate forecast system version 2 of national centers for environmental prediction with respect to observed precipitation has been assessed. The space-time structure of the daily modes for summer monsoon rainfall has been identified by using multi-channel singular spectrum analysis (MSSA). The MSSA is applied on daily anomalies of rainfall data over the South Asian monsoon region (40°E-160°E, 30°S-35°N) for the period of 2001-2013 with a lag window of 61 days for June-July-August-September season. The broad spectrum around 45 and 50 days was obtained from the observed and model data during the time domain of our study. The space-time structure of the modes obtained from the model shows good resemblance with respect to the observation. The observed northeastward propagation of oscillatory mode is well simulated by the model. The significant improvement in the space-time structure, period of oscillation, and propagation of oscillatory modes was found in the model. The observed connectivity of oscillatory and persisting modes with the sea surface temperature of Indian and Pacific Ocean has also been investigated and it was found that the model is able to predict it reasonably well.

  17. Predicting binding poses and affinities for protein - ligand complexes in the 2015 D3R Grand Challenge using a physical model with a statistical parameter estimation

    Science.gov (United States)

    Grudinin, Sergei; Kadukova, Maria; Eisenbarth, Andreas; Marillet, Simon; Cazals, Frédéric

    2016-09-01

    The 2015 D3R Grand Challenge provided an opportunity to test our new model for the binding free energy of small molecules, as well as to assess our protocol to predict binding poses for protein-ligand complexes. Our pose predictions were ranked 3-9 for the HSP90 dataset, depending on the assessment metric. For the MAP4K dataset the ranks are very dispersed and equal to 2-35, depending on the assessment metric, which does not provide any insight into the accuracy of the method. The main success of our pose prediction protocol was the re-scoring stage using the recently developed Convex-PL potential. We make a thorough analysis of our docking predictions made with AutoDock Vina and discuss the effect of the choice of rigid receptor templates, the number of flexible residues in the binding pocket, the binding pocket size, and the benefits of re-scoring. However, the main challenge was to predict experimentally determined binding affinities for two blind test sets. Our affinity prediction model consisted of two terms, a pairwise-additive enthalpy, and a non pairwise-additive entropy. We trained the free parameters of the model with a regularized regression using affinity and structural data from the PDBBind database. Our model performed very well on the training set, however, failed on the two test sets. We explain the drawback and pitfalls of our model, in particular in terms of relative coverage of the test set by the training set and missed dynamical properties from crystal structures, and discuss different routes to improve it.

  18. Predicting important residues and interaction pathways in proteins using Gaussian Network Model: binding and stability of HLA proteins.

    Directory of Open Access Journals (Sweden)

    Turkan Haliloglu

    Full Text Available A statistical thermodynamics approach is proposed to determine structurally and functionally important residues in native proteins that are involved in energy exchange with a ligand and other residues along an interaction pathway. The structure-function relationships, ligand binding and allosteric activities of ten structures of HLA Class I proteins of the immune system are studied by the Gaussian Network Model. Five of these models are associated with inflammatory rheumatic disease and the remaining five are properly functioning. In the Gaussian Network Model, the protein structures are modeled as an elastic network where the inter-residue interactions are harmonic. Important residues and the interaction pathways in the proteins are identified by focusing on the largest eigenvalue of the residue interaction matrix. Predicted important residues match those known from previous experimental and clinical work. Graph perturbation is used to determine the response of the important residues along the interaction pathway. Differences in response patterns of the two sets of proteins are identified and their relations to disease are discussed.

  19. Acrosin-binding protein (ACRBP) and triosephosphate isomerase (TPI) are good markers to predict boar sperm freezing capacity.

    Science.gov (United States)

    Vilagran, Ingrid; Castillo, Judit; Bonet, Sergi; Sancho, Sílvia; Yeste, Marc; Estanyol, Josep M; Oliva, Rafael

    2013-09-15

    Sperm cryopreservation is the most efficient method for storing boar sperm samples for a long time. However, one of the inconveniences of this method is the large variation between and within boars in the cryopreservation success of their sperm. The aim of the present work was thus to find reliable and useful predictive biomarkers of the good and poor capacity to withstand the freeze-thawing process in boar ejaculates. To find these biomarkers, the amount of proteins present in the total proteome in sperm cells were compared between good freezability ejaculates (GFE) and poor freezability ejaculates (PFE) using the two-dimensional difference gel electrophoresis technique. Samples were classified as GFE and PFE using progressive motility and viability of the sperm at 30 and 240 minutes after thawing, and the proteomes from each group, before starting cryopreservation protocols, were compared. Because two proteins, acrosin binding protein (ACRBP) and triosephosphate isomerase (TPI), presented the highest significant differences between GFE and PFE groups in two-dimensional difference gel electrophoresis assessment, Western blot analyses for ACRBP and TPI were also performed for validation. ACRBP normalized content was significantly lower in PFE than in GFE (P sperm viability and motility was confirmed using Pearson's linear correlation. In conclusion, ACRBP and TPI can be used as markers of boar sperm freezability before starting the cryopreservation procedure, thereby avoiding unnecessary costs involved in this practice.

  20. Structure–property reduced order model for viscosity prediction in single-component CO 2 -binding organic liquids

    Energy Technology Data Exchange (ETDEWEB)

    Cantu, David C.; Malhotra, Deepika; Koech, Phillip K.; Heldebrant, David J.; Zheng, Feng (Richard); Freeman, Charles J.; Rousseau, Roger; Glezakou, Vassiliki-Alexandra

    2016-01-01

    CO2 capture from power generation with aqueous solvents remains energy intensive due to the high water content of the current technology, or the high viscosity of non-aqueous alternatives. Quantitative reduced models, connecting molecular structure to bulk properties, are key for developing structure-property relationships that enable molecular design. In this work, we describe such a model that quantitatively predicts viscosities of CO2 binding organic liquids (CO2BOLs) based solely on molecular structure and the amount of bound CO2. The functional form of the model correlates the viscosity with the CO2 loading and an electrostatic term describing the charge distribution between the CO2-bearing functional group and the proton-receiving amine. Molecular simulations identify the proton shuttle between these groups within the same molecule to be the critical indicator of low viscosity. The model, developed to allow for quick screening of solvent libraries, paves the way towards the rational design of low viscosity non-aqueous solvent systems for post-combustion CO2 capture. Following these theoretical recommendations, synthetic efforts of promising candidates and viscosity measurement provide experimental validation and verification.

  1. ¹³C NMR-distance matrix descriptors: optimal abstract 3D space granularity for predicting estrogen binding.

