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Sample records for binding mode prediction

  1. 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....

  2. 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.

  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. PMID:17427957

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

    Science.gov (United States)

    Nutho, Bodee; Khuntawee, Wasinee; Rungnim, Chompoonut; Pongsawasdi, Piamsook; Wolschann, Peter; Karpfen, Alfred; Kungwan, Nawee

    2014-01-01

    Summary 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. PMID:25550745

  5. 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.

  6. Predicting novel binding modes of agonists to β adrenergic receptors using all-atom molecular dynamics simulations.

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    Stefano Vanni

    Full Text Available Understanding the binding mode of agonists to adrenergic receptors is crucial to enabling improved rational design of new therapeutic agents. However, so far the high conformational flexibility of G protein-coupled receptors has been an obstacle to obtaining structural information on agonist binding at atomic resolution. In this study, we report microsecond classical molecular dynamics simulations of β(1 and β(2 adrenergic receptors bound to the full agonist isoprenaline and in their unliganded form. These simulations show a novel agonist binding mode that differs from the one found for antagonists in the crystal structures and from the docking poses reported by in silico docking studies performed on rigid receptors. Internal water molecules contribute to the stabilization of novel interactions between ligand and receptor, both at the interface of helices V and VI with the catechol group of isoprenaline as well as at the interface of helices III and VII with the ethanolamine moiety of the ligand. Despite the fact that the characteristic N-C-C-OH motif is identical in the co-crystallized ligands and in the full agonist isoprenaline, the interaction network between this group and the anchor site formed by Asp(3.32 and Asn(7.39 is substantially different between agonists and inverse agonists/antagonists due to two water molecules that enter the cavity and contribute to the stabilization of a novel network of interactions. These new binding poses, together with observed conformational changes in the extracellular loops, suggest possible determinants of receptor specificity.

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

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    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.

  8. 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.

  9. 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. PMID:27327045

  10. 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.

  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. PMID:26945790

  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. Cooperative binding modes of Cu(II) in prion protein

    Science.gov (United States)

    Hodak, Miroslav; Chisnell, Robin; Lu, Wenchang; Bernholc, Jerry

    2007-03-01

    The misfolding of the prion protein, PrP, is responsible for a group of neurodegenerative diseases including mad cow disease and Creutzfeldt-Jakob disease. It is known that the PrP can efficiently bind copper ions; four high-affinity binding sites located in the octarepeat region of PrP are now well known. Recent experiments suggest that at low copper concentrations new binding modes, in which one copper ion is shared between two or more binding sites, are possible. Using our hybrid Thomas-Fermi/DFT computational scheme, which is well suited for simulations of biomolecules in solution, we investigate the geometries and energetics of two, three and four binding sites cooperatively binding one copper ion. These geometries are then used as inputs for classical molecular dynamics simulations. We find that copper binding affects the secondary structure of the PrP and that it stabilizes the unstructured (unfolded) part of the protein.

  15. 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...

  16. Binding modes of peptidomimetics designed to inhibit STAT3.

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    Ankur Dhanik

    Full Text Available STAT3 is a transcription factor that has been found to be constitutively activated in a number of human cancers. Dimerization of STAT3 via its SH2 domain and the subsequent translocation of the dimer to the nucleus leads to transcription of anti-apoptotic genes. Prevention of the dimerization is thus an attractive strategy for inhibiting the activity of STAT3. Phosphotyrosine-based peptidomimetic inhibitors, which mimic pTyr-Xaa-Yaa-Gln motif and have strong to weak binding affinities, have been previously investigated. It is well-known that structures of protein-inhibitor complexes are important for understanding the binding interactions and designing stronger inhibitors. Experimental structures of inhibitors bound to the SH2 domain of STAT3 are, however, unavailable. In this paper we describe a computational study that combined molecular docking and molecular dynamics to model structures of 12 peptidomimetic inhibitors bound to the SH2 domain of STAT3. A detailed analysis of the modeled structures was performed to evaluate the characteristics of the binding interactions. We also estimated the binding affinities of the inhibitors by combining MMPB/GBSA-based energies and entropic cost of binding. The estimated affinities correlate strongly with the experimentally obtained affinities. Modeling results show binding modes that are consistent with limited previous modeling studies on binding interactions involving the SH2 domain and phosphotyrosine(pTyr-based inhibitors. We also discovered a stable novel binding mode that involves deformation of two loops of the SH2 domain that subsequently bury the C-terminal end of one of the stronger inhibitors. The novel binding mode could prove useful for developing more potent inhibitors aimed at preventing dimerization of cancer target protein STAT3.

  17. 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.

  18. 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....

  19. 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.  

  20. Binding modes of thrombin binding aptamers investigated by simulations and experiments

    Science.gov (United States)

    Trapaidze, A.; Bancaud, A.; Brut, M.

    2015-01-01

    Thrombin binding aptamers HD1 and HD22 are the most studied aptamers, both for therapeutic and sensing purposes. Yet, there is still no commercialized aptamer-based sensor device for thrombin detection, suggesting that the binding modes of these aptamers remain to be precisely described. Here, we investigate thrombin-aptamer interactions with molecular dynamics simulations, and show that the different solved structures of HD1-thrombin complex are energetically similar and consequently possibly co-existing. Conversely, HD22 folding is much more stable, and its binding energy with thrombin is significantly larger than that of HD1 complexes. These results are confronted to experiments, which consist in monitoring aggregation of aptamer-functionalized gold nanoparticles triggered by thrombin. HD1 alone, but not HD22, can trigger aggregation, meaning that this aptamer has multiple sites of interactions with thrombin. Furthermore, pre-incubation of HD22 with thrombin impedes HD1 aggregation, suggesting that HD1 and HD22 have competing affinities for the same binding site. Altogether, this study shows that the characterization of aptamer-thrombin interactions by structural and kinetic experiments joined to simulations is necessary for the development of biosensors.

  1. 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.

  2. 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...

  3. 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)

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

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    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.

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

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    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

  6. 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/).

  7. Exploration of the binding mode between (-)-zampanolide and tubulin using docking and molecular dynamics simulation.

    Science.gov (United States)

    Liao, Si-Yan; Mo, Guang-Quan; Chen, Jin-Can; Zheng, Kang-Cheng

    2014-02-01

    The binding mode of (-)-zampanolide (ZMP) to tubulin was investigated using docking, molecular dynamics (MD) simulation, and binding free-energy calculations. The docking studies validated the experimental results indicating that the paclitaxel site is the binding site for (-)-ZMP. The 18 ns MD simulation shows the docking mode has changed a lot, whereas it offers more reliable binding data. MM-PBSA binding free-energy calculations further confirmed the results of the MD simulation. The study revealed that hydrophobic interactions play an important role in stabilizing the binding, and the strong hydrogen bond formed with Asp224 enhances the affinity for tubulin. Meanwhile, the results support the assumption that (-)-ZMP can be attacked by His227, leading to a nucleophilic reaction and covalent binding. These theoretical results lead to a greater understanding of the mechanism of action of binding to tubulin, and will therefore aid the design of new compounds with higher affinities for tubulin. PMID:24478043

  8. Peptide binding predictions for HLA DR, DP and DQ molecules

    DEFF Research Database (Denmark)

    Wang, P.; Sidney, J.; Kim, Y.;

    2010-01-01

    their performance. CONCLUSION: We found that 1) prediction methodologies developed for HLA DR molecules perform equally well for DP or DQ molecules. 2) Prediction performances were significantly increased compared to previous reports due to the larger amounts of training data available. 3) The presence...... include all training data for maximum performance. 4) The recently developed NN-align prediction method significantly outperformed all other algorithms, including a naïve consensus based on all prediction methods. A new consensus method dropping the comparably weak ARB prediction method could outperform......BACKGROUND: MHC class II binding predictions are widely used to identify epitope candidates in infectious agents, allergens, cancer and autoantigens. The vast majority of prediction algorithms for human MHC class II to date have targeted HLA molecules encoded in the DR locus. This reflects...

  9. 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.

  10. 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/.

  11. 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.

  12. AB-Bind: Antibody binding mutational database for computational affinity predictions.

    Science.gov (United States)

    Sirin, Sarah; Apgar, James R; Bennett, Eric M; Keating, Amy E

    2016-02-01

    Antibodies (Abs) are a crucial component of the immune system and are often used as diagnostic and therapeutic agents. The need for high-affinity and high-specificity antibodies in research and medicine is driving the development of computational tools for accelerating antibody design and discovery. We report a diverse set of antibody binding data with accompanying structures that can be used to evaluate methods for modeling antibody interactions. Our Antibody-Bind (AB-Bind) database includes 1101 mutants with experimentally determined changes in binding free energies (ΔΔG) across 32 complexes. Using the AB-Bind data set, we evaluated the performance of protein scoring potentials in their ability to predict changes in binding free energies upon mutagenesis. Numerical correlations between computed and observed ΔΔG values were low (r = 0.16-0.45), but the potentials exhibited predictive power for classifying variants as improved vs weakened binders. Performance was evaluated using the area under the curve (AUC) for receiver operator characteristic (ROC) curves; the highest AUC values for 527 mutants with |ΔΔG| > 1.0 kcal/mol were 0.81, 0.87, and 0.88 using STATIUM, FoldX, and Discovery Studio scoring potentials, respectively. Some methods could also enrich for variants with improved binding affinity; FoldX and Discovery Studio were able to correctly rank 42% and 30%, respectively, of the 80 most improved binders (those with ΔΔG < -1.0 kcal/mol) in the top 5% of the database. This modest predictive performance has value but demonstrates the continuing need to develop and improve protein energy functions for affinity prediction. PMID:26473627

  13. 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.

  14. 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.

  15. 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....

  16. 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

  17. Predicting protein ligand binding motions with the conformation explorer

    Directory of Open Access Journals (Sweden)

    Flores Samuel C

    2011-10-01

    Full Text Available Abstract Background Knowledge of the structure of proteins bound to known or potential ligands is crucial for biological understanding and drug design. Often the 3D structure of the protein is available in some conformation, but binding the ligand of interest may involve a large scale conformational change which is difficult to predict with existing methods. Results We describe how to generate ligand binding conformations of proteins that move by hinge bending, the largest class of motions. First, we predict the location of the hinge between domains. Second, we apply an Euler rotation to one of the domains about the hinge point. Third, we compute a short-time dynamical trajectory using Molecular Dynamics to equilibrate the protein and ligand and correct unnatural atomic positions. Fourth, we score the generated structures using a novel fitness function which favors closed or holo structures. By iterating the second through fourth steps we systematically minimize the fitness function, thus predicting the conformational change required for small ligand binding for five well studied proteins. Conclusions We demonstrate that the method in most cases successfully predicts the holo conformation given only an apo structure.

  18. Vibrational study on the cobalt binding mode of Carnosine

    Science.gov (United States)

    Torreggiani, Armida; Taddei, Paola; Tinti, Anna; Fini, Giancarlo

    2002-10-01

    The Co(II)- L-Carnosine (Carnos) system was investigated at different pH and metal/ligand molar ratios by Raman and IR spectroscopy. Raman spectra present some marker bands yielding information on the ability of the Co(II)/Carnos system to bind molecular oxygen and to identify the metal co-ordination site of the imidazole ring (N π or N τ atom) of Carnos. The existence of different oxygenated species is greatly affected by pH and the structure of the predominant complexes depends on the available nitrogen atoms. Under basic conditions, binuclear complexes binding molecular oxygen are the predominant species and two forms (monobridged and dibridged) were identified by the Raman νO-O band (750-850 cm -1). Decreasing pH to 7, the species present in the system are less able to bind oxygen. Hydrogen peroxide and a Co(III) chelate not binding O 2, were formed with a significant conversion of peroxo into superoxo complexes. A slight excess of Carnos does not enhance metal chelation. In slightly acidic conditions, the formation of H 2O 2 and superoxo species is more enhanced than at pH 7 and another Co(III) chelate is probably formed.

  19. 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...

  20. Theoretical Study of Sequence Selectivity and Preferred Binding Mode of Psoralen with DNA

    Directory of Open Access Journals (Sweden)

    Patricia Saenz-Méndez

    2007-01-01

    Full Text Available Psoralen interaction with two models of DNA was investigated using molecular mechanics and molecular dynamics methods. Calculated energies of minor groove binding and intercalation were compared in order to define a preferred binding mode for the ligand. We found that both binding modes are possible, explaining the low efficiency for monoadduct formation from intercalated ligands. A comparison between the interaction energy for intercalation between different base pairs suggests that the observed sequence selectivity is due to favorable intercalation in 5′-TpA in (ATn sequences.