    Science.gov (United States)

    Slavov, Svetoslav H; Geesaman, Elizabeth L; Pearce, Bruce A; Schnackenberg, Laura K; Buzatu, Dan A; Wilkes, Jon G; Beger, Richard D

    2012-07-23

    An improved three-dimensional quantitative spectral data-activity relationship (3D-QSDAR) methodology was used to build and validate models relating the activity of 130 estrogen receptor binders to specific structural features. In 3D-QSDAR, each compound is represented by a unique fingerprint constructed from (13)C chemical shift pairs and associated interatomic distances. Grids of different granularity can be used to partition the abstract fingerprint space into congruent "bins" for which the optimal size was previously unexplored. For this purpose, the endocrine disruptor knowledge base data were used to generate 50 3D-QSDAR models with bins ranging in size from 2 ppm × 2 ppm × 0.5 Å to 20 ppm × 20 ppm × 2.5 Å, each of which was validated using 100 training/test set partitions. Best average predictivity in terms of R(2)test was achieved at 10 ppm ×10 ppm × Z Å (Z = 0.5, ..., 2.5 Å). It was hypothesized that this optimum depends on the chemical shifts' estimation error (±4.13 ppm) and the precision of the calculated interatomic distances. The highest ranked bins from partial least-squares weights were found to be associated with structural features known to be essential for binding to the estrogen receptor.

  2. Shielding Characteristics Using an Ultrasonic Configurable Fan Artificial Noise Source to Generate Modes - Experimental Measurements and Analytical Predictions

    Science.gov (United States)

    Sutliff, Daniel L.; Walker, Bruce E.

    2014-01-01

    An Ultrasonic Configurable Fan Artificial Noise Source (UCFANS) was designed, built, and tested in support of the NASA Langley Research Center's 14x22 wind tunnel test of the Hybrid Wing Body (HWB) full 3-D 5.8% scale model. The UCFANS is a 5.8% rapid prototype scale model of a high-bypass turbofan engine that can generate the tonal signature of proposed engines using artificial sources (no flow). The purpose of the program was to provide an estimate of the acoustic shielding benefits possible from mounting an engine on the upper surface of a wing; a flat plate model was used as the shielding surface. Simple analytical simulations were used to preview the radiation patterns - Fresnel knife-edge diffraction was coupled with a dense phased array of point sources to compute shielded and unshielded sound pressure distributions for potential test geometries and excitation modes. Contour plots of sound pressure levels, and integrated power levels, from nacelle alone and shielded configurations for both the experimental measurements and the analytical predictions are presented in this paper.

  3. New insights into the structure and mode of action of Mo-CBP3, an antifungal chitin-binding protein of Moringa oleifera seeds.

    Directory of Open Access Journals (Sweden)

    Adelina B Batista

    Full Text Available Mo-CBP3 is a chitin-binding protein purified from Moringa oleifera Lam. seeds that displays inhibitory activity against phytopathogenic fungi. This study investigated the structural properties and the antifungal mode of action of this protein. To this end, circular dichroism spectroscopy, antifungal assays, measurements of the production of reactive oxygen species and microscopic analyses were utilized. Mo-CBP3 is composed of 30.3% α-helices, 16.3% β-sheets, 22.3% turns and 30.4% unordered forms. The Mo-CBP3 structure is highly stable and retains its antifungal activity regardless of temperature and pH. Fusarium solani was used as a model organism for studying the mechanisms by which this protein acts as an antifungal agent. Mo-CBP3 significantly inhibited spore germination and mycelial growth at 0.05 mg.mL-1. Mo-CBP3 has both fungistatic and fungicidal effects, depending on the concentration used. Binding of Mo-CBP3 to the fungal cell surface is achieved, at least in part, via electrostatic interactions, as salt was able to reduce its inhibitory effect. Mo-CBP3 induced the production of ROS and caused disorganization of both the cytoplasm and the plasma membrane in F. solani cells. Based on its high stability and specific toxicity, with broad-spectrum efficacy against important phytopathogenic fungi at low inhibitory concentrations but not to human cells, Mo-CBP3 has great potential for the development of new antifungal drugs or transgenic crops with enhanced resistance to phytopathogens.

  4. New insights into the structure and mode of action of Mo-CBP3, an antifungal chitin-binding protein of Moringa oleifera seeds.

    Science.gov (United States)

    Batista, Adelina B; Oliveira, José T A; Gifoni, Juliana M; Pereira, Mirella L; Almeida, Marina G G; Gomes, Valdirene M; Da Cunha, Maura; Ribeiro, Suzanna F F; Dias, Germana B; Beltramini, Leila M; Lopes, José Luiz S; Grangeiro, Thalles B; Vasconcelos, Ilka M

    2014-01-01

    Mo-CBP3 is a chitin-binding protein purified from Moringa oleifera Lam. seeds that displays inhibitory activity against phytopathogenic fungi. This study investigated the structural properties and the antifungal mode of action of this protein. To this end, circular dichroism spectroscopy, antifungal assays, measurements of the production of reactive oxygen species and microscopic analyses were utilized. Mo-CBP3 is composed of 30.3% α-helices, 16.3% β-sheets, 22.3% turns and 30.4% unordered forms. The Mo-CBP3 structure is highly stable and retains its antifungal activity regardless of temperature and pH. Fusarium solani was used as a model organism for studying the mechanisms by which this protein acts as an antifungal agent. Mo-CBP3 significantly inhibited spore germination and mycelial growth at 0.05 mg.mL-1. Mo-CBP3 has both fungistatic and fungicidal effects, depending on the concentration used. Binding of Mo-CBP3 to the fungal cell surface is achieved, at least in part, via electrostatic interactions, as salt was able to reduce its inhibitory effect. Mo-CBP3 induced the production of ROS and caused disorganization of both the cytoplasm and the plasma membrane in F. solani cells. Based on its high stability and specific toxicity, with broad-spectrum efficacy against important phytopathogenic fungi at low inhibitory concentrations but not to human cells, Mo-CBP3 has great potential for the development of new antifungal drugs or transgenic crops with enhanced resistance to phytopathogens.

  5. Computational study on the inhibitor binding mode and allosteric regulation mechanism in hepatitis C virus NS3/4A protein.

    Directory of Open Access Journals (Sweden)

    Weiwei Xue

    Full Text Available HCV NS3/4A protein is an attractive therapeutic target responsible for harboring serine protease and RNA helicase activities during the viral replication. Small molecules binding at the interface between the protease and helicase domains can stabilize the closed conformation of the protein and thus block the catalytic function of HCV NS3/4A protein via an allosteric regulation mechanism. But the detailed mechanism remains elusive. Here, we aimed to provide some insight into the inhibitor binding mode and allosteric regulation mechanism of HCV NS3/4A protein by using computational methods. Four simulation systems were investigated. They include: apo state of HCV NS3/4A protein, HCV NS3/4A protein in complex with an allosteric inhibitor and the truncated form of the above two systems. The molecular dynamics simulation results indicate HCV NS3/4A protein in complex with the allosteric inhibitor 4VA adopts a closed conformation (inactive state, while the truncated apo protein adopts an open conformation (active state. Further residue interaction network analysis suggests the communication of the domain-domain interface play an important role in the transition from closed to open conformation of HCV NS3/4A protein. However, the inhibitor stabilizes the closed conformation through interaction with several key residues from both the protease and helicase domains, including His57, Asp79, Asp81, Asp168, Met485, Cys525 and Asp527, which blocks the information communication between the functional domains interface. Finally, a dynamic model about the allosteric regulation and conformational changes of HCV NS3/4A protein was proposed and could provide fundamental insights into the allosteric mechanism of HCV NS3/4A protein function regulation and design of new potent inhibitors.