  1. Computational study of the binding modes of caffeine to the adenosine A2A receptor.

    Science.gov (United States)

    Liu, Yuli; Burger, Steven K; Ayers, Paul W; Vöhringer-Martinez, Esteban

    2011-12-01

    Using the recently solved crystal structure of the human adenosine A(2A) receptor, we applied MM/PBSA to compare the binding modes of caffeine with those of the high-affinity selective antagonist ZM241385. MD simulations were performed in the environment of the lipid membrane bilayer. Four low-energy binding modes of caffeine-A(2A) were found, all of which had similar energies. Assuming an equal contribution of each binding mode of caffeine, the computed binding free energy difference between caffeine and ZM241385 is -2.4 kcal/mol, which compares favorably with the experimental value, -3.6 kcal/mol. The configurational entropy contribution of -0.9 kcal/mol from multiple binding modes of caffeine helps explain how a small molecule like caffeine can compete with a significantly larger molecule, ZM241385, which can form many more interactions with the receptor. We also performed residue-wise energy decomposition and found that Phe168, Leu249, and Ile274 contribute most significantly to the binding modes of caffeine and ZM241385. PMID:21970461

  2. 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. PMID:27600555

  3. 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

  4. Prediction of chloride ingress and binding in cement paste

    DEFF Research Database (Denmark)

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

    2007-01-01

    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...... 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...... profiles for the Cl/Ca ratio predicted by the model and those determined experimentally on 0.45 water/powder ratio Portland cement pastes exposed to 650 mM NaCl for 70 days. This confirms the assumption of essentially instantaneous binding where quasi-equilibrium is established locally. This does not imply...

  5. 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.

  6. 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...

  7. 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.

  8. 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.

  9. 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.

  10. 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).

  11. 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.

  12. 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

  13. 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/.

  14. 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.

  15. Relevance of arginines in the mode of binding of H1 histones to DNA.

    Science.gov (United States)

    Piscopo, Marina; Conte, Mariachiara; Di Paola, Flaviano; Conforti, Salvatore; Rana, Gina; De Petrocellis, Luciano; Fucci, Laura; Geraci, Giuseppe

    2010-07-01

    The mode of binding of sperm and somatic H1 histones to DNA has been investigated by analyzing the effect of their addition on the electrophoretic mobility of linear and circular plasmid molecules. Low concentrations of sperm histones do not appear to alter the electrophoretic mobility of DNA, whereas at increasing concentrations, an additional DNA band is observed near the migration origin. This band then becomes the only component at higher values. In contrast, somatic histones cause a gradual retardation in the mobility of the DNA band at low concentrations and aggregated structures are observed only at higher values. Experiments on the H1 globular domain obtained by limited proteolysis indicate that the mode of binding to DNA depends on the H1 globular domain. The arginine residues appear to be relevant for the different effects as indicated by experiments on sperm histone and on protamine with arginines deguanidinated to ornithines. The modified molecules influence DNA mobility like somatic H1s, indicating that the positive guanidino groups of arginines cannot be substituted by the positive amino groups of ornithines. Modifications of the amino groups of lysines show that these residues are necessary for the binding of H1 histones to DNA but they have no influence on the binding mode. PMID:20438368

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. Influence of the protonation state on the binding mode of methyl orange with cucurbiturils

    Science.gov (United States)

    He, Suhang; Sun, Xuzhuo; Zhang, Haibo

    2016-03-01

    Binding modes of methyl orange (MO) with cucurbiturils (CBs) have been investigated by Single Crystal X-ray Diffraction and NMR Spectroscopy. Detailed study of intermolecular interactions was supported by the Hirshfeld surface analysis. Protonation state of the anionic part of methyl orange has greatly influenced the binding mode of the complex. Stabilized by hydrogen bonding at the portal, hydrophobic and dispersion interactions in the cavity, the protonated methyl orange was deeply inserted into the cavity. On the contrary, the anionic methyl orange has been pushed towards the outside of the cavity by the electrostatic repulsion between the azo group and the portal oxygen. A "water bridge" was found in MO@CB8 linking both host and guest via hydrogen bonds.

  1. 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.

  2. 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.

  3. 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

    of peptide binding, therefore, determines the accuracy of the overall method. Computational predictions of peptide binding to HLA, both class I and class II, use a variety of algorithms ranging from binding motifs to advanced machine learning techniques ( [Brusic et al., 2004] and [Lafuente and Reche, 2009...

  4. 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

  5. Exploring binding mode for styrylquinoline HIV-1 integrase inhibitors using comparative molecular field analysis and docking studies

    Institute of Scientific and Technical Information of China (English)

    Xiao-hui MA; Xiao-yi ZHANG; Jian-jun TAN; Wei-zu CHEN; Cun-xin WANG

    2004-01-01

    AIM: To understand pharmacophore properties of styrylquinoline derivatives and to design inhibitors of HIV-1integrase. METHODS: Comparative molecular field analysis (CoMFA) was performed to analyze three-dimensional quantitative structure-activity relationship (3D-QSAR) of styrylquinoline derivatives. Thirty-eight compounds were randomly divided into a training set of 28 compounds and a test set of 10 compounds. The stability of 3DQSAR models was proved by the analysis of cross-validated and non-cross-validated methods. Moreover, the binding mode of these compounds and integrase was constructed by AutoDock program. RESULTS: The CoMFA model of the training compounds was reasonably predicted with cross-validated coefficient (q2) and conventional (r2) values (up to 0.696 and 0.754). Then the model was validated by the test set. The resulting CoMFA maps visualized structural requirements for the biological activity of these inhibitors. Docking results showed that a carboxyl group at C-7 and a hydroxyl group at C-8 in the quinoline subunit, bound closely to the divalent metal cofactor (Mg2+) around the integrase catalytic site. Moreover, there is a linear correlation between the binding energy of the inhibitors with integrase and their inhibitory effect. CONCLUSIONS: The present study indicated that the CoMFA model together with docking results could give us helpful hints for drug design as well as interpretation of the binding affinity between these inhibitors and integrase.

  6. The HSP90 binding mode of a radicicol-like E-oxime from docking, binding free energy estimations, and NMR 15N chemical shifts

    Science.gov (United States)

    Spichty, Martin; Taly, Antoine; Hagn, Franz; Kessler, Horst; Barluenga, Sofia; Winssinger, Nicolas; Karplus, Martin

    2009-01-01

    We determine the binding mode of a macrocyclic radicicol-like oxime to yeast HSP90 by combining computer simulations and experimental measurements. We sample the macrocyclic scaffold of the unbound ligand by parallel tempering simulations and dock the most populated conformations to yeast HSP90. Docking poses are then evaluated by the use of binding free energy estimations with the linear interaction energy method. Comparison of QM/MM-calculated NMR chemical shifts with experimental shift data for a selective subset of back-bone 15N provides an additional evaluation criteria. As a last test we check the binding modes against available structure-activity-relationships. We find that the most likely binding mode of the oxime to yeast HSP90 is very similar to the known structure of the radicicol-HSP90 complex. PMID:19482409

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

    DEFF Research Database (Denmark)

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

    2009-01-01

    immunologists in interpreting cellular immune responses in large out-bred populations is demonstrated. Further, we used NetMHCpan-2.0 to predict potential binding peptides for the pig MHC class I molecule SLA-1*0401. Ninety-three percent of the predicted peptides were demonstrated to bind stronger than 500 n...

  8. Computational Prediction of Heme-Binding Residues by Exploiting Residue Interaction Network

    OpenAIRE

    Rong Liu; Jianjun Hu

    2011-01-01

    Computational identification of heme-binding residues is beneficial for predicting and designing novel heme proteins. Here we proposed a novel method for heme-binding residue prediction by exploiting topological properties of these residues in the residue interaction networks derived from three-dimensional structures. Comprehensive analysis showed that key residues located in heme-binding regions are generally associated with the nodes with higher degree, closeness and betweenness, but lower ...

  9. Binding Mode of an α-Amino Acid-Linked Quinoxaline-2,3-dione Analogue at Glutamate Receptor Subtype GluK1

    DEFF Research Database (Denmark)

    Demmer, Charles S; Møller, Charlotte; Brown, Patricia M G E;

    2015-01-01

    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...... 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 Glu...

  10. 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.

  11. 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.

  12. 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.

  13. 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

  14. 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

  15. Multiple CaMKII Binding Modes to the Actin Cytoskeleton Revealed by Single-Molecule Imaging.

    Science.gov (United States)

    Khan, Shahid; Conte, Ianina; Carter, Tom; Bayer, K Ulrich; Molloy, Justin E

    2016-07-26

    Localization of the Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) to dendritic spine synapses is determined in part by the actin cytoskeleton. We determined binding of GFP-tagged CaMKII to tag-RFP-labeled actin cytoskeleton within live cells using total internal reflection fluorescence microscopy and single-molecule tracking. Stepwise photobleaching showed that CaMKII formed oligomeric complexes. Photoactivation experiments demonstrated that diffusion out of the evanescent field determined the track lifetimes. Latrunculin treatment triggered a coupled loss of actin stress fibers and the colocalized, long-lived CaMKII tracks. The CaMKIIα (α) isoform, which was previously thought to lack F-actin interactions, also showed binding, but this was threefold weaker than that observed for CaMKIIβ (β). The βE' splice variant bound more weakly than α, showing that binding by β depends critically on the interdomain linker. The mutations βT287D and αT286D, which mimic autophosphorylation states, also abolished F-actin binding. Autophosphorylation triggers autonomous CaMKII activity, but does not impair GluN2B binding, another important synaptic protein interaction of CaMKII. The CaMKII inhibitor tatCN21 or CaMKII mutations that inhibit GluN2B association by blocking binding of ATP (βK43R and αK42M) or Ca(2+)/calmodulin (βA303R) had no effect on the interaction with F-actin. These results provide the first rationale for the reduced synaptic spine localization of the αT286D mutant, indicating that transient F-actin binding contributes to the synaptic localization of the CaMKIIα isoform. The track lifetime distributions had a stretched exponential form consistent with a heterogeneously diffusing population. This heterogeneity suggests that CaMKII adopts different F-actin binding modes, which is most easily rationalized by multiple subunit contacts between the CaMKII dodecamer and the F-actin cytoskeleton that stabilize the initial weak (micromolar

  16. 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/.

  17. Perturbation Approaches for Exploring Protein Binding Site Flexibility to Predict Transient Binding Pockets.

    Science.gov (United States)

    Kokh, Daria B; Czodrowski, Paul; Rippmann, Friedrich; Wade, Rebecca C

    2016-08-01

    Simulations of the long-time scale motions of a ligand binding pocket in a protein may open up new perspectives for the design of compounds with steric or chemical properties differing from those of known binders. However, slow motions of proteins are difficult to access using standard molecular dynamics (MD) simulations and are thus usually neglected in computational drug design. Here, we introduce two nonequilibrium MD approaches to identify conformational changes of a binding site and detect transient pockets associated with these motions. The methods proposed are based on the rotamerically induced perturbation (RIP) MD approach, which employs perturbation of side-chain torsional motion for initiating large-scale protein movement. The first approach, Langevin-RIP (L-RIP), entails a series of short Langevin MD simulations, each starting with perturbation of one of the side-chains lining the binding site of interest. L-RIP provides extensive sampling of conformational changes of the binding site. In less than 1 ns of MD simulation with L-RIP, we observed distortions of the α-helix in the ATP binding site of HSP90 and flipping of the DFG loop in Src kinase. In the second approach, RIPlig, a perturbation is applied to a pseudoligand placed in different parts of a binding pocket, which enables flexible regions of the binding site to be identified in a small number of 10 ps MD simulations. The methods were evaluated for four test proteins displaying different types and degrees of binding site flexibility. Both methods reveal all transient pocket regions in less than a total of 10 ns of simulations, even though many of these regions remained closed in 100 ns conventional MD. The proposed methods provide computationally efficient tools to explore binding site flexibility and can aid in the functional characterization of protein pockets, and the identification of transient pockets for ligand design. PMID:27399277

  18. 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 ar...

  19. 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.

  20. 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 6×10(5)M(-1)from 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. PMID:27367618

  1. A Community Resource Benchmarking Predictions of Peptide Binding to MHC-I Molecules

    OpenAIRE

    Bjoern Peters; Huynh-Hoa Bui; Sune Frankild; Morten Nielson; Claus Lundegaard; Emrah Kostem; Derek Basch; Kasper Lamberth; Mikkel Harndahl; Ward Fleri; Wilson, Stephen S; John Sidney; Ole Lund; Soren Buus; Alessandro Sette

    2006-01-01

    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, an...

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

    OpenAIRE

    Bjoern Peters; Huynh-Hoa Bui; Sune Frankild; Morten Nielson; Claus Lundegaard; Emrah Kostem; Derek Basch; Kasper Lamberth; Mikkel Harndahl; Ward Fleri; Wilson, Stephen S; John Sidney; Ole Lund; Soren Buus; Alessandro Sette

    2006-01-01

    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, an...

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

    OpenAIRE

    Peters, B; Bui, HH; Pletscher-Frankild, Sune; Nielsen, Morten; Lundegaard, Claus; Kostem, E; Basch, D; Lamberth, K.; Harndahl, M.; Fleri, W.; Wilson, SS; Sidney, J; Lund, Ole; Buus, S.; Sette, Alessandro

    2006-01-01

    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, an...

  4. 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.

  5. 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.

  6. Prediction of SAMPL3 Host-Guest Affinities with the Binding Energy Distribution Analysis Method (BEDAM)

    OpenAIRE

    Gallicchio, Emilio; Ronald M Levy

    2012-01-01

    BEDAM calculations are described to predict the free energies of binding of a series of anaesthetic drugs to a recently characterized acyclic cucurbituril host. The modeling predictions, conducted as part of the SAMPL3 host-guest affinity blind challenge, are generally in good quantitative agreement with the experimental measurements. The correlation coefficient between computed and measured binding free energies is 70% with high statistical significance. Multiple conformational stereoisomers...

  7. 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

    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...... 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...

  8. 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

  9. Resilience of the standard predictions for primordial tensor modes

    CERN Document Server

    Creminelli, Paolo; Noreña, Jorge; Vernizzi, Filippo

    2014-01-01

    We show that the prediction for the primordial tensor power spectrum cannot be modified at leading order in derivatives. Indeed, one can always set to unity the speed of propagation of gravitational waves during inflation by a suitable disformal transformation of the metric, while a conformal one can make the Planck mass time-independent. Therefore, the tensor-to-scalar ratio unambiguously fixes the energy scale of inflation. Using the Effective Field Theory of Inflation, we check that predictions are independent of the choice of frame, as expected. The first corrections to the standard prediction come from two parity violating operators with three derivatives. Also the correlator $\\langle\\gamma\\gamma\\gamma\\rangle$ is standard and only receives higher derivative corrections. These results hold also in multifield models of inflation and in alternatives to inflation and make the connection between a (quasi) scale-invariant tensor spectrum and inflation completely robust.

  10. A Novel Approach to Predict Core Residues on Cancer-Related DNA-Binding Domains

    OpenAIRE

    Ka-Chun Wong

    2016-01-01

    Protein–DNA interactions are involved in different cancer pathways. In particular, the DNA-binding domains of proteins can determine where and how gene regulatory regions are bound in different cell lines at different stages. Therefore, it is essential to develop a method to predict and locate the core residues on cancer-related DNA-binding domains. In this study, we propose a computational method to predict and locate core residues on DNA-binding domains. In particular, we have selected the ...

  11. 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.

  12. Computational prediction of heme-binding residues by exploiting residue interaction network.

    Directory of Open Access Journals (Sweden)

    Rong Liu

    Full Text Available Computational identification of heme-binding residues is beneficial for predicting and designing novel heme proteins. Here we proposed a novel method for heme-binding residue prediction by exploiting topological properties of these residues in the residue interaction networks derived from three-dimensional structures. Comprehensive analysis showed that key residues located in heme-binding regions are generally associated with the nodes with higher degree, closeness and betweenness, but lower clustering coefficient in the network. HemeNet, a support vector machine (SVM based predictor, was developed to identify heme-binding residues by combining topological features with existing sequence and structural features. The results showed that incorporation of network-based features significantly improved the prediction performance. We also compared the residue interaction networks of heme proteins before and after heme binding and found that the topological features can well characterize the heme-binding sites of apo structures as well as those of holo structures, which led to reliable performance improvement as we applied HemeNet to predicting the binding residues of proteins in the heme-free state. HemeNet web server is freely accessible at http://mleg.cse.sc.edu/hemeNet/.

  13. Computational prediction of heme-binding residues by exploiting residue interaction network.

    Science.gov (United States)

    Liu, Rong; Hu, Jianjun

    2011-01-01

    Computational identification of heme-binding residues is beneficial for predicting and designing novel heme proteins. Here we proposed a novel method for heme-binding residue prediction by exploiting topological properties of these residues in the residue interaction networks derived from three-dimensional structures. Comprehensive analysis showed that key residues located in heme-binding regions are generally associated with the nodes with higher degree, closeness and betweenness, but lower clustering coefficient in the network. HemeNet, a support vector machine (SVM) based predictor, was developed to identify heme-binding residues by combining topological features with existing sequence and structural features. The results showed that incorporation of network-based features significantly improved the prediction performance. We also compared the residue interaction networks of heme proteins before and after heme binding and found that the topological features can well characterize the heme-binding sites of apo structures as well as those of holo structures, which led to reliable performance improvement as we applied HemeNet to predicting the binding residues of proteins in the heme-free state. HemeNet web server is freely accessible at http://mleg.cse.sc.edu/hemeNet/. PMID:21991319

  14. Prediction of MHC binding peptides and epitopes from alfalfa mosaic virus.

    Science.gov (United States)

    Gomase, Virendra S; Kale, Karbhari V; Chikhale, Nandkishor J; Changbhale, Smruti S

    2007-08-01

    Peptide fragments from alfalfa mosaic virus involved multiple antigenic components directing and empowering the immune system to protect the host from infection. MHC molecules are cell surface proteins, which take active part in host immune reactions and involvement of MHC class-I & II in response to almost all antigens. Coat protein of alfalfa mosaic virus contains 221 aa residues. Analysis found five MHC ligands in coat protein as 64-LSSFNGLGV-72; 86- RILEEDLIY-94; 96-MVFSITPSY-104; 100- ITPSYAGTF-108; 110- LTDDVTTED-118; having rescaled binding affinity and c-terminal cleavage affinity more than 0.5. The predicted binding affinity is normalized by the 1% fractil. The MHC peptide binding is predicted using neural networks trained on c-terminals of known epitopes. In analysis predicted MHC/peptide binding is a log transformed value related to the IC50 values in nM units. Total numbers of peptides found are 213. Predicted MHC binding regions act like red flags for antigen specific and generate immune response against the parent antigen. So a small fragment of antigen can induce immune response against whole antigen. This theme is implemented in designing subunit and synthetic peptide vaccines. The sequence analysis method allows potential drug targets to identify active sites against plant diseases. The method integrates prediction of peptide MHC class I binding; proteosomal c-terminal cleavage and TAP transport efficiency. PMID:17691913

  15. 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.

  16. Platelet Serotonin Transporter Function Predicts Default-Mode Network Activity

    OpenAIRE

    Christian Scharinger; Ulrich Rabl; Christian H. Kasess; Meyer, Bernhard M.; Tina Hofmaier; Kersten Diers; Lucie Bartova; Gerald Pail; Wolfgang Huf; Zeljko Uzelac; Beate Hartinger; Klaudius Kalcher; Thomas Perkmann; Helmuth Haslacher; Andreas Meyer-Lindenberg

    2014-01-01

    Background 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. Methods A functional magnetic resonance study was performed in 48 healthy...

  17. 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...

  18. String-theory-based predictions for nonhydrodynamic collective modes in strongly interacting Fermi gases

    Science.gov (United States)

    Bantilan, H.; Brewer, J. T.; Ishii, T.; Lewis, W. E.; Romatschke, P.

    2016-09-01

    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 nonhydrodynamic 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 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.

  19. Precise Ab-initio prediction of terahertz vibrational modes in crystalline systems

    DEFF Research Database (Denmark)

    Jepsen, Peter Uhd; Clark, Stewart J.

    2007-01-01

    We use a combination of experimental THz time-domain spectroscopy and ab-initio density functional perturbative theory to accurately predict the terahertz vibrational spectrum of molecules in the crystalline phase. Our calculations show that distinct vibrational modes found in solid-state materials...... are best described as phonon modes with strong coupling to the intramolecular degrees of freedom. Hence a computational method taking the periodicity of the crystal lattice as well as intramolecular motion into account is a prerequisite for the correct prediction of vibrational modes in such materials....

  20. 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.

  1. 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

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

    Science.gov (United States)

    Kang, Juanjuan; Ru, Beibei; Zhou, Peng

    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 < 0.001) of peptides were correctly classified. As a 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.

  3. 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. PMID:27610387

  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. Prediction of dominant intraseasonal modes in the East Asian-western North Pacific summer monsoon

    Science.gov (United States)

    Oh, Hyoeun; Ha, Kyung-Ja

    2016-10-01

    Intraseasonal monsoon prediction is the most imperative task, but there remains an enduring challenge in climate science. The present study aims to provide a physical understanding of the sources for prediction of dominant intraseasonal modes in the East Asian-western North Pacific summer monsoon (EA-WNPSM): pre-Meiyu&Baiu, Changma&Meiyu, WNPSM, and monsoon gyre modes classified by the self-organizing map analysis. Here, we use stepwise regression to determine the predictors for the four modes in the EA-WNPSM. The selected predictors are based on the persistent and tendency signals of the sea surface temperature (SST)/2m air temperature and sea level pressure fields, which reflect the asymmetric response to the El Niño Southern Oscillation (ENSO) and the ocean and land surface anomalous conditions. For the pre-Meiyu&Baiu mode, the SST cooling tendency over the western North Pacific (WNP), which persists into summer, is the distinguishing contributor that results in strong baroclinic instability. A major precursor for the Changma&Meiyu mode is related to the WNP subtropical high, induced by the persistent SST difference between the Indian Ocean and the western Pacific. The WNPSM mode is mostly affected by the Pacific-Japan pattern, and monsoon gyre mode is primarily associated with a persistent SST cooling over the tropical Indian Ocean by the preceding ENSO signal. This study carries important implications for prediction by establishing valuable precursors of the four modes including nonlinear characteristics.

  6. 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.

  7. Prediction of the key binding site of odorant-binding protein of Holotrichia oblita Faldermann (Coleoptera: Scarabaeida).

    Science.gov (United States)

    Zhuang, X; Wang, Q; Wang, B; Zhong, T; Cao, Y; Li, K; Yin, J

    2014-06-01

    The scarab beetle Holotrichia oblita Faldermann (Coleoptera: Scarabaeidae) is a predominant underground pest in the northern parts of China, and its larvae (grubs) cause great economic losses because of its wide range of host plants and covert habitats. Environmentally friendly strategies for controlling adults would have novel and broad potential applications. One potential pest management measure is the regulation of olfactory chemoreception to control target insect pests. In the process of olfactory recognition, odorant-binding proteins (OBPs) are believed to carry hydrophobic odorants from the environment to the surface of olfactory receptor neurons. To obtain a better understanding of the relationship between OBP structures and their ligands, homology modelling and molecular docking have been conducted on the interaction between HoblOBP1 and hexyl benzoate in the present study. Based on the results, site-directed mutagenesis and binding experiments were combined to describe the binding sites of HoblOBP1 and to explore its ligand-binding mechanism. After homology modelling of HoblOBP1, it was found that the three-dimensional structure of HoblOBP1 consists of six α-helices and three disulphide bridges that connect the helices, and the hydrophobic pockets are both composed of five helices. Based on the docking study, we found that van der Waals interactions and hydrophobic interactions are both important in the bonding between HoblOBP1 and hexyl benzoate. Intramolecular residues formed the hydrogen bonds in the C terminus of the protein and the bonds are crucial for the ligand-binding specificity. Finally, MET48, ILE80 and TYR111 are binding sites predicted for HoblOBP1. Using site-directed mutagenesis and fluorescence assays, it was found that ligands could not be recognized by mutant of Tyr111. A possible explanation is that the compound could not be recognized by the mutant, and remains in the binding cavity because of the loss of the intramolecular

  8. 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).

  9. Cross-class metallo-β-lactamase inhibition by bisthiazolidines reveals multiple binding modes.

    Science.gov (United States)

    Hinchliffe, Philip; González, Mariano M; Mojica, Maria F; González, Javier M; Castillo, Valerie; Saiz, Cecilia; Kosmopoulou, Magda; Tooke, Catherine L; Llarrull, Leticia I; Mahler, Graciela; Bonomo, Robert A; Vila, Alejandro J; Spencer, James

    2016-06-28

    Metallo-β-lactamases (MBLs) hydrolyze almost all β-lactam antibiotics and are unaffected by clinically available β-lactamase inhibitors (βLIs). Active-site architecture divides MBLs into three classes (B1, B2, and B3), complicating development of βLIs effective against all enzymes. Bisthiazolidines (BTZs) are carboxylate-containing, bicyclic compounds, considered as penicillin analogs with an additional free thiol. Here, we show both l- and d-BTZ enantiomers are micromolar competitive βLIs of all MBL classes in vitro, with Kis of 6-15 µM or 36-84 µM for subclass B1 MBLs (IMP-1 and BcII, respectively), and 10-12 µM for the B3 enzyme L1. Against the B2 MBL Sfh-I, the l-BTZ enantiomers exhibit 100-fold lower Kis (0.26-0.36 µM) than d-BTZs (26-29 µM). Importantly, cell-based time-kill assays show BTZs restore β-lactam susceptibility of Escherichia coli-producing MBLs (IMP-1, Sfh-1, BcII, and GOB-18) and, significantly, an extensively drug-resistant Stenotrophomonas maltophilia clinical isolate expressing L1. BTZs therefore inhibit the full range of MBLs and potentiate β-lactam activity against producer pathogens. X-ray crystal structures reveal insights into diverse BTZ binding modes, varying with orientation of the carboxylate and thiol moieties. BTZs bind the di-zinc centers of B1 (IMP-1; BcII) and B3 (L1) MBLs via the free thiol, but orient differently depending upon stereochemistry. In contrast, the l-BTZ carboxylate dominates interactions with the monozinc B2 MBL Sfh-I, with the thiol uninvolved. d-BTZ complexes most closely resemble β-lactam binding to B1 MBLs, but feature an unprecedented disruption of the D120-zinc interaction. Cross-class MBL inhibition therefore arises from the unexpected versatility of BTZ binding. PMID:27303030

  10. Blind prediction of host-guest binding affinities: A new SAMPL3 challenge

    OpenAIRE

    Muddana, Hari S.; Varnado, C. Daniel; Bielawski, Christopher W.; Urbach, Adam R.; Isaacs, Lyle; Geballe, Matthew T; Gilson, Michael K.