  6. A physiologically based pharmacokinetic model to predict the pharmacokinetics of highly protein-bound drugs and the impact of errors in plasma protein binding.

    Science.gov (United States)

    Ye, Min; Nagar, Swati; Korzekwa, Ken

    2016-04-01

    Predicting the pharmacokinetics of highly protein-bound drugs is difficult. Also, since historical plasma protein binding data were often collected using unbuffered plasma, the resulting inaccurate binding data could contribute to incorrect predictions. This study uses a generic physiologically based pharmacokinetic (PBPK) model to predict human plasma concentration-time profiles for 22 highly protein-bound drugs. Tissue distribution was estimated from in vitro drug lipophilicity data, plasma protein binding and the blood: plasma ratio. Clearance was predicted with a well-stirred liver model. Underestimated hepatic clearance for acidic and neutral compounds was corrected by an empirical scaling factor. Predicted values (pharmacokinetic parameters, plasma concentration-time profile) were compared with observed data to evaluate the model accuracy. Of the 22 drugs, less than a 2-fold error was obtained for the terminal elimination half-life (t1/2 , 100% of drugs), peak plasma concentration (Cmax , 100%), area under the plasma concentration-time curve (AUC0-t , 95.4%), clearance (CLh , 95.4%), mean residence time (MRT, 95.4%) and steady state volume (Vss , 90.9%). The impact of fup errors on CLh and Vss prediction was evaluated. Errors in fup resulted in proportional errors in clearance prediction for low-clearance compounds, and in Vss prediction for high-volume neutral drugs. For high-volume basic drugs, errors in fup did not propagate to errors in Vss prediction. This is due to the cancellation of errors in the calculations for tissue partitioning of basic drugs. Overall, plasma profiles were well simulated with the present PBPK model. Copyright © 2016 John Wiley & Sons, Ltd.

  7. Study on prediction of railway noise by mode prediction method%模式预测法应用于铁路噪声的预测研究

    Institute of Scientific and Technical Information of China (English)

    赵尊宇; 陈文瑛

    2011-01-01

    With the development of new railways, adding the second line and large-scale electrification reform project construction, railway noise pollution and disturb residents problem due to railway construction and business have becoming more and more serious. A prediction method of noise, which was mode method, was elected for railway noise evaluation reasonably in term of propagation characteristics of railway noise. Theory and calculation formulas and boundary conditions of noise predictive methods of mode were emphasized. One of representative of railway lines of China's central and western regions was deemed to be the research object, and the effects of scale of engineering, quality of line, train speed, and change of transportation organization on noise level along railways were analyzed and discussed. Day and night Equivalent Continuous Sound Level of typical section from the outer rail center line of 30m, 60m, 120m were supplied quantitatively. After analyzing noise contribution value and sound environment adaptability, the impacts of railway noise on surrounding environment were described qualitatively. The research results could offer useful evidences for controlling railway noise impacting environment and scientific advices on dividing the land utilization function zone along the railway engineering.%伴随新建铁路、既有线增建二线、电气化改造等项目的大规模建设,围绕铁路建设、运营由来已久的铁路噪声污染和扰民的问题却更为突出.根据铁路噪声的传播特性,合理地选取了一种噪声预测方法,即模式预测法作为铁路噪声预测方法,并重点介绍了噪声模式法的理论依据、计算公式和边界条件.以我国中西部地区具有代表性的铁路干线之一作为研究对象,分析讨论由于工程规模、线路质量、列车速度、运输组织的变化,引起的铁路噪声对沿线声环境的影响,定量给出了典型区段距铁路外轨中心线30m、60m、120m处

  8. An integrative computational framework based on a two-step random forest algorithm improves prediction of zinc-binding sites in proteins.

    Directory of Open Access Journals (Sweden)

    Cheng Zheng

    Full Text Available Zinc-binding proteins are the most abundant metalloproteins in the Protein Data Bank where the zinc ions usually have catalytic, regulatory or structural roles critical for the function of the protein. Accurate prediction of zinc-binding sites is not only useful for the inference of protein function but also important for the prediction of 3D structure. Here, we present a new integrative framework that combines multiple sequence and structural properties and graph-theoretic network features, followed by an efficient feature selection to improve prediction of zinc-binding sites. We investigate what information can be retrieved from the sequence, structure and network levels that is relevant to zinc-binding site prediction. We perform a two-step feature selection using random forest to remove redundant features and quantify the relative importance of the retrieved features. Benchmarking on a high-quality structural dataset containing 1,103 protein chains and 484 zinc-binding residues, our method achieved >80% recall at a precision of 75% for the zinc-binding residues Cys, His, Glu and Asp on 5-fold cross-validation tests, which is a 10%-28% higher recall at the 75% equal precision compared to SitePredict and zincfinder at residue level using the same dataset. The independent test also indicates that our method has achieved recall of 0.790 and 0.759 at residue and protein levels, respectively, which is a performance better than the other two methods. Moreover, AUC (the Area Under the Curve and AURPC (the Area Under the Recall-Precision Curve by our method are also respectively better than those of the other two methods. Our method can not only be applied to large-scale identification of zinc-binding sites when structural information of the target is available, but also give valuable insights into important features arising from different levels that collectively characterize the zinc-binding sites. The scripts and datasets are available at http://protein.cau.edu.cn/zincidentifier/.

  9. Peptide binding specificity of major histocompatibility complex class I resolved into an array of apparently independent subspecificities: quantitation by peptide libraries and improved prediction of binding

    DEFF Research Database (Denmark)

    Stryhn, A; Pedersen, L O; Romme, T

    1996-01-01

    size are distributed into positional scanning combinatorial peptide libraries (PSCPL) to develop a highly efficient, universal and unbiased approach to address MHC specificity. The PSCPL approach appeared qualitatively and quantitatively superior to other currently used strategies. The average effect...... of any amino acid in each position was quantitated, allowing a detailed description of extended peptide binding motifs including primary and secondary anchor residues. It also identified disfavored residues which were found to be surprisingly important in shaping MHC class I specificity. Assuming...

  10. gDNA-Prot: Predict DNA-binding proteins by employing support vector machine and a novel numerical characterization of protein sequence.

    Science.gov (United States)

    Zhang, Yan-Ping; Wuyunqiqige; Zheng, Wei; Liu, Shuyi; Zhao, Chunguang

    2016-10-01

    DNA-binding proteins are the functional proteins in cells, which play an important role in various essential biological activities. An effective and fast computational method gDNA-Prot is proposed to predict DNA-binding proteins in this paper, which is a DNA-binding predictor that combines the support vector machine classifier and a novel kind of feature called graphical representation. The DNA-binding protein sequence information was described with the 20 probabilities of amino acids and the 23 new numerical graphical representation features of a protein sequence, based on 23 physicochemical properties of 20 amino acids. The Principal Components Analysis (PCA) was employed as feature selection method for removing the irrelevant features and reducing redundant features. The Sigmod function and Min-max normalization methods for PCA were applied to accelerate the training speed and obtain higher accuracy. Experiments demonstrated that the Principal Components Analysis with Sigmod function generated the best performance. The gDNA-Prot method was also compared with the DNAbinder, iDNA-Prot and DNA-Prot. The results suggested that gDNA-Prot outperformed the DNAbinder and iDNA-Prot. Although the DNA-Prot outperformed gDNA-Prot, gDNA-Prot was faster and convenient to predict the DNA-binding proteins. Additionally, the proposed gNDA-Prot method is available at http://sourceforge.net/projects/gdnaprot.