    2012-01-01

    The computational prediction of protein-ligand binding affinities is of central interest in early-stage drug-discovery, and there is a widely recognized need for improved methods. Low molecular weight receptors and their ligands—i.e. host-guest systems – represent valuable test-beds for such affinity prediction methods, because their small size makes for fast calculations and relatively facile numerical convergence. The SAMPL3 community exercise included the first ever blind prediction challe...

  11. Regression applied to protein binding site prediction and comparison with classification

    Directory of Open Access Journals (Sweden)

    Gala Jean-Luc

    2009-09-01

    Full Text Available Abstract Background The structural genomics centers provide hundreds of protein structures of unknown function. Therefore, developing methods enabling the determination of a protein function automatically is imperative. The determination of a protein function can be achieved by studying the network of its physical interactions. In this context, identifying a potential binding site between proteins is of primary interest. In the literature, methods for predicting a potential binding site location generally are based on classification tools. The aim of this paper is to show that regression tools are more efficient than classification tools for patches based binding site predictors. For this purpose, we developed a patches based binding site localization method usable with either regression or classification tools. Results We compared predictive performances of regression tools with performances of machine learning classifiers. Using leave-one-out cross-validation, we showed that regression tools provide better predictions than classification ones. Among regression tools, Multilayer Perceptron ranked highest in the quality of predictions. We compared also the predictive performance of our patches based method using Multilayer Perceptron with the performance of three other methods usable through a web server. Our method performed similarly to the other methods. Conclusion Regression is more efficient than classification when applied to our binding site localization method. When it is possible, using regression instead of classification for other existing binding site predictors will probably improve results. Furthermore, the method presented in this work is flexible because the size of the predicted binding site is adjustable. This adaptability is useful when either false positive or negative rates have to be limited.

  12. 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.

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

    Directory of Open Access Journals (Sweden)

    Marharyta Petukh

    2016-04-01

    Full Text Available 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/.

  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. 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.

  16. 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.

  17. 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.

  18. 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

  19. 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

  20. 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

    Successful predictions of peptide MHC binding typically require a large set of binding data for the specific MHC molecule that is examined. Structure based prediction methods promise to circumvent this requirement by evaluating the physical contacts a peptide can make with an MHC molecule based...... 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...

  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. 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.

  3. Predicting the Impact of Missense Mutations on Protein-Protein Binding Affinity.

    Science.gov (United States)

    Li, Minghui; Petukh, Marharyta; Alexov, Emil; Panchenko, Anna R

    2014-04-01

    The crucial prerequisite for proper biological function is the protein's ability to establish highly selective interactions with macromolecular partners. A missense mutation that alters the protein binding affinity may cause significant perturbations or complete abolishment of the function, potentially leading to diseases. The availability of computational methods to evaluate the impact of mutations on protein-protein binding is critical for a wide range of biomedical applications. Here, we report an efficient computational approach for predicting the effect of single and multiple missense mutations on protein-protein binding affinity. It is based on a well-tested simulation protocol for structure minimization, modified MM-PBSA and statistical scoring energy functions with parameters optimized on experimental sets of several thousands of mutations. Our simulation protocol yields very good agreement between predicted and experimental values with Pearson correlation coefficients of 0.69 and 0.63 and root-mean-square errors of 1.20 and 1.90 kcal mol(-1) for single and multiple mutations, respectively. Compared with other available methods, our approach achieves high speed and prediction accuracy and can be applied to large datasets generated by modern genomics initiatives. In addition, we report a crucial role of water model and the polar solvation energy in estimating the changes in binding affinity. Our analysis also reveals that prediction accuracy and effect of mutations on binding strongly depends on the type of mutation and its location in a protein complex. PMID:24803870

  4. 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

  5. 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

    2016-09-28

    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. PMID:27452185

  6. 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.

  7. 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.

  8. Computational predictions suggest that structural similarity in viral polymerases may lead to comparable allosteric binding sites.

    Science.gov (United States)

    Brown, Jodian A; Espiritu, Marie V; Abraham, Joel; Thorpe, Ian F

    2016-08-15

    The identification of ligand-binding sites is often the first step in drug targeting and design. To date there are numerous computational tools available to predict ligand binding sites. These tools can guide or mitigate the need for experimental methods to identify binding sites, which often require significant resources and time. Here, we evaluate four ligand-binding site predictor (LBSP) tools for their ability to predict allosteric sites within the Hepatitis C Virus (HCV) polymerase. Our results show that the LISE LBSP is able to identify all three target allosteric sites within the HCV polymerase as well as a known allosteric site in the Coxsackievirus polymerase. LISE was then employed to identify novel binding sites within the polymerases of the Dengue, West Nile, and Foot-and-mouth Disease viruses. Our results suggest that all three viral polymerases have putative sites that share structural or chemical similarities with allosteric pockets of the HCV polymerase. Thus, these binding locations may represent an evolutionarily conserved structural feature of several viral polymerases that could be exploited for the development of small molecule therapeutics. PMID:27262620

  9. Predicting RNA-binding sites of proteins using support vector machines and evolutionary information

    Directory of Open Access Journals (Sweden)

    Su Emily

    2008-12-01

    Full Text Available Abstract Background RNA-protein interaction plays an essential role in several biological processes, such as protein synthesis, gene expression, posttranscriptional regulation and viral infectivity. Identification of RNA-binding sites in proteins provides valuable insights for biologists. However, experimental determination of RNA-protein interaction remains time-consuming and labor-intensive. Thus, computational approaches for prediction of RNA-binding sites in proteins have become highly desirable. Extensive studies of RNA-binding site prediction have led to the development of several methods. However, they could yield low sensitivities in trade-off for high specificities. Results We propose a method, RNAProB, which incorporates a new smoothed position-specific scoring matrix (PSSM encoding scheme with a support vector machine model to predict RNA-binding sites in proteins. Besides the incorporation of evolutionary information from standard PSSM profiles, the proposed smoothed PSSM encoding scheme also considers the correlation and dependency from the neighboring residues for each amino acid in a protein. Experimental results show that smoothed PSSM encoding significantly enhances the prediction performance, especially for sensitivity. Using five-fold cross-validation, our method performs better than the state-of-the-art systems by 4.90%~6.83%, 0.88%~5.33%, and 0.10~0.23 in terms of overall accuracy, specificity, and Matthew's correlation coefficient, respectively. Most notably, compared to other approaches, RNAProB significantly improves sensitivity by 7.0%~26.9% over the benchmark data sets. To prevent data over fitting, a three-way data split procedure is incorporated to estimate the prediction performance. Moreover, physicochemical properties and amino acid preferences of RNA-binding proteins are examined and analyzed. Conclusion Our results demonstrate that smoothed PSSM encoding scheme significantly enhances the performance of RNA-binding

  10. Predictive Modeling of Estrogen Receptor Binding Agents Using Advanced Cheminformatics Tools and Massive Public Data

    Science.gov (United States)

    Ribay, Kathryn; Kim, Marlene T.; Wang, Wenyi; Pinolini, Daniel; Zhu, Hao

    2016-01-01

    Estrogen receptors (ERα) are a critical target for drug design as well as a potential source of toxicity when activated unintentionally. Thus, evaluating potential ERα binding agents is critical in both drug discovery and chemical toxicity areas. Using computational tools, e.g., Quantitative Structure-Activity Relationship (QSAR) models, can predict potential ERα binding agents before chemical synthesis. The purpose of this project was to develop enhanced predictive models of ERα binding agents by utilizing advanced cheminformatics tools that can integrate publicly available bioassay data. The initial ERα binding agent data set, consisting of 446 binders and 8307 non-binders, was obtained from the Tox21 Challenge project organized by the NIH Chemical Genomics Center (NCGC). After removing the duplicates and inorganic compounds, this data set was used to create a training set (259 binders and 259 non-binders). This training set was used to develop QSAR models using chemical descriptors. The resulting models were then used to predict the binding activity of 264 external compounds, which were available to us after the models were developed. The cross-validation results of training set [Correct Classification Rate (CCR) = 0.72] were much higher than the external predictivity of the unknown compounds (CCR = 0.59). To improve the conventional QSAR models, all compounds in the training set were used to search PubChem and generate a profile of their biological responses across thousands of bioassays. The most important bioassays were prioritized to generate a similarity index that was used to calculate the biosimilarity score between each two compounds. The nearest neighbors for each compound within the set were then identified and its ERα binding potential was predicted by its nearest neighbors in the training set. The hybrid model performance (CCR = 0.94 for cross validation; CCR = 0.68 for external prediction) showed significant improvement over the original QSAR

  11. 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.

  12. Prediction and experimental characterization of nsSNPs altering human PDZ-binding motifs.

    Directory of Open Access Journals (Sweden)

    David Gfeller

    Full Text Available Single nucleotide polymorphisms (SNPs are a major contributor to genetic and phenotypic variation within populations. Non-synonymous SNPs (nsSNPs modify the sequence of proteins and can affect their folding or binding properties. Experimental analysis of all nsSNPs is currently unfeasible and therefore computational predictions of the molecular effect of nsSNPs are helpful to guide experimental investigations. While some nsSNPs can be accurately characterized, for instance if they fall into strongly conserved or well annotated regions, the molecular consequences of many others are more challenging to predict. In particular, nsSNPs affecting less structured, and often less conserved regions, are difficult to characterize. Binding sites that mediate protein-protein or other protein interactions are an important class of functional sites on proteins and can be used to help interpret nsSNPs. Binding sites targeted by the PDZ modular peptide recognition domain have recently been characterized. Here we use this data to show that it is possible to computationally identify nsSNPs in PDZ binding motifs that modify or prevent binding to the proteins containing the motifs. We confirm these predictions by experimentally validating a selected subset with ELISA. Our work also highlights the importance of better characterizing linear motifs in proteins as many of these can be affected by genetic variations.

  13. 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

  14. Hot spots and transient pockets: predicting the determinants of small-molecule binding to a protein-protein interface.

    Science.gov (United States)

    Metz, Alexander; Pfleger, Christopher; Kopitz, Hannes; Pfeiffer-Marek, Stefania; Baringhaus, Karl-Heinz; Gohlke, Holger

    2012-01-23

    Protein-protein interfaces are considered difficult targets for small-molecule protein-protein interaction modulators (PPIMs ). Here, we present for the first time a computational strategy that simultaneously considers aspects of energetics and plasticity in the context of PPIM binding to a protein interface. The strategy aims at identifying the determinants of small-molecule binding, hot spots, and transient pockets, in a protein-protein interface in order to make use of this knowledge for predicting binding modes of and ranking PPIMs with respect to their affinity. When applied to interleukin-2 (IL-2), the computationally inexpensive constrained geometric simulation method FRODA outperforms molecular dynamics simulations in sampling hydrophobic transient pockets. We introduce the PPIAnalyzer approach for identifying transient pockets on the basis of geometrical criteria only. A sequence of docking to identified transient pockets, starting structure selection based on hot spot information, RMSD clustering and intermolecular docking energies, and MM-PBSA calculations allows one to enrich IL-2 PPIMs from a set of decoys and to discriminate between subgroups of IL-2 PPIMs with low and high affinity. Our strategy will be applicable in a prospective manner where nothing else than a protein-protein complex structure is known; hence, it can well be the first step in a structure-based endeavor to identify PPIMs. PMID:22087639

  15. 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....

  16. 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

    2016-01-01

    MicroRNAs (miRNAs) are a class of endogenous short noncoding 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 cross-linking immunoprecipitation (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 (Liu et al., Nucleic Acids Res 41:e138, 2013). 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

  17. 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.

  18. 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.

  19. Two Distinctive Binding Modes of Endonuclease Inhibitors to the N-Terminal Region of Influenza Virus Polymerase Acidic Subunit.

    Science.gov (United States)

    Fudo, Satoshi; Yamamoto, Norio; Nukaga, Michiyoshi; Odagiri, Takato; Tashiro, Masato; Hoshino, Tyuji

    2016-05-10

    Influenza viruses are global threat to humans, and the development of new antiviral agents are still demanded to prepare for pandemics and to overcome the emerging resistance to the current drugs. Influenza polymerase acidic protein N-terminal domain (PAN) has endonuclease activity and is one of the appropriate targets for novel antiviral agents. First, we performed X-ray cocrystal analysis on the complex structures of PAN with two endonuclease inhibitors. The protein crystallization and the inhibitor soaking were done at pH 5.8. The binding modes of the two inhibitors were different from a common binding mode previously reported for the other influenza virus endonuclease inhibitors. We additionally clarified the complex structures of PAN with the same two endonuclease inhibitors at pH 7.0. In one of the crystal structures, an additional inhibitor molecule, which chelated to the two metal ions in the active site, was observed. On the basis of the crystal structures at pH 7.0, we carried out 100 ns molecular dynamics (MD) simulations for both of the complexes. The analysis of simulation results suggested that the binding mode of each inhibitor to PAN was stable in spite of the partial deviation of the simulation structure from the crystal one. Furthermore, crystal structure analysis and MD simulation were performed for PAN in complex with an inhibitor, which was already reported to have a high compound potency for comparison. The findings on the presence of multiple binding sites at around the PAN substrate-binding pocket will provide a hint for enhancing the binding affinity of inhibitors. PMID:27088785

  20. 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.

  1. Prediction of mean monthly river discharges in Colombia through Empirical Mode Decomposition

    Science.gov (United States)

    Carmona, A. M.; Poveda, G.

    2015-04-01

    The hydro-climatology of Colombia exhibits strong natural variability at a broad range of time scales including: inter-decadal, decadal, inter-annual, annual, intra-annual, intra-seasonal, and diurnal. Diverse applied sectors rely on quantitative predictions of river discharges for operational purposes including hydropower generation, agriculture, human health, fluvial navigation, territorial planning and management, risk preparedness and mitigation, among others. Various methodologies have been used to predict monthly mean river discharges that are based on "Predictive Analytics", an area of statistical analysis that studies the extraction of information from historical data to infer future trends and patterns. Our study couples the Empirical Mode Decomposition (EMD) with traditional methods, e.g. Autoregressive Model of Order 1 (AR1) and Neural Networks (NN), to predict mean monthly river discharges in Colombia, South America. The EMD allows us to decompose the historical time series of river discharges into a finite number of intrinsic mode functions (IMF) that capture the different oscillatory modes of different frequencies associated with the inherent time scales coexisting simultaneously in the signal (Huang et al. 1998, Huang and Wu 2008, Rao and Hsu, 2008). Our predictive method states that it is easier and simpler to predict each IMF at a time and then add them up together to obtain the predicted river discharge for a certain month, than predicting the full signal. This method is applied to 10 series of monthly mean river discharges in Colombia, using calibration periods of more than 25 years, and validation periods of about 12 years. Predictions are performed for time horizons spanning from 1 to 12 months. Our results show that predictions obtained through the traditional methods improve when the EMD is used as a previous step, since errors decrease by up to 13% when the AR1 model is used, and by up to 18% when using Neural Networks is combined with the

  2. 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.

  3. 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.

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

    Directory of Open Access Journals (Sweden)

    Daniel Barry Roche

    2015-12-01

    Full Text Available 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.

  5. 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.

  6. 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.

  7. Genome-wide de novo prediction of cis-regulatory binding sites in prokaryotes

    Science.gov (United States)

    Zhang, Shaoqiang; Xu, Minli; Su, Zhengchang

    2009-01-01

    Although cis-regulatory binding sites (CRBSs) are at least as important as the coding sequences in a genome, our general understanding of them in most sequenced genomes is very limited due to the lack of efficient and accurate experimental and computational methods for their characterization, which has largely hindered our understanding of many important biological processes. In this article, we describe a novel algorithm for genome-wide de novo prediction of CRBSs with high accuracy. We designed our algorithm to circumvent three identified difficulties for CRBS prediction using comparative genomics principles based on a new method for the selection of reference genomes, a new metric for measuring the similarity of CRBSs, and a new graph clustering procedure. When operon structures are correctly predicted, our algorithm can predict 81% of known individual binding sites belonging to 94% of known cis-regulatory motifs in the Escherichia coli K12 genome, while achieving high prediction specificity. Our algorithm has also achieved similar prediction accuracy in the Bacillus subtilis genome, suggesting that it is very robust, and thus can be applied to any other sequenced prokaryotic genome. When compared with the prior state-of-the-art algorithms, our algorithm outperforms them in both prediction sensitivity and specificity. PMID:19383880

  8. 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.

  9. On the verification of binding modes of p-dimethylaminobenzaldehyde thiosemicarbazone with mercury(II). The solid state studies

    Science.gov (United States)

    Trzesowska-Kruszynska, Agata

    2014-08-01

    Two coordination compounds of p-dimethylaminobenzaldehyde thiosemicarbazone, fluorescent chemosensor, have been synthesised from the mercury(II) nitrate and mercury(II) chloride, and subsequently characterised by IR spectroscopy, thermal analysis, as well as single crystal X-ray diffraction technique. The inorganic anion has a distinct influence on binding mode of thiosemicarbazone ligand to Hg(II) ion. In both compounds the metal to ligand stoichiometry is 1:2 and the organic ligands coordinate to Hg ion in the neutral thione form, but they differ in a ligand binding mode and the conformation of the ligand. The crystal packing of mercury(II) nitrate complex with thiosemicarbazone is controlled by the mercury chelate ring-phenylene ring π···π stacking interactions.

  10. 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

  11. Predicting the Inception Cavitation of a Reversible Pump- Turbine in Pump Mode

    Science.gov (United States)

    Tao, Ran; Xiao, Ruofu; Zhu, Di; Liu, Weichao

    2015-12-01

    Inception cavitation is a crucial indicator for reversible pump-turbines especially in pump mode. In actual applications, it is difficult to use CFD for the inception cavitation character. In this study, CFD simulation is conducted to find a proper way to evaluate the inception cavitation, different levels of vapor volume fraction in the impeller is predicted based on the tested results. Results show that the prediction of the location and scale of cavitation is accurate. The predicted cavitation number also matches the experimental data well. The vapor volume fraction levels from 0.0001% to 0.001% are recommended as the criterion of inception cavitation.

  12. 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.

  13. 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.

  14. 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/.

  15. Theoretical prediction of the binding free energy for mutants of replication protein A.

    Science.gov (United States)

    Carra, Claudio; Saha, Janapriya; Cucinotta, Francis A

    2012-07-01

    The replication protein A (RPA) is a heterotrimeric (70, 32, and 14 kDa subunits), single stranded DNA (ssDNA) binding protein required for pivotal functions in the cell metabolism, such as chromosomal replication, prevention of hairpin formation, DNA repair and recombination, and signaling after DNA damage. Studies based on deletions and mutations have identified the high affinity ssDNA binding domains in the 70 kDa subunit of RPA, regions A and B. Individually, the domain A and B have a low affinity for ssDNA, while tandems composed of AA, AB, BB, and BA sequences bind the ssDNA with moderate to high affinity. Single and double point mutations on polar residues in the binding domains leads to a reduction in affinity of RPA for ssDNA, in particular when two hydrophilic residues are involved. In view of these results, we performed a study based on molecular dynamics simulation aimed to reproduce the experimental change in binding free energy, ΔΔG, of RPA70 mutants to further elucidate the nature of the protein-ssDNA interaction. The MM-PB(GB)SA methods implemented in Amber10 and the code FoldX were used to estimate the binding free energy. The theoretical and experimental ΔΔG values correlate better when the results are obtained by MM-PBSA calculated on individual trajectories for each mutant. In these conditions, the correlation coefficient between experimental and theoretical ΔΔG reaches a value of 0.95 despite the overestimation of the energy change by one order of magnitude. The decomposition of the MM-GBSA energy per residue allows us to correlate the change of the affinity with the residue polarity and energy contribution to the binding. The method revealed reliable predictions of the change in the affinity in function of mutations, and can be used to identify new mutants with distinct binding properties. PMID:22160652

  16. 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.

  17. 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.

  18. Predicting sequence and structural specificities of RNA binding regions recognized by splicing factor SRSF1

    Directory of Open Access Journals (Sweden)

    Wang Xin

    2011-12-01

    secondary structure play complementary roles during binding site recognition by SRSF1. Conclusion In this study, we presented a computational model to predict the sequence consensus and optimal RNA secondary structure for protein-RNA binding regions. The successful implementation on SRSF1 CLIP-seq data demonstrates great potential to improve our understanding on the binding specificity of RNA binding proteins.

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

    Science.gov (United States)

    Xu, Minli; Su, Zhengchang

    2009-01-01

    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 loss of CRPs in these species

  20. 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

  1. The different ligand-binding modes of relaxin family peptide receptors RXFP1 and RXFP2.

    Science.gov (United States)

    Scott, Daniel J; Rosengren, K Johan; Bathgate, Ross A D

    2012-11-01

    Relaxin and insulin-like peptide 3 (INSL3) are peptide hormones with a number of important physiological roles in reproduction, regulation of extracellular matrix turnover, and cardiovascular function. Relaxin and INSL3 mediate their actions through the closely related G-protein coupled receptors, relaxin family peptide receptors 1 and 2 (RXFP1 and RXFP2), respectively. These receptors have large extracellular domains (ECD) that contain high-affinity ligand-binding sites within their 10 leucine-rich repeat (LRR)-containing modules. Although relaxin can bind and activate both RXFP1 and RXFP2, INSL3 can only bind and activate RXFP2. To investigate whether this difference is related to the nature of the high-affinity ECD binding site or to differences in secondary binding sites involving the receptor transmembrane (TM) domain, we created a suite of constructs with RXFP1/2 chimeric ECD attached to single TM helices. We show that by changing as little as one LRR, representing four amino acid substitutions, we were able to engineer a high-affinity INSL3-binding site into the ECD of RXFP1. Molecular modeling of the INSL3-RXFP2 interaction based on extensive experimental data highlights the differences in the binding mechanisms of relaxin and INSL3 to the ECD of their cognate receptors. Interestingly, when the engineered RXFP1/2 ECD were introduced into full-length RXFP1 constructs, INSL3 exhibited only low affinity and efficacy on these receptors. These results highlight critical differences both in the ECD binding and in the coordination of the ECD-binding site with the TM domain, and provide new mechanistic insights into the binding and activation events of RXFP1 and RXFP2 by their native hormone ligands. PMID:22973049

  2. 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

  3. 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

  4. 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.

  5. Genome-wide de novo prediction of cis-regulatory binding sites in prokaryotes

    OpenAIRE

    Zhang, Shaoqiang; Xu, Minli; Li, Shan; Su, Zhengchang

    2009-01-01

    Although cis-regulatory binding sites (CRBSs) are at least as important as the coding sequences in a genome, our general understanding of them in most sequenced genomes is very limited due to the lack of efficient and accurate experimental and computational methods for their characterization, which has largely hindered our understanding of many important biological processes. In this article, we describe a novel algorithm for genome-wide de novo prediction of CRBSs with high accuracy. We desi...

  6. 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.

  7. 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.

  8. A Novel Binding Mode Reveals Two Distinct Classes of NMDA Receptor GluN2B-selective Antagonists.

    Science.gov (United States)

    Stroebel, David; Buhl, Derek L; Knafels, John D; Chanda, Pranab K; Green, Michael; Sciabola, Simone; Mony, Laetitia; Paoletti, Pierre; Pandit, Jayvardhan

    2016-05-01

    N-methyl-d-aspartate receptors (NMDARs) are glutamate-gated ion channels that play key roles in brain physiology and pathology. Because numerous pathologic conditions involve NMDAR overactivation, subunit-selective antagonists hold strong therapeutic potential, although clinical successes remain limited. Among the most promising NMDAR-targeting drugs are allosteric inhibitors of GluN2B-containing receptors. Since the discovery of ifenprodil, a range of GluN2B-selective compounds with strikingly different structural motifs have been identified. This molecular diversity raises the possibility of distinct binding sites, although supporting data are lacking. Using X-ray crystallography, we show that EVT-101, a GluN2B antagonist structurally unrelated to the classic phenylethanolamine pharmacophore, binds at the same GluN1/GluN2B dimer interface as ifenprodil but adopts a remarkably different binding mode involving a distinct subcavity and receptor interactions. Mutagenesis experiments demonstrate that this novel binding site is physiologically relevant. Moreover, in silico docking unveils that GluN2B-selective antagonists broadly divide into two distinct classes according to binding pose. These data widen the allosteric and pharmacological landscape of NMDARs and offer a renewed structural framework for designing next-generation GluN2B antagonists with therapeutic value for brain disorders. PMID:26912815

  9. Rapid and accurate prediction and scoring of water molecules in protein binding sites.

    Directory of Open Access Journals (Sweden)

    Gregory A Ross

    Full Text Available Water plays a critical role in ligand-protein interactions. However, it is still challenging to predict accurately not only where water molecules prefer to bind, but also which of those water molecules might be displaceable. The latter is often seen as a route to optimizing affinity of potential drug candidates. Using a protocol we call WaterDock, we show that the freely available AutoDock Vina tool can be used to predict accurately the binding sites of water molecules. WaterDock was validated using data from X-ray crystallography, neutron diffraction and molecular dynamics simulations and correctly predicted 97% of the water molecules in the test set. In addition, we combined data-mining, heuristic and machine learning techniques to develop probabilistic water molecule classifiers. When applied to WaterDock predictions in the Astex Diverse Set of protein ligand complexes, we could identify whether a water molecule was conserved or displaced to an accuracy of 75%. A second model predicted whether water molecules were displaced by polar groups or by non-polar groups to an accuracy of 80%. These results should prove useful for anyone wishing to undertake rational design of new compounds where the displacement of water molecules is being considered as a route to improved affinity.

  10. The complex binding mode of the peptide hormone H2 relaxin to its receptor RXFP1

    OpenAIRE

    Sethi, Ashish; Bruell, Shoni; Patil, Nitin; Hossain, Mohammed Akhter; Scott, Daniel J.; Petrie, Emma J.; Bathgate, Ross A. D.; Gooley, Paul R.