  11. Effects of Mode Shares on Mode Choice

    OpenAIRE

    Carlos Carrion; Nebiyou Tilahun; David Levinson

    2011-01-01

    This study considers the influence of the knowledge of existing mode shares on travelers mode choice. This contrasts with traditional mode choice models, where the main objective is to predict the overall mode shares as the aggregate of individual mode choices according to variables encompassing attributes of the modes, and characteristics of the travelers. In this study, a computer-administered adaptive stated preference survey is developed and applied to a sample of subjects selected from t...

  12. New hypotheses for the binding mode of 4- and 7-substituted indazoles in the active site of neuronal nitric oxide synthase.

    Science.gov (United States)

    Lohou, Elodie; Sopkova-de Oliveira Santos, Jana; Schumann-Bard, Pascale; Boulouard, Michel; Stiebing, Silvia; Rault, Sylvain; Collot, Valérie

    2012-09-01

    Taking into account the potency of 4- and 7-nitro and haloindazoles as nNOS inhibitors previously reported in the literature by our team, a multidisciplinary study, described in this article, has recently been carried out to elucidate their binding mode in the enzyme active site. Firstly, nitrogenous fastening points on the indazole building block have been investigated referring to molecular modeling hypotheses and thanks to the in vitro biological evaluation of N(1)- and N(2)-methyl and ethyl-4-substituted indazoles on nNOS. Secondly, we attempted to confirm the importance of the substitution in position 4 or 7 by a hydrogen bond acceptor group thanks to the synthesis and the in vitro biological evaluation of a new analogous 4-substituted derivative, the 4-cyanoindazole. Finally, by opposition to previous hypotheses describing NH function in position 1 of the indazole as a key fastening point, the present work speaks in favour of a crucial role of nitrogen in position 2.

  13. Determination of the binding mode for the cyclopentapeptide CXCR4 antagonist FC131 using a dual approach of ligand modifications and receptor mutagenesis

    DEFF Research Database (Denmark)

    Thiele, Stefanie; Mungalpara, J; Steen, A

    2014-01-01

    pocket) respectively. Arg(1) forms charge-charge interactions with Asp(187) in ECL-2, while D-Tyr(5) points to the extracellular side of CXCR4. Furthermore, the backbone of FC131 interacts with the chemokine receptor-conserved Glu(288) via two water molecules. Intriguingly, Tyr(116) and Glu(288) form a H......BACKGROUND AND PURPOSE: The cyclopentapeptide FC131 (cyclo(-L-Arg(1) -L-Arg(2) -L-2-Nal(3) -Gly(4) -D-Tyr(5) -)) is an antagonist at the CXC chemokine receptor CXCR4, which plays a role in human immunodeficiency virus infection, cancer and stem cell recruitment. Binding modes for FC131 in CXCR4...... activation) of FC131 and three analogues were performed on wild-type CXCR4 and 25 receptor mutants. Computational modelling was used to rationalize the experimental data. KEY RESULTS: The Arg(2) and 2-Nal(3) side chains of FC131 interact with residues in TM-3 (His(113) , Asp(171) ) and TM-5 (hydrophobic...

  14. Interactome-Wide Prediction of Protein-Protein Binding Sites Reveals Effects of Protein Sequence Variation in Arabidopsis thaliana

    NARCIS (Netherlands)

    Valentim, F.L.; Neven, F.; Boyen, P.; Dijk, van A.D.J.

    2012-01-01

    The specificity of protein-protein interactions is encoded in those parts of the sequence that compose the binding interface. Therefore, understanding how changes in protein sequence influence interaction specificity, and possibly the phenotype, requires knowing the location of binding sites in thos

  15. An improved method for TAL effectors DNA-binding sites prediction reveals functional convergence in TAL repertoires of Xanthomonas oryzae strains.

    Directory of Open Access Journals (Sweden)

    Alvaro L Pérez-Quintero

    Full Text Available Transcription Activators-Like Effectors (TALEs belong to a family of virulence proteins from the Xanthomonas genus of bacterial plant pathogens that are translocated into the plant cell. In the nucleus, TALEs act as transcription factors inducing the expression of susceptibility genes. A code for TALE-DNA binding specificity and high-resolution three-dimensional structures of TALE-DNA complexes were recently reported. Accurate prediction of TAL Effector Binding Elements (EBEs is essential to elucidate the biological functions of the many sequenced TALEs as well as for robust design of artificial TALE DNA-binding domains in biotechnological applications. In this work a program with improved EBE prediction performances was developed using an updated specificity matrix and a position weight correction function to account for the matching pattern observed in a validation set of TALE-DNA interactions. To gain a systems perspective on the large TALE repertoires from X. oryzae strains, this program was used to predict rice gene targets for 99 sequenced family members. Integrating predictions and available expression data in a TALE-gene network revealed multiple candidate transcriptional targets for many TALEs as well as several possible instances of functional convergence among TALEs.

  16. A Bayesian network model for predicting aquatic toxicity mode of action using two dimensional theoretical molecular descriptors-abstract

    Science.gov (United States)

    The mode of toxic action (MoA) has been recognized as a key determinant of chemical toxicity but MoA classification in aquatic toxicology has been limited. We developed a Bayesian network model to classify aquatic toxicity mode of action using a recently published dataset contain...

  17. In silico peptide-binding predictions of passerine MHC class I reveal similarities across distantly related species, suggesting convergence on the level of protein function

    DEFF Research Database (Denmark)

    Follin, Elna; Karlsson, Maria; Lundegaard, Claus

    2013-01-01

    compared to most mammals. To elucidate the reason for this large number of genes, we compared 14 MHC class I alleles (α1–α3 domains), from great reed warbler, house sparrow and tree sparrow, via phylogenetic analysis, homology modelling and in silico peptide-binding predictions to investigate......, there were also overlapping peptide-binding specificities in the allomorphs from house sparrow and great reed warbler, although these species diverged 30 MYA. This overlap was not found in a tree based on amino acid sequences. Our interpretation is that convergent evolution on the level of the protein...... function, possibly driven by selection from shared pathogens, has resulted in allomorphs with similar peptide-binding repertoires, although trans-species evolution in combination with gene conversion cannot be ruled out....

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

    Science.gov (United States)

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

    2015-06-09

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

  19. Structure and in silico substrate-binding mode of ADP-L-glycero-D-manno-heptose 6-epimerase from Burkholderia thailandensis.