    2016-01-01

    H2 relaxin activates the relaxin family peptide receptor-1 (RXFP1), a class A G-protein coupled receptor, by a poorly understood mechanism. The ectodomain of RXFP1 comprises an N-terminal LDLa module, essential for activation, tethered to a leucine-rich repeat (LRR) domain by a 32-residue linker. H2 relaxin is hypothesized to bind with high affinity to the LRR domain enabling the LDLa module to bind and activate the transmembrane domain of RXFP1. Here we define a relaxin-binding site on the L...

  11. 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.

  12. In Silico Investigation of the Neurotensin Receptor 1 Binding Site: Overlapping Binding Modes for Small Molecule Antagonists and the Endogenous Peptide Agonist.

    Science.gov (United States)

    Lückmann, Michael; Holst, Birgitte; Schwartz, Thue W; Frimurer, Thomas M

    2016-01-01

    The neurotensin receptor 1 (NTSR1) belongs to the family of 7TM, G protein-coupled receptors, and is activated by the 13-amino-acid peptide neurotensin (NTS) that has been shown to play important roles in neurological disorders and the promotion of cancer cells. Recently, a high-resolution x-ray crystal structure of NTSR1 in complex with NTS8-13 has been determined, providing novel insights into peptide ligand recognition by 7TM receptors. SR48692, a potent and selective small molecule antagonist has previously been used extensively as a tool compound to study NTSR1 receptor signaling properties. To investigate the binding mode of SR48692 and other small molecule compounds to NTSR1, we applied an Automated Ligand-guided Backbone Ensemble Receptor Optimization protocol (ALiBERO), taking receptor flexibility and ligand knowledge into account. Structurally overlapping binding poses for SR48692 and NTS8-13 were observed, despite their distinct chemical nature and inverse pharmacological profiles. The optimized models showed significantly improved ligand recognition in a large-scale virtual screening assessment compared to the crystal structure. Our models provide new insights into small molecule ligand binding to NTSR1 and could facilitate the structure-based design of non-peptide ligands for the evaluation of the pharmacological potential of NTSR1 in neurological disorders and cancer. PMID:27491650

  13. Probing Difference in Binding Modes of Inhibitors to MDMX by Molecular Dynamics Simulations and Different Free Energy Methods.

    Directory of Open Access Journals (Sweden)

    Shuhua Shi

    Full Text Available The p53-MDMX interaction has attracted extensive attention of anti-cancer drug development in recent years. This current work adopted molecular dynamics (MD simulations and cross-correlation analysis to investigate conformation changes of MDMX caused by inhibitor bindings. The obtained information indicates that the binding cleft of MDMX undergoes a large conformational change and the dynamic behavior of residues obviously change by the presence of different structural inhibitors. Two different methods of binding free energy predictions were employed to carry out a comparable insight into binding mechanisms of four inhibitors PMI, pDI, WK23 and WW8 to MDMX. The data show that the main factor controlling the inhibitor bindings to MDMX arises from van der Waals interactions. The binding free energies were further divided into contribution of each residue and the derived information gives a conclusion that the hydrophobic interactions, such as CH-CH, CH-π and π-π interactions, are responsible for the inhibitor associations with MDMX.

  14. Probing Difference in Binding Modes of Inhibitors to MDMX by Molecular Dynamics Simulations and Different Free Energy Methods.

    Science.gov (United States)

    Shi, Shuhua; Zhang, Shaolong; Zhang, Qinggang

    2015-01-01

    The p53-MDMX interaction has attracted extensive attention of anti-cancer drug development in recent years. This current work adopted molecular dynamics (MD) simulations and cross-correlation analysis to investigate conformation changes of MDMX caused by inhibitor bindings. The obtained information indicates that the binding cleft of MDMX undergoes a large conformational change and the dynamic behavior of residues obviously change by the presence of different structural inhibitors. Two different methods of binding free energy predictions were employed to carry out a comparable insight into binding mechanisms of four inhibitors PMI, pDI, WK23 and WW8 to MDMX. The data show that the main factor controlling the inhibitor bindings to MDMX arises from van der Waals interactions. The binding free energies were further divided into contribution of each residue and the derived information gives a conclusion that the hydrophobic interactions, such as CH-CH, CH-π and π-π interactions, are responsible for the inhibitor associations with MDMX. PMID:26513747

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

    OpenAIRE

    Murakami, Yoichi; Ruth V Spriggs; 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 acces...

  16. 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.

  17. 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.

  18. Prediction of multipactor in the iris region of rf deflecting mode cavities

    Science.gov (United States)

    Burt, G.; Dexter, A. C.

    2011-12-01

    Multipactor is a major cause of field limitation in many superconducting rf cavities. Multipacting is a particular issue for deflecting mode cavities as the typical behavior is not well studied, understood, or parametrized. In this paper an approximate analytical model for the prediction of multipactor in the iris region of deflecting mode cavities is developed. This new but simple model yields a clear explanation on the broad range of rf field levels over which the multipactor can occur. The principle multipactors under investigation here are two-point multipactors associated with cyclotron motion in the cavity’s rf magnetic field. The predictions from the model are compared to numerical simulations and good agreement is obtained. The results are also compared to experimental results previously reported by KEK and are also found in good agreement.

  19. 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....

  20. 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.

  1. 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.

  2. Molecular modeling on Zn(Ⅱ) binding modes of Alzheimer's amyloid β-peptide in insoluble aggregates and soluble complexes

    Institute of Scientific and Technical Information of China (English)

    HAN Daxiong; YANG Pin

    2004-01-01

    Aggregation of the amyloid β-peptide (A β) into insoluble fibrils is a key pathological event in Alzheimer's disease. Zn(Ⅱ) ion induces significant Aβ aggregation at nearly physiological concentrations in vitro. In order to explore the induce mechanism, the possible binding modes of Zn(Ⅱ) in Aβ peptide are studied by molecular modeling method. First, the Aβ species containing 1,2,4 and 12 peptides are established respectively. And next a Zn(Ⅱ) ion is manually hold the different sits of the Aβ species based on the experimental data and subsequently the coordinate atom and number are assigned. Finally, the optimum binding site is found by the system energy minimization. Modeling results show that in soluble Zn(Ⅱ) complex, Nτ of imidazole ring of His14, O of carbonyl of main-chain, and two O of water occupy the four ligand positions of the tetrahedral complex; in the aggregation of Aβ, the His13(Nτ)-Zn(Ⅱ)-His14(Nτ)bridges are formed by Zn(Ⅱ) cross-linking action. Therefore, the possible Zn(Ⅱ) binding mode obtained by the studies will be helpful to reveal the form mechanism of pathogenic aggregates in brain.

  3. 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.

  4. Low-Quality Structural and Interaction Data Improves Binding Affinity Prediction via Random Forest

    Directory of Open Access Journals (Sweden)

    Hongjian Li

    2015-06-01

    Full Text Available Docking scoring functions can be used to predict the strength of protein-ligand binding. It is widely believed that training a scoring function with low-quality data is detrimental for its predictive performance. Nevertheless, there is a surprising lack of systematic validation experiments in support of this hypothesis. In this study, we investigated to which extent training a scoring function with data containing low-quality structural and binding data is detrimental for predictive performance. We actually found that low-quality data is not only non-detrimental, but beneficial for the predictive performance of machine-learning scoring functions, though the improvement is less important than that coming from high-quality data. Furthermore, we observed that classical scoring functions are not able to effectively exploit data beyond an early threshold, regardless of its quality. This demonstrates that exploiting a larger data volume is more important for the performance of machine-learning scoring functions than restricting to a smaller set of higher data quality.

  5. Predicting the binding patterns of hub proteins: a study using yeast protein interaction networks.

    Directory of Open Access Journals (Sweden)

    Carson M Andorf

    Full Text Available BACKGROUND: Protein-protein interactions are critical to elucidating the role played by individual proteins in important biological pathways. Of particular interest are hub proteins that can interact with large numbers of partners and often play essential roles in cellular control. Depending on the number of binding sites, protein hubs can be classified at a structural level as singlish-interface hubs (SIH with one or two binding sites, or multiple-interface hubs (MIH with three or more binding sites. In terms of kinetics, hub proteins can be classified as date hubs (i.e., interact with different partners at different times or locations or party hubs (i.e., simultaneously interact with multiple partners. METHODOLOGY: Our approach works in 3 phases: Phase I classifies if a protein is likely to bind with another protein. Phase II determines if a protein-binding (PB protein is a hub. Phase III classifies PB proteins as singlish-interface versus multiple-interface hubs and date versus party hubs. At each stage, we use sequence-based predictors trained using several standard machine learning techniques. CONCLUSIONS: Our method is able to predict whether a protein is a protein-binding protein with an accuracy of 94% and a correlation coefficient of 0.87; identify hubs from non-hubs with 100% accuracy for 30% of the data; distinguish date hubs/party hubs with 69% accuracy and area under ROC curve of 0.68; and SIH/MIH with 89% accuracy and area under ROC curve of 0.84. Because our method is based on sequence information alone, it can be used even in settings where reliable protein-protein interaction data or structures of protein-protein complexes are unavailable to obtain useful insights into the functional and evolutionary characteristics of proteins and their interactions. AVAILABILITY: We provide a web server for our three-phase approach: http://hybsvm.gdcb.iastate.edu.

  6. The complex binding mode of the peptide hormone H2 relaxin to its receptor RXFP1.

    Science.gov (United States)

    Sethi, Ashish; Bruell, Shoni; Patil, Nitin; Hossain, Mohammed Akhter; Scott, Daniel J; Petrie, Emma J; Bathgate, Ross A D; Gooley, Paul R

    2016-01-01

    H2 relaxin activates the relaxin family peptide receptor-1 (RXFP1), a class A G-protein coupled receptor, by a poorly understood mechanism. The ectodomain of RXFP1 comprises an N-terminal LDLa module, essential for activation, tethered to a leucine-rich repeat (LRR) domain by a 32-residue linker. H2 relaxin is hypothesized to bind with high affinity to the LRR domain enabling the LDLa module to bind and activate the transmembrane domain of RXFP1. Here we define a relaxin-binding site on the LDLa-LRR linker, essential for the high affinity of H2 relaxin for the ectodomain of RXFP1, and show that residues within the LDLa-LRR linker are critical for receptor activation. We propose H2 relaxin binds and stabilizes a helical conformation of the LDLa-LRR linker that positions residues of both the linker and the LDLa module to bind the transmembrane domain and activate RXFP1. PMID:27088579

  7. Binding mode of inhibitors and Cryptosporidium parvum IMP dehydrogenase: A combined ligand- and receptor-based study.

    Science.gov (United States)

    Li, R-J; Wang, Y-L; Wang, Q-H; Huang, W-X; Wang, J; Cheng, M-S

    2015-01-01

    A combined ligand- and target-based approach was used to analyse the interaction models of Cryptosporidium parvum inosine 5'-monophosphate dehydrogenase (CpIMPDH) with selective inhibitors. First, a ligand-based pharmacophore model was generated from 20 NAD(+) competitive CpIMPDH inhibitors with the HipHop module. The characteristic of the NAD(+) binding site of CpIMPDH was then described, and the binding modes of the representative inhibitors were studied by molecular docking. The combination of the pharmacophore model and the docking results allowed us to evaluate the pharmacophore features and structural information of the NAD(+) binding site of CpIMPDH. This research supports the proposal of an interaction model inside the NAD(+) binding site of CpIMPDH, consisting of four key interaction points: two hydrophobic-aromatic groups, a hydrophobic-aliphatic group and a hydrogen bond donor. This study also provides guidance for the design of more potent CpIMPDH inhibitors for the treatment of Cryptosporidium infections. PMID:25978645

  8. A Comparative Reverse Docking Strategy to Identify Potential Antineoplastic Targets of Tea Functional Components and Binding Mode

    Directory of Open Access Journals (Sweden)

    Rong Zheng

    2011-08-01

    Full Text Available The main functional components of green tea, such as epigallocatechin gallate (EGCG, epigallocatechin (EGC, epicatechin gallate (ECG and epicatechin (EC, are found to have a broad antineoplastic activity. The discovery of their targets plays an important role in revealing the antineoplastic mechanism. Therefore, to identify potential target proteins for tea polyphenols, we have taken a comparative virtual screening approach using two reverse docking systems, one based on Autodock software and the other on Tarfisdock. Two separate in silico workflows were implemented to derive a set of target proteins related to human diseases and ranked by the binding energy score. Several conventional clinically important proteins with anti-tumor effects are screened out from the PDTD protein database as the potential receptors by both procedures. To further analyze the validity of docking results, we study the binding mode of EGCG and the potential target protein Leukotriene A4 hydrolase in detail. We indicate that interactions mediated by electrostatic and hydrogen bond play a key role in ligand binding. EGCG binds to the enzyme with certain orientation and conformation that is suitable for nucleophilic attacks by several electrical residues inside the enzyme’s activity cavity. This study provides useful information for studying the antitumor mechanism of tea’s functional components. The comparative reverse docking strategy presented generates a tractable set of antineoplastic proteins for future experimental validation as drug targets against tumors.

  9. 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.