    Science.gov (United States)

    Kim, Mi-Sun; Lim, Areum; Yang, Seung Won; Park, Jimin; Lee, Daeun; Shin, Dong Hae

    2013-04-01

    ADP-L-glycero-D-manno-heptose 6-epimerase (AGME), the product of the rfaD gene, is the last enzyme in the heptose-biosynthesis pathway; it converts ADP-D-glycero-D-manno-heptose (ADP-D,D-Hep) to ADP-L-glycero-D-manno-heptose (ADP-L,D-Hep). AGME contains a catalytic triad involved in catalyzing hydride transfer with the aid of NADP(+). Defective lipopolysaccharide is found in bacterial mutants lacking this gene. Therefore, it is an interesting target enzyme for a novel epimerase inhibitor for use as a co-therapy with antibiotics. The crystal structure of AGME from Burkholderia thailandensis (BtAGME), a surrogate organism for studying the pathogenicity of melioidosis caused by B. pseudomallei, has been determined. The crystal structure determined with co-purified NADP(+) revealed common as well as unique structural properties of the AGME family when compared with UDP-galactose 4-epimerase homologues. They form a similar architecture with conserved catalytic residues. Nevertheless, there are differences in the substrate- and cofactor-binding cavities and the oligomerization domains. Structural comparison of BtAGME with AGME from Escherichia coli indicates that they may recognize their substrate in a `lock-and-key' fashion. Unique structural features of BtAGME are found in two regions. The first region is the loop between β8 and β9, affecting the binding affinity of BtAGME for the ADP moiety of ADP-D,D-Hep. The second region is helix α8, which induces decamerization at low pH that is not found in other AGMEs. With the E210G mutant, it was observed that the resistance of the wild type to acid-induced denaturation is related to the decameric state. An in silico study was performed using the Surflex-Dock GeomX module of the SYBYL-X 1.3 software to predict the catalytic mechanism of BtAGME with its substrate, ADP-D,D-Hep. In the in silico study, the C7'' hydroxymethyl group of ADP-D,D-Hep is predicted to form hydrogen bonds to Ser116 and Gln293. With the aid of these

  20. Prediction of N-Methyl-D-Aspartate Receptor GluN1-Ligand Binding Affinity by a Novel SVM-Pose/SVM-Score Combinatorial Ensemble Docking Scheme

    Science.gov (United States)

    Leong, Max K.; Syu, Ren-Guei; Ding, Yi-Lung; Weng, Ching-Feng

    2017-01-01

    The glycine-binding site of the N-methyl-D-aspartate receptor (NMDAR) subunit GluN1 is a potential pharmacological target for neurodegenerative disorders. A novel combinatorial ensemble docking scheme using ligand and protein conformation ensembles and customized support vector machine (SVM)-based models to select the docked pose and to predict the docking score was generated for predicting the NMDAR GluN1-ligand binding affinity. The predicted root mean square deviation (RMSD) values in pose by SVM-Pose models were found to be in good agreement with the observed values (n = 30, r2 = 0.928–0.988,  = 0.894–0.954, RMSE = 0.002–0.412, s = 0.001–0.214), and the predicted pKi values by SVM-Score were found to be in good agreement with the observed values for the training samples (n = 24, r2 = 0.967,  = 0.899, RMSE = 0.295, s = 0.170) and test samples (n = 13, q2 = 0.894, RMSE = 0.437, s = 0.202). When subjected to various statistical validations, the developed SVM-Pose and SVM-Score models consistently met the most stringent criteria. A mock test asserted the predictivity of this novel docking scheme. Collectively, this accurate novel combinatorial ensemble docking scheme can be used to predict the NMDAR GluN1-ligand binding affinity for facilitating drug discovery.

  1. Predicting core losses and efficiency of SRM in continuous current mode of operation using improved analytical technique

    Energy Technology Data Exchange (ETDEWEB)

    Parsapour, Amir, E-mail: amirparsapour@gmail.com [Department of Electrical Engineering, University of Isfahan, Isfahan (Iran, Islamic Republic of); Dehkordi, Behzad Mirzaeian, E-mail: mirzaeian@eng.ui.ac.ir [Department of Electrical Engineering, University of Isfahan, Isfahan (Iran, Islamic Republic of); Moallem, Mehdi, E-mail: moallem@cc.iut.ac.ir [Department of Electrical Engineering, Isfahan University of Technology, Isfahan (Iran, Islamic Republic of)

    2015-03-15

    In applications in which the high torque per ampere at low speed and rated power at high speed are required, the continuous current method is the best solution. However, there is no report on calculating the core loss of SRM in continuous current mode of operation. Efficiency and iron loss calculation which are complex tasks in case of conventional mode of operation is even more involved in continuous current mode of operation. In this paper, the Switched Reluctance Motor (SRM) is modeled using finite element method and core loss and copper loss of SRM in discontinuous and continuous current modes of operation are calculated using improved analytical techniques to include the minor loop losses in continuous current mode of operation. Motor efficiency versus speed in both operation modes is obtained and compared. - Highlights: • Continuous current method for Switched Reluctance Motor (SRM) is explained. • An improved analytical technique is presented for SRM core loss calculation. • SRM losses in discontinuous and continuous current operation modes are presented. • Effect of mutual inductances on SRM performance is investigated.

  2. [Predicting the cadmium bioavailability in the soil of sugarcane field based on the diffusive gradients in thin films with binding phase of sodium polyacrylate].

    Science.gov (United States)

    Wang, Fang-Li; Song, Ning-Ning; Zhao, Yu-Jie; Zhang, Chang-Bo; Shen, Yue; Liu, Zhong-Qi

    2012-10-01

    The diffusive gradients in thin films (DGT) technique with solid-state binding phases has been widely used for in situ collection and measurement of available heavy metals in waters, soils or sediments, whereas DGT with liquid binding phase is primarily used in the in situ analysis of heavy metals in waters. In this paper, rhizosphere soils of sugarcane were collected in Guangxi and the concentrations of cadmium (Cd) were determined by DGT with a solid-state binding phase of chelex100 (chelex100-DGT) and modified DGT with a liquid binding phase of sodium polyacrylate (CDM-PAAS-DGT). The result showed that the Cd contents in soils measured by DGT with both binding phases and Cd in the roots, leaves and unpolished stems of sugarcane had significant positive correlation. The extraction ability of the CDM-PAAAS-DGT was much higher than that of the chelex100-DGT. In addition, multivariate analyses were used to assess the impact of pH, cation exchange capacity (CEC), soil organic matter (OM) and texture. Two principal components were extracted and the linear regression models were established. The Cd bioavailability in soils could be accurately predicted by the CDM-PAAAS-DGT technique, which expanded its applicable area.

  3. Predicting the Structure-Activity Relationship of Hydroxyapatite-Binding Peptides by Enhanced-Sampling Molecular Simulation.