  10. Binding mode of dihydroquinazolinones with lysozyme and its antifungal activity against Aspergillus species.

    Science.gov (United States)

    Hemalatha, K; Madhumitha, G; Ravi, Lokesh; Khanna, V Gopiesh; Al-Dhabi, Naif Abdullah; Arasu, Mariadhas Valan

    2016-08-01

    Aspergillosis is one of the infectious fungal diseases affecting mainly the immunocompromised patients. The scarcity of the antifungal targets has identified the importance of N-myristoyl transferase (NMT) in the regulation of fungal pathway. The dihydroquinazolinone molecules were designed on the basis of fragments responsible for binding with the target enzyme. The aryl halide, 1(a-g), aryl boronic acid and potassium carbonate were heated together in water and dioxane mixture to yield new CC bond formation in dihydroquinazolinone. The bis(triphenylphosphine)palladium(II) dichloride was used as catalyst for the CC bond formation. The synthesized series were screened for their in vitro antifungal activity against Aspergillus niger and Aspergillus fumigatus. The binding interactions of the active compound with lysozyme were explored using multiple spectroscopic studies. Molecular docking study of dihydroquinazolinones with the enzyme revealed the information regarding various binding forces involved in the interaction. PMID:27214045

  11. 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.

  12. 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.

  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. Mode of Ezrin-Membrane Interaction as a Function of PIP2 Binding and Pseudophosphorylation.

    Science.gov (United States)

    Shabardina, Victoria; Kramer, Corinna; Gerdes, Benjamin; Braunger, Julia; Cordes, Andrea; Schäfer, Jonas; Mey, Ingo; Grill, David; Gerke, Volker; Steinem, Claudia

    2016-06-21

    Ezrin, a protein of the ezrin, radixin, moesin (ERM) family, provides a regulated linkage between the plasma membrane and the cytoskeleton. The hallmark of this linkage is the activation of ezrin by phosphatidylinositol-4,5-bisphosphate (PIP2) binding and a threonine phosphorylation at position 567. To analyze the influence of these activating factors on the organization of ezrin on lipid membranes and the proposed concomitant oligomer-monomer transition, we made use of supported lipid bilayers in conjunction with atomic force microscopy and fluorescence microscopy. Bilayers doped with either PIP2 as the natural receptor lipid of ezrin or a Ni-nitrilotriacetic acid-equipped lipid to bind the proteins via their His6-tags to the lipid membrane were used to bind two different ezrin variants: ezrin wild-type and ezrin T567D mimicking the phosphorylated state. Using a combination of reflectometric interference spectroscopy, atomic force microscopy, and Förster resonance energy transfer experiments, we show that only the ezrin T567D mutant, upon binding to PIP2-containing bilayers, undergoes a remarkable conformational change, which we attribute to an opening of the conformation resulting in monomeric protein on the lipid bilayer. PMID:27332129

  15. PEPTIDE BINDING AS A MODE OF ACTION FOR THE CARCINOGENICITY AND TOXICITY OF ARSENIC

    Science.gov (United States)

    Arsenic exposure leads to tumors in human skin, lung, urinary bladder, kidney and liver. Three likely initial stages of arsenical-macromolecular interaction are (1) binding of trivalent arsenicals to the sulfhydryl groups of peptides and proteins, (2) arsenical-induced generation...

  16. Differential modes of DNA binding by mismatch uracil DNA glycosylase from Escherichia coli: implications for abasic lesion processing and enzyme communication in the base excision repair pathway

    OpenAIRE

    Grippon, Seden; Zhao, Qiyuan; Robinson, Tom; Marshall, Jacqueline J. T.; O’Neill, Rory J.; Manning, Hugh; Kennedy, Gordon; Dunsby, Christopher; Neil, Mark; Halford, Stephen E.; French, Paul M. W.; Baldwin, Geoff S.

    2010-01-01

    Mismatch uracil DNA glycosylase (Mug) from Escherichia coli is an initiating enzyme in the base-excision repair pathway. As with other DNA glycosylases, the abasic product is potentially more harmful than the initial lesion. Since Mug is known to bind its product tightly, inhibiting enzyme turnover, understanding how Mug binds DNA is of significance when considering how Mug interacts with downstream enzymes in the base-excision repair pathway. We have demonstrated differential binding modes o...

  17. 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.

  18. MetaMHCpan, A Meta Approach for Pan-Specific MHC Peptide Binding Prediction.

    Science.gov (United States)

    Xu, Yichang; Luo, Cheng; Mamitsuka, Hiroshi; Zhu, Shanfeng

    2016-01-01

    Recent computational approaches in bioinformatics can achieve high performance, by which they can be a powerful support for performing real biological experiments, making biologists pay more attention to bioinformatics than before. In immunology, predicting peptides which can bind to MHC alleles is an important task, being tackled by many computational approaches. However, this situation causes a serious problem for immunologists to select the appropriate method to be used in bioinformatics. To overcome this problem, we develop an ensemble prediction-based Web server, which we call MetaMHCpan, consisting of two parts: MetaMHCIpan and MetaMHCIIpan, for predicting peptides which can bind MHC-I and MHC-II, respectively. MetaMHCIpan and MetaMHCIIpan use two (MHC2SKpan and LApan) and four (TEPITOPEpan, MHC2SKpan, LApan, and MHC2MIL) existing predictors, respectively. MetaMHCpan is available at http://datamining-iip.fudan.edu.cn/MetaMHCpan/index.php/pages/view/info . PMID:27076335

  19. Development of computational methods for the prediction of protein structure, protein binding, and mutational effects using free energy calculations.

    OpenAIRE

    Becker, Caroline

    2014-01-01

    A molecular understanding of protein-protein or protein-ligand binding is of crucial importance for the design of proteins or ligands with defined binding characteristics. The comprehensive analysis of biomolecular binding and the coupled rational in silico design of protein-ligand interfaces requires both, accurate and computationally fast methods for the prediction of free energies. Accurate free energy methods usually involve atomistic molecular dynamics simulations that are computationall...

  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. 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.

  2. Neighbourhood, Route and Workplace-Related Environmental Characteristics Predict Adults' Mode of Travel to Work.

    Directory of Open Access Journals (Sweden)

    Alice M Dalton

    Full Text Available Commuting provides opportunities for regular physical activity which can reduce the risk of chronic disease. Commuters' mode of travel may be shaped by their environment, but understanding of which specific environmental characteristics are most important and might form targets for intervention is limited. This study investigated associations between mode choice and a range of objectively assessed environmental characteristics.Participants in the Commuting and Health in Cambridge study reported where they lived and worked, their usual mode of travel to work and a variety of socio-demographic characteristics. Using geographic information system (GIS software, 30 exposure variables were produced capturing characteristics of areas around participants' homes and workplaces and their shortest modelled routes to work. Associations between usual mode of travel to work and personal and environmental characteristics were investigated using multinomial logistic regression.Of the 1124 respondents, 50% reported cycling or walking as their usual mode of travel to work. In adjusted analyses, home-work distance was strongly associated with mode choice, particularly for walking. Lower odds of walking or cycling rather than driving were associated with a less frequent bus service (highest versus lowest tertile: walking OR 0.61 [95% CI 0.20-1.85]; cycling OR 0.43 [95% CI 0.23-0.83], low street connectivity (OR 0.22, [0.07-0.67]; OR 0.48 [0.26-0.90] and free car parking at work (OR 0.24 [0.10-0.59]; OR 0.55 [0.32-0.95]. Participants were less likely to cycle if they had access to fewer destinations (leisure facilities, shops and schools close to work (OR 0.36 [0.21-0.62] and a railway station further from home (OR 0.53 [0.30-0.93]. Covariates strongly predicted travel mode (pseudo r-squared 0.74.Potentially modifiable environmental characteristics, including workplace car parking, street connectivity and access to public transport, are associated with travel mode

  3. 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.

  4. 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.

  5. 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.

  6. 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.

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

    Science.gov (United States)

    Nikabdullah, N.; Singh, S. S. K.; Alebrahim, R.; Azizi, M. A.; K, Elwaleed A.; Noorani, M. S. M.

    2014-06-01

    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.

  8. 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.

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

    International Nuclear Information System (INIS)

    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

  10. Binding mode and potency of N-indolyloxopyridinyl-4-aminopropanyl-based inhibitors targeting Trypanosoma cruzi CYP51.

    Science.gov (United States)

    Vieira, Debora F; Choi, Jun Yong; Calvet, Claudia M; Siqueira-Neto, Jair Lage; Johnston, Jonathan B; Kellar, Danielle; Gut, Jiri; Cameron, Michael D; McKerrow, James H; Roush, William R; Podust, Larissa M

    2014-12-11

    Chagas disease is a chronic infection in humans caused by Trypanosoma cruzi and manifested in progressive cardiomyopathy and/or gastrointestinal dysfunction. Limited therapeutic options to prevent and treat Chagas disease put 8 million people infected with T. cruzi worldwide at risk. CYP51, involved in the biosynthesis of the membrane sterol component in eukaryotes, is a promising drug target in T. cruzi. We report the structure-activity relationships (SAR) of an N-arylpiperazine series of N-indolyloxopyridinyl-4-aminopropanyl-based inhibitors designed to probe the impact of substituents in the terminal N-phenyl ring on binding mode, selectivity and potency. Depending on the substituents at C-4, two distinct ring binding modes, buried and solvent-exposed, have been observed by X-ray structure analysis (resolution of 1.95-2.48 Å). The 5-chloro-substituted analogs 9 and 10 with no substituent at C-4 demonstrated improved selectivity and potency, suppressing ≥ 99.8% parasitemia in mice when administered orally at 25 mg/kg, b.i.d., for 4 days. PMID:25393646

  11. 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/....

  12. 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

    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...... benchmark data set, and SMM-align prediction method (NetMHCII) are made publicly available....

  13. Potent Glycosidase Inhibition with Heterovalent Fullerenes: Unveiling the Binding Modes Triggering Multivalent Inhibition.

    Science.gov (United States)

    Abellán Flos, Marta; García Moreno, M Isabel; Ortiz Mellet, Carmen; García Fernández, Jose Manuel; Nierengarten, Jean-Francois; Vincent, Stéphane P

    2016-08-01

    Glycosidases are key enzymes in metabolism, pathogenic/antipathogenic mechanisms and normal cellular functions. Recently, a novel approach for glycosidase inhibition that conveys multivalent glycomimetic conjugates has emerged. Many questions regarding the mechanism(s) of multivalent enzyme inhibition remain unanswered. Herein we report the synthesis of a collection of novel homo- and heterovalent glyco(mimetic)-fullerenes purposely conceived for probing the contribution of non-catalytic pockets in glysosidases to the multivalent inhibitory effect. Their affinities towards selected glycosidases were compared with data from homovalent fullerene conjugates. An original competitive glycosidase-lectin binding assay demonstrated that the multivalent derivatives and the substrate compete for low affinity non-glycone binding sites of the enzyme, leading to inhibition by a "recognition and blockage" mechanism. Most notably, this work provides evidence for enzyme inhibition by multivalent glycosystems, which will likely have a strong impact in the glycosciences given the utmost relevance of multivalency in Nature. PMID:27374430

  14. The Different Ligand-Binding Modes of Relaxin Family Peptide Receptors RXFP1 and RXFP2

    OpenAIRE

    Scott, Daniel J.; Rosengren, K. Johan; Bathgate, Ross A. D.

    2012-01-01

    Relaxin and insulin-like peptide 3 (INSL3) are peptide hormones with a number of important physiological roles in reproduction, regulation of extracellular matrix turnover, and cardiovascular function. Relaxin and INSL3 mediate their actions through the closely related G-protein coupled receptors, relaxin family peptide receptors 1 and 2 (RXFP1 and RXFP2), respectively. These receptors have large extracellular domains (ECD) that contain high-affinity ligand-binding sites within their 10 leuci...

  15. 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...

  16. Prediction of pressure induced structural phase transitions and internal mode frequency changes in solid N2+

    International Nuclear Information System (INIS)

    A rhombohedral distortion of the Pm3n structure is introduced which shows that a low temperature phase transition occurs from P42/mnm into the R3c calcite structure at P approx. = 19.2 kbar with a volume change of 0.125 cm3/mole. This transition agrees with recent Raman scattering measurements. Another transition from R3c into R3m is predicted at P approx. = 67.5 kbar, with a volume change of 0.1 cm3/mole. The pressure dependence of the intramolecular mode frequencies for the R3c structure is in reasonably good agreement with the two main branches observed experimentally

  17. 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.

  18. Comparison of Performance of Docking, LIE, Metadynamics and QSAR in Predicting Binding Affinity of Benzenesulfonamides.

    Science.gov (United States)

    Raškevičius, Vytautas; Kairys, Visvaldas

    2015-01-01

    The design of inhibitors specific for one relevant carbonic anhydrase isozyme is the major challenge in the new therapeutic agents development. Comparative computational chemical structure and biological activity relationship studies on a series of carbonic anhydrase II inhibitors, benzenesulfonamide derivatives, bearing pyrimidine moieties are reported in this paper using docking, Linear Interaction Energy (LIE), Metadynamics and Quantitative Structure Activity Relationship (QSAR) methods. The computed binding affinities were compared with the experimental data with the goal to explore strengths and weaknesses of various approaches applied to the investigated carbonic anhydrase/inhibitor system. From the tested methods initially only QSAR showed promising results (R2=0.83-0.89 between experimentally determined versus predicted pKd values.). Possible reasons for this performance were discussed. A modification of the LIE method was suggested which used an alternative LIE-like equation yielding significantly improved results (R2 between the experimentally determined versus the predicted ΔG(bind) improved from 0.24 to 0.50).