    Science.gov (United States)

    Zhao, Weilong; Xu, Zhijun; Cui, Qiang; Sahai, Nita

    2016-07-12

    Understanding the molecular structural and energetic basis of the interactions between peptides and inorganic surfaces is critical to their applications in tissue engineering and biomimetic material synthesis. Despite recent experimental progresses in the identification and functionalization of hydroxyapatite (HAP)-binding peptides, the molecular mechanisms of their interactions with HAP surfaces are yet to be explored. In particular, the traditional method of molecular dynamics (MD) simulation suffers from insufficient sampling at the peptide-inorganic interface that renders the molecular-level observation dubious. Here we demonstrate that an integrated approach combining bioinformatics, MD, and metadynamics provides a powerful tool for investigating the structure-activity relationship of HAP-binding peptides. Four low charge density peptides, previously identified by phage display, have been considered. As revealed by bioinformatics and MD, the binding conformation of the peptides is controlled by both the sequence and the amino acid composition. It was found that formation of hydrogen bonds between lysine residue and phosphate ions on the surface dictates the binding of positively charged peptide to HAP. The binding affinities of the peptides to the surface are estimated by free energy calculation using parallel-tempering metadynamics, and the results compare favorably to measurements reported in previous experimental studies. The calculation suggests that the charge density of the peptide primarily controls the binding affinity to the surface, while the backbone secondary structure that may restrain side chain orientation toward the surface plays a minor role. We also report that the application of enhanced-sampling metadynamics effects a major advantage over the steered MD method by significantly improving the reliability of binding free energy calculation. In general, our novel integration of diverse sampling techniques should contribute to the rational

  4. H.264/AVC帧内预测模式的快速选择算法%Fast Mode Decision Algorithm for Intra Prediction in H.264/AVC

    Institute of Scientific and Technical Information of China (English)

    丁道林; 张玲华

    2012-01-01

    The intra prediction technology of H. 264/AVC selects the best prediction mode by rate-distortion optimization strategy, which improves the encoding efficiency of the I-frames. However, the computational complexity of encoding process is increased at the same time. A fast mode decision algorithm for inlra prediction is proposed in this paper. This fast algorithm based on the directional features of current luminance block could get the best intra luminance prediction mode by rate-distortion cost calculation among a few of more probable prediction modes which could be obtained by a little simple computation. And the computation of SATD instead of the rate-distortion cost are used to selects the best intra chrominance prediction mode, fliis fast algorithm could reduce the computational complexity and improves the speed of the encoding process. Experimental results show that with the similar image quality, this fast algorithm can efficiently reduce the encoding time about 48% with little increase of bit rate averagely.%H.264/AVC帧内预测技术采用率失真优化策略进行最优化编码模式选择,提高了Ⅰ帧的编码效率,但同时也提高了计算复杂度.提出了一种帧内预测模式的快速选择算法,基于亮度块的方向特性,通过一些复杂度不大的计算,选择少数几个可能性较大的预测模式进行率失真代价计算,得到最佳亮度预测模式,并以SATD计算代替率失真代价计算选择最佳色度预测模式,降低了计算复杂度,提高了编码速度.实验结果表明,提出的算法在保证图像质量的同时,编码时间平均降低了48%,而码率增加很小.

  5. Proteochemometric modelling coupled to in silico target prediction: an integrated approach for the simultaneous prediction of polypharmacology and binding affinity/potency of small molecules.

    Science.gov (United States)

    Paricharak, Shardul; Cortés-Ciriano, Isidro; IJzerman, Adriaan P; Malliavin, Thérèse E; Bender, Andreas

    2015-01-01

    The rampant increase of public bioactivity databases has fostered the development of computational chemogenomics methodologies to evaluate potential ligand-target interactions (polypharmacology) both in a qualitative and quantitative way. Bayesian target prediction algorithms predict the probability of an interaction between a compound and a panel of targets, thus assessing compound polypharmacology qualitatively, whereas structure-activity relationship techniques are able to provide quantitative bioactivity predictions. We propose an integrated drug discovery pipeline combining in silico target prediction and proteochemometric modelling (PCM) for the respective prediction of compound polypharmacology and potency/affinity. The proposed pipeline was evaluated on the retrospective discovery of Plasmodium falciparum DHFR inhibitors. The qualitative in silico target prediction model comprised 553,084 ligand-target associations (a total of 262,174 compounds), covering 3,481 protein targets and used protein domain annotations to extrapolate predictions across species. The prediction of bioactivities for plasmodial DHFR led to a recall value of 79% and a precision of 100%, where the latter high value arises from the structural similarity of plasmodial DHFR inhibitors and T. gondii DHFR inhibitors in the training set. Quantitative PCM models were then trained on a dataset comprising 20 eukaryotic, protozoan and bacterial DHFR sequences, and 1,505 distinct compounds (in total 3,099 data points). The most predictive PCM model exhibited R (2) 0 test and RMSEtest values of 0.79 and 0.59 pIC50 units respectively, which was shown to outperform models based exclusively on compound (R (2) 0 test/RMSEtest = 0.63/0.78) and target information (R (2) 0 test/RMSEtest = 0.09/1.22), as well as inductive transfer knowledge between targets, with respective R (2) 0 test and RMSEtest values of 0.76 and 0.63 pIC50 units. Finally, both methods were integrated to predict the protein

  6. Dissecting the Binding Mode of Low Affinity Phage Display Peptide Ligands to Protein Targets by Hydrogen/Deuterium Exchange Coupled to Mass Spectrometry

    DEFF Research Database (Denmark)

    Leurs, Ulrike; Lohse, Brian; Ming, Shonoi A;

    2014-01-01

    Phage display (PD) is frequently used to discover peptides capable of binding to biological protein targets. The structural characterization of peptide-protein complexes is often challenging due to their low binding affinities and high structural flexibility. Here, we investigate the use of hydro......Phage display (PD) is frequently used to discover peptides capable of binding to biological protein targets. The structural characterization of peptide-protein complexes is often challenging due to their low binding affinities and high structural flexibility. Here, we investigate the use...

  7. Conformational restriction approach to β-secretase (BACE1) inhibitors III: effective investigation of the binding mode by combinational use of X-ray analysis, isothermal titration calorimetry and theoretical calculations.

    Science.gov (United States)

    Yonezawa, Shuji; Fujiwara, Kenichiro; Yamamoto, Takahiko; Hattori, Kazunari; Yamakawa, Hidekuni; Muto, Chie; Hosono, Motoko; Tanaka, Yoshikazu; Nakano, Toru; Takemoto, Hiroshi; Arisawa, Mitsuhiro; Shuto, Satoshi

    2013-11-01

    For further investigation of BACE1 inhibitors using conformational restriction with sp(3) hybridized carbon, we applied this approach to 6-substituted aminopyrimidone derivatives 3 to improve the inhibitory activity by reducing the entropic energy loss upon binding to BACE1. Among eight stereoisomers synthesized, [trans-(1'R,2'R),6S] isomer 6 exhibited the best BACE1 inhibitory activity, which was statistically superior to that of the corresponding ethylene linker compound (R)-3. Combinational examinations of the binding mode of 6 were performed, which included isothermal titration calorimetry (ITC), X-ray crystallographic structure analysis and theoretical calculations, to clarify the effect of our conformational restriction approach. From the ITC measurement, the binding entropy of 6 was found to be ∼0.5kcal larger than that of (R)-3, which is considered to be affected by conformational restriction with a cyclopropane ring.

  8. Oligosaccharide binding to barley alpha-amylase 1

    DEFF Research Database (Denmark)

    Robert, X.; Haser, R.; Mori, H.;

    2005-01-01

    Enzymatic subsite mapping earlier predicted 10 binding subsites in the active site substrate binding cleft of barley alpha-amylase isozymes. The three-dimensional structures of the oligosaccharide complexes with barley alpha-amylase isozyme 1 (AMY1) described here give for the first time a thorough...... insight into the substrate binding by describing residues defining 9 subsites, namely -7 through +2. These structures support that the pseudotetrasaccharide inhibitor acarbose is hydrolyzed by the active enzymes. Moreover, sugar binding was observed to the starch granule-binding site previously determined...... in barley alpha-amylase isozyme 2 (AMY2), and the sugar binding modes are compared between the two isozymes. The "sugar tongs" surface binding site discovered in the AMY1-thio-DP4 complex is confirmed in the present work. A site that putatively serves as an entrance for the substrate to the active site...

  9. Measurement of binding of basic drugs to acidic phospholipids using surface plasmon resonance and incorporation of the data into mechanistic tissue composition equations to predict steady-state volume of distribution.

    Science.gov (United States)

    Small, Helen; Gardner, Iain; Jones, Hannah M; Davis, John; Rowland, Malcolm

    2011-10-01

    Acidic phospholipid binding plays an important role in determining the tissue distribution of basic drugs. This article describes the use of surface plasmon resonance to measure binding affinity (K(D)) of three basic drugs to phosphatidylserine, a major tissue acidic phospholipid. The data are incorporated into mechanistic tissue composition equations to allow prediction of the steady-state volume of distribution (V(ss)). The prediction accuracy of V(ss) using this approach is compared with the original methodology described by Rodgers et al. (J Pharm Sci 94:1259-1276), in which the binding to acidic phospholipids is calculated from the blood/plasma concentration ratio (BPR). The compounds used in this study [amlodipine, propranolol, and 3-dimethylaminomethyl-4-(4-methylsulfanyl-phenoxy)-benzenesulfonamide (UK-390957)] showed higher affinity binding to phosphatidylserine than to phosphatidylcholine. When the binding affinity to phosphatidylserine was incorporated into mechanistic tissue composition equations, the V(ss) was more accurately predicted for all three compounds by using the surface plasmon resonance measurement than by using the BPR to estimate acidic phospholipid binding affinity. The difference was particularly marked for UK-390957, a sulfonamide that has a high BPR due to binding to carbonic anhydrase. The novel approach described in this article allows the binding affinity of drugs to an acidic phospholipid (phosphatidylserine) to be measured directly and demonstrates the utility of the binding data in the prediction of V(ss).

  10. Predicting of parameters of reliability two-cascade thermoelectrical cooling device in a mode Q0max

    Directory of Open Access Journals (Sweden)

    Khramova L. F.

    2009-10-01

    Full Text Available The parities for an estimation of parameters of reliability two-cascade ТED of a various design depending on their basic parameters in a mode Q0max are received. The results of accounts for differences of temperature ΔТ=60, 70, 80 K in view of thermal loading and temperature dependence of parameters, and also in a mode of the thermal pump (at ΔТ=0 are given. The estimation maximal coldproductivity two-cascade TED of a various design for various conditions of operation is carried out.

  11. Coarse-grained/molecular mechanics of the TAS2R38 bitter taste receptor: experimentally-validated detailed structural prediction of agonist binding.

    Directory of Open Access Journals (Sweden)

    Alessandro Marchiori

    Full Text Available Bitter molecules in humans are detected by ∼25 G protein-coupled receptors (GPCRs. The lack of atomic resolution structure for any of them is complicating an in depth understanding of the molecular mechanisms underlying bitter taste perception. Here, we investigate the molecular determinants of the interaction of the TAS2R38 bitter taste receptor with its agonists phenylthiocarbamide (PTC and propylthiouracil (PROP. We use the recently developed hybrid Molecular Mechanics/Coarse Grained (MM/CG method tailored specifically for GPCRs. The method, through an extensive exploration of the conformational space in the binding pocket, allows the identification of several residues important for agonist binding that would have been very difficult to capture from the standard bioinformatics/docking approach. Our calculations suggest that both agonists bind to Asn103, Phe197, Phe264 and Trp201, whilst they do not interact with the so-called extra cellular loop 2, involved in cis-retinal binding in the GPCR rhodopsin. These predictions are consistent with data sets based on more than 20 site-directed mutagenesis and functional calcium imaging experiments of TAS2R38. The method could be readily used for other GPCRs for which experimental information is currently lacking.

  12. Coarse-grained/molecular mechanics of the TAS2R38 bitter taste receptor: experimentally-validated detailed structural prediction of agonist binding.

    Science.gov (United States)

    Marchiori, Alessandro; Capece, Luciana; Giorgetti, Alejandro; Gasparini, Paolo; Behrens, Maik; Carloni, Paolo; Meyerhof, Wolfgang

    2013-01-01

    Bitter molecules in humans are detected by ∼25 G protein-coupled receptors (GPCRs). The lack of atomic resolution structure for any of them is complicating an in depth understanding of the molecular mechanisms underlying bitter taste perception. Here, we investigate the molecular determinants of the interaction of the TAS2R38 bitter taste receptor with its agonists phenylthiocarbamide (PTC) and propylthiouracil (PROP). We use the recently developed hybrid Molecular Mechanics/Coarse Grained (MM/CG) method tailored specifically for GPCRs. The method, through an extensive exploration of the conformational space in the binding pocket, allows the identification of several residues important for agonist binding that would have been very difficult to capture from the standard bioinformatics/docking approach. Our calculations suggest that both agonists bind to Asn103, Phe197, Phe264 and Trp201, whilst they do not interact with the so-called extra cellular loop 2, involved in cis-retinal binding in the GPCR rhodopsin. These predictions are consistent with data sets based on more than 20 site-directed mutagenesis and functional calcium imaging experiments of TAS2R38. The method could be readily used for other GPCRs for which experimental information is currently lacking.

  13. Urinary liver-type fatty acid-binding protein predicts progression to nephropathy in type 1 diabetic patients

    DEFF Research Database (Denmark)

    Nielsen, Stine Elkjaer; Sugaya, Takeshi; Hovind, Peter;

    2010-01-01

    Urinary liver-type fatty acid-binding protein (u-LFABP) is a marker of tubulointerstitial inflammation and has been shown to be increased in patients with type 1 diabetes and is further increased in patients who progress to micro- and macroalbuminuria. Our aim was to evaluate u-LFABP as a predictor...

  14. Predicting Allosteric Effects from Orthosteric Binding in Hsp90-Ligand Interactions: Implications for Fragment-Based Drug Design

    Science.gov (United States)

    Larsson, Andreas; Nordlund, Paer; Jansson, Anna; Anand, Ganesh S.

    2016-01-01

    A key question in mapping dynamics of protein-ligand interactions is to distinguish changes at binding sites from those associated with long range conformational changes upon binding at distal sites. This assumes a greater challenge when considering the interactions of low affinity ligands (dissociation constants, KD, in the μM range or lower). Amide hydrogen deuterium Exchange mass spectrometry (HDXMS) is a robust method that can provide both structural insights and dynamics information on both high affinity and transient protein-ligand interactions. In this study, an application of HDXMS for probing the dynamics of low affinity ligands to proteins is described using the N-terminal ATPase domain of Hsp90. Comparison of Hsp90 dynamics between high affinity natural inhibitors (KD ~ nM) and fragment compounds reveal that HDXMS is highly sensitive in mapping the interactions of both high and low affinity ligands. HDXMS reports on changes that reflect both orthosteric effects and allosteric changes accompanying binding. Orthosteric sites can be identified by overlaying HDXMS onto structural information of protein-ligand complexes. Regions distal to orthosteric sites indicate long range conformational changes with implications for allostery. HDXMS, thus finds powerful utility as a high throughput method for compound library screening to identify binding sites and describe allostery with important implications for fragment-based ligand discovery (FBLD). PMID:27253209

  15. Predicting Allosteric Effects from Orthosteric Binding in Hsp90-Ligand Interactions: Implications for Fragment-Based Drug Design.

    Directory of Open Access Journals (Sweden)

    Arun Chandramohan

    2016-06-01

    Full Text Available A key question in mapping dynamics of protein-ligand interactions is to distinguish changes at binding sites from those associated with long range conformational changes upon binding at distal sites. This assumes a greater challenge when considering the interactions of low affinity ligands (dissociation constants, KD, in the μM range or lower. Amide hydrogen deuterium Exchange mass spectrometry (HDXMS is a robust method that can provide both structural insights and dynamics information on both high affinity and transient protein-ligand interactions. In this study, an application of HDXMS for probing the dynamics of low affinity ligands to proteins is described using the N-terminal ATPase domain of Hsp90. Comparison of Hsp90 dynamics between high affinity natural inhibitors (KD ~ nM and fragment compounds reveal that HDXMS is highly sensitive in mapping the interactions of both high and low affinity ligands. HDXMS reports on changes that reflect both orthosteric effects and allosteric changes accompanying binding. Orthosteric sites can be identified by overlaying HDXMS onto structural information of protein-ligand complexes. Regions distal to orthosteric sites indicate long range conformational changes with implications for allostery. HDXMS, thus finds powerful utility as a high throughput method for compound library screening to identify binding sites and describe allostery with important implications for fragment-based ligand discovery (FBLD.

  16. Predictions of thermal expansion coefficients of rare-earth zirconate pyrochlores: A quasi-harmonic approximation based on stable phonon modes

    Science.gov (United States)

    Lan, Guoqiang; Ouyang, Bin; Xu, Yushuai; Song, Jun; Jiang, Yong

    2016-06-01

    Rare-earth (RE) pyrochlores are considered as promising candidate materials for the thermal barrier coating. In this study, we performed first-principles calculations, augmented by quasi-harmonic phonon calculations, to investigate the thermal expansion behaviors of several RE2Zr2O7 (RE = La, Nd, Sm, Gd) pyrochlores. Our findings show that RE2Zr2O7 pyrochlores exhibit low-lying optical phonon frequencies that correspond to RE-cation rattling vibrational modes. These frequencies become imaginary upon volume expansion, preventing correct determination of the free energy versus volume relation and thereby quantification of thermal expansion using QH phonon calculations. To address this challenge, we proposed a QH approximation approach based on stable phonon modes where the RE-cation rattling modes were systematically eliminated. This approach is shown to provide accurate predictions of the coefficients of thermal expansion (CTEs) of RE2Zr2O7 pyrochlores, in good agreement with experimental measurements and data from first-principles molecular dynamics simulations. In addition, we showed that the QH Debye model considerably overestimates the magnitudes and wrongly predicts the trend for the CTEs of RE2Zr2O7 pyrochlores.

  17. Prediction of enzyme binding: human thrombin inhibition study by quantum chemical and artificial intelligence methods based on X-ray structures.

    Science.gov (United States)

    Mlinsek, G; Novic, M; Hodoscek, M; Solmajer, T

    2001-01-01

    Thrombin is a serine protease which plays important roles in the human body, the key one being the control of thrombus formation. The inhibition of thrombin has become a target for new antithrombotics. The aim of our work was to (i) construct a model which would enable us to predict Ki values for the binding of an inhibitor into the active site of thrombin based on a database of known X-ray structures of inhibitor-enzyme complexes and (ii) to identify the structural and electrostatic characteristics of inhibitor molecules crucially important to their effective binding. To retain as much of the 3D structural information of the bound inhibitor as possible, we implemented the quantum mechanical/molecular mechanical (QM/MM) procedure for calculating the molecular electrostatic potential (MEP) at the van der Waals surfaces of atoms in the protein's active site. The inhibitor was treated quantum mechanically, while the rest of the complex was treated by classical means. The obtained MEP values served as inputs into the counter-propagation artificial neural network (CP-ANN), and a genetic algorithm was subsequently used to search for the combination of atoms that predominantly influences the binding. The constructed CP-ANN model yielded Ki values predictions with a correlation coefficient of 0.96, with Ki values extended over 7 orders of magnitude. Our approach also shows the relative importance of the various amino acid residues present in the active site of the enzyme for inhibitor binding. The list of residues selected by our automatic procedure is in good correlation with the current consensus regarding the importance of certain crucial residues in thrombin's active site.

  18. Positive priming and intentional binding: eye-blink rate predicts reward information effects on the sense of agency.

    Science.gov (United States)

    Aarts, Henk; Bijleveld, Erik; Custers, Ruud; Dogge, Myrthel; Deelder, Merel; Schutter, Dennis; Haren, Neeltje E M van

    2012-01-01

    Human society is strongly rooted in people's experiences of agency; that is, the pervasive feeling that one engages in voluntary behavior and causes one's own actions and resulting outcomes. Rewards and positive affect play an important role in the control of voluntary action. However, the role of positive reward signals in the sense of agency is poorly understood. This study examined effects of reward-related information on the sense of agency by employing the intentional binding paradigm. This paradigm measures the extent to which actions and their effects subjectively shift together across time, reflecting a crucial component of people's sense of agency. Results showed that intentional binding is stronger when participants are primed with reward-related information via brief exposure to positive pictures. Interestingly, this positive priming effect was moderated by baseline eye-blink rates (an indirect marker of striatal dopaminergic functioning); reward-related information increased intentional binding mainly for participants displaying higher baseline eye-blink rates. These findings suggest a possible role for striatal dopamine activity in the process by which reward-related information shapes the way people see themselves as agents.

  19. The PRC2-binding long non-coding RNAs in human and mouse genomes are associated with predictive sequence features<