  19. Prediction of Water Binding to Protein Hydration Sites with a Discrete, Semiexplicit Solvent Model.

    Science.gov (United States)

    Setny, Piotr

    2015-12-01

    Buried water molecules are ubiquitous in protein structures and are found at the interface of most protein-ligand complexes. Determining their distribution and thermodynamic effect is a challenging yet important task, of great of practical value for the modeling of biomolecular structures and their interactions. In this study, we present a novel method aimed at the prediction of buried water molecules in protein structures and estimation of their binding free energies. It is based on a semiexplicit, discrete solvation model, which we previously introduced in the context of small molecule hydration. The method is applicable to all macromolecular structures described by a standard all-atom force field, and predicts complete solvent distribution within a single run with modest computational cost. We demonstrate that it indicates positions of buried hydration sites, including those filled by more than one water molecule, and accurately differentiates them from sterically accessible to water but void regions. The obtained estimates of water binding free energies are in fair agreement with reference results determined with the double decoupling method. PMID:26642995

  20. 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.

  1. 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.

  2. 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. PMID:26209847

  3. Prediction and dissection of widely-varying association rate constants of actin-binding proteins.

    Directory of Open Access Journals (Sweden)

    Xiaodong Pang

    Full Text Available Actin is an abundant protein that constitutes a main component of the eukaryotic cytoskeleton. Its polymerization and depolymerization are regulated by a variety of actin-binding proteins. Their functions range from nucleation of actin polymerization to sequestering G-actin in 1∶1 complexes. The kinetics of forming these complexes, with rate constants varying at least three orders of magnitude, is critical to the distinct regulatory functions. Previously we have developed a transient-complex theory for computing protein association mechanisms and association rate constants. The transient complex refers to an intermediate in which the two associating proteins have near-native separation and relative orientation but have yet to form short-range specific interactions of the native complex. The association rate constant is predicted as k(a = k(a0 e(-ΔG(el*/k(BT, where k(a0 is the basal rate constant for reaching the transient complex by free diffusion, and the Boltzmann factor captures the bias of long-range electrostatic interactions. Here we applied the transient-complex theory to study the association kinetics of seven actin-binding proteins with G-actin. These proteins exhibit three classes of association mechanisms, due to their different molecular shapes and flexibility. The 1000-fold k(a variations among them can mostly be attributed to disparate electrostatic contributions. The basal rate constants also showed variations, resulting from the different shapes and sizes of the interfaces formed by the seven actin-binding proteins with G-actin. This study demonstrates the various ways that actin-binding proteins use physical properties to tune their association mechanisms and rate constants to suit distinct regulatory functions.

  4. Improved pan-specific MHC class I peptide-binding predictions using a novel representation of the MHC-binding cleft environment

    DEFF Research Database (Denmark)

    Carrasco Pro, S.; Zimic, M.; Nielsen, Morten

    2014-01-01

    Major histocompatibility complex (MHC) molecules play a key role in cell-mediated immune responses presenting bounded peptides for recognition by the immune system cells. Several in silico methods have been developed to predict the binding affinity of a given peptide to a specific MHC molecule. One...... of the current state-of-the-art methods for MHC class I is NetMHCpan, which has a core ingredient for the representation of the MHC class I molecule using a pseudo-sequence representation of the binding cleft amino acid environment. New and large MHC-peptide-binding data sets are constantly being made available......, and also new structures of MHC class I molecules with a bound peptide have been published. In order to test if the NetMHCpan method can be improved by integrating this novel information, we created new pseudo-sequence definitions for the MHC-binding cleft environment from sequence and structural analyses...

  5. 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.

  6. Structures of 5-Methylthioribose Kinase Reveal Substrate Specificity and Unusual Mode of Nucleotide Binding

    Energy Technology Data Exchange (ETDEWEB)

    Ku,S.; Yip, P.; Cornell, K.; Riscoe, M.; Behr, J.; Guillerm, G.; Howell, P.

    2007-01-01

    The methionine salvage pathway is ubiquitous in all organisms, but metabolic variations exist between bacteria and mammals. 5-Methylthioribose (MTR) kinase is a key enzyme in methionine salvage in bacteria and the absence of a mammalian homolog suggests that it is a good target for the design of novel antibiotics. The structures of the apo-form of Bacillus subtilis MTR kinase, as well as its ADP, ADP-PO4, AMPPCP, and AMPPCP-MTR complexes have been determined. MTR kinase has a bilobal eukaryotic protein kinase fold but exhibits a number of unique features. The protein lacks the DFG motif typically found at the beginning of the activation loop and instead coordinates magnesium via a DXE motif (Asp{sup 250}-Glu{sup 252}). In addition, the glycine-rich loop of the protein, analogous to the 'Gly triad' in protein kinases, does not interact extensively with the nucleotide. The MTR substrate-binding site consists of Asp{sup 233} of the catalytic HGD motif, a novel twin arginine motif (Arg{sup 340}/Arg{sup 341}), and a semi-conserved W-loop, which appears to regulate MTR binding specificity. No lobe closure is observed for MTR kinase upon substrate binding. This is probably because the enzyme lacks the lobe closure/inducing interactions between the C-lobe of the protein and the ribosyl moiety of the nucleotide that are typically responsible for lobe closure in protein kinases. The current structures suggest that MTR kinase has a dissociative mechanism.

  7. 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 (R2=0.91, Q2=0.77, QExt2=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. PMID:25344841

  8. 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...... are filled by other ligand fragments. This novel binding mode shows that the acyl moiety can flip out of its classical binding pocket and bind elsewhere, suggesting a mechanism for the acyl-CoA transfer between ACBP and the active site of a target enzyme. This mechanism is of possible relevance...

  9. DNA-binding protein prediction using plant specific support vector machines: validation and application of a new genome annotation tool.

    Science.gov (United States)

    Motion, Graham B; Howden, Andrew J M; Huitema, Edgar; Jones, Susan

    2015-12-15

    There are currently 151 plants with draft genomes available but levels of functional annotation for putative protein products are low. Therefore, accurate computational predictions are essential to annotate genomes in the first instance, and to provide focus for the more costly and time consuming functional assays that follow. DNA-binding proteins are an important class of proteins that require annotation, but current computational methods are not applicable for genome wide predictions in plant species. Here, we explore the use of species and lineage specific models for the prediction of DNA-binding proteins in plants. We show that a species specific support vector machine model based on Arabidopsis sequence data is more accurate (accuracy 81%) than a generic model (74%), and based on this we develop a plant specific model for predicting DNA-binding proteins. We apply this model to the tomato proteome and demonstrate its ability to perform accurate high-throughput prediction of DNA-binding proteins. In doing so, we have annotated 36 currently uncharacterised proteins by assigning a putative DNA-binding function. Our model is publically available and we propose it be used in combination with existing tools to help increase annotation levels of DNA-binding proteins encoded in plant genomes. PMID:26304539

  10. Escherichia coli Topoisomerase IV E Subunit and an Inhibitor Binding Mode Revealed by NMR Spectroscopy.

    Science.gov (United States)

    Li, Yan; Wong, Ying Lei; Ng, Fui Mee; Liu, Boping; Wong, Yun Xuan; Poh, Zhi Ying; Liu, Shuang; Then, Siew Wen; Lee, Michelle Yueqi; Ng, Hui Qi; Huang, Qiwei; Hung, Alvin W; Cherian, Joseph; Hill, Jeffrey; Keller, Thomas H; Kang, CongBao

    2016-08-19

    Bacterial topoisomerases are attractive antibacterial drug targets because of their importance in bacterial growth and low homology with other human topoisomerases. Structure-based drug design has been a proven approach of efficiently developing new antibiotics against these targets. Past studies have focused on developing lead compounds against the ATP binding pockets of both DNA gyrase and topoisomerase IV. A detailed understanding of the interactions between ligand and target in a solution state will provide valuable information for further developing drugs against topoisomerase IV targets. Here we describe a detailed characterization of a known potent inhibitor containing a 9H-pyrimido[4,5-b]indole scaffold against the N-terminal domain of the topoisomerase IV E subunit from Escherichia coli (eParE). Using a series of biophysical and biochemical experiments, it has been demonstrated that this inhibitor forms a tight complex with eParE. NMR studies revealed the exact protein residues responsible for inhibitor binding. Through comparative studies of two inhibitors of markedly varied potencies, it is hypothesized that gaining molecular interactions with residues in the α4 and residues close to the loop of β1-α2 and residues in the loop of β3-β4 might improve the inhibitor potency. PMID:27365392

  11. 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.

  12. 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.

  13. Predicting the aquatic toxicity mode of action using logistic regression and linear discriminant analysis.

    Science.gov (United States)

    Ren, Y Y; Zhou, L C; Yang, L; Liu, P Y; Zhao, B W; Liu, H X

    2016-09-01

    The paper highlights the use of the logistic regression (LR) method in the construction of acceptable statistically significant, robust and predictive models for the classification of chemicals according to their aquatic toxic modes of action. Essentials accounting for a reliable model were all considered carefully. The model predictors were selected by stepwise forward discriminant analysis (LDA) from a combined pool of experimental data and chemical structure-based descriptors calculated by the CODESSA and DRAGON software packages. Model predictive ability was validated both internally and externally. The applicability domain was checked by the leverage approach to verify prediction reliability. The obtained models are simple and easy to interpret. In general, LR performs much better than LDA and seems to be more attractive for the prediction of the more toxic compounds, i.e. compounds that exhibit excess toxicity versus non-polar narcotic compounds and more reactive compounds versus less reactive compounds. In addition, model fit and regression diagnostics was done through the influence plot which reflects the hat-values, studentized residuals, and Cook's distance statistics of each sample. Overdispersion was also checked for the LR model. The relationships between the descriptors and the aquatic toxic behaviour of compounds are also discussed. PMID:27653817

  14. 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.

  15. Interaction and Binding Modes of bis-Ruthenium(II Complex to Synthetic DNAs

    Directory of Open Access Journals (Sweden)

    Hasi Rani Barai

    2016-06-01

    Full Text Available [μ-(linkerL2(dipyrido[3,2-a:2′,3′-c]phenazine2(phenanthroline2Ru(II2]2+ with linker: 1,3-bis-(4-pyridyl-propane, L: PF6 (bis-Ru-bpp was synthesized and their binding properties to a various polynucleotides were investigated by spectroscopy, including normal absorption, circular dichroism(CD, linear dichroism(LD, and luminescence techniques in this study. On binding to polynucleotides, the bis-Ru-bpp complex with poly[d(A-T2], and poly[d(I-C2] exhibited a negative LDr signal whose intensity was as large as that in the DNA absorption region, followed by a complicated LDr signal in the metal-to-ligand charge transfer region. Also, the emission intensity and equilibrium constant of the bis-Ru-bpp complex with poly[d(A-T2], and poly[d(I-C2] were enhanced. It was reported that both of dppz ligand of the bis-Ru-bpp complex intercalated between DNA base-pairs when bound to native, mixed sequence DNA. Observed spectral properties resemble to those observed for poly[d(A-T2] and poly[d(I-C2], led us to be concluded that both dppz ligands intercalate between alternated AT and IC bases-pairs In contrast when bis-Ru-bpp complex was bound to poly[d(G-C2], the magnitude of the LDr in the dppz absorption region, as well as the emission intensity, was half in comparison to that of bound to poly[d(A-T2], and poly[d(I-C2]. Therefore the spectral properties of the bis-Ru-bpp-poly[d(G-C2] complex suggested deviation from bis-intercalation model in the poly[d(G-C2] case. These results can be explained by a model whereby one of the dppz ligands is intercalated while the other is exposed to solvent or may exist near to phosphate. Also it is indicative that the amine group of guanine in the minor groove provides the steric hindrance for incoming intercalation binder and it also takes an important role in a difference in binding of bis-Ru-bpp bound to poly[d(A-T2] and poly[d(I-C2].

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

    DEFF Research Database (Denmark)

    Buus, S; Lauemøller, S L; Worning, P;

    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...

  17. 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

  18. 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.

  19. sNebula, a network-based algorithm to predict binding between human leukocyte antigens and peptides

    Science.gov (United States)

    Luo, Heng; Ye, Hao; Ng, Hui Wen; Sakkiah, Sugunadevi; Mendrick, Donna L.; Hong, Huixiao

    2016-01-01

    Understanding the binding between human leukocyte antigens (HLAs) and peptides is important to understand the functioning of the immune system. Since it is time-consuming and costly to measure the binding between large numbers of HLAs and peptides, computational methods including machine learning models and network approaches have been developed to predict HLA-peptide binding. However, there are several limitations for the existing methods. We developed a network-based algorithm called sNebula to address these limitations. We curated qualitative Class I HLA-peptide binding data and demonstrated the prediction performance of sNebula on this dataset using leave-one-out cross-validation and five-fold cross-validations. This algorithm can predict not only peptides of different lengths and different types of HLAs, but also the peptides or HLAs that have no existing binding data. We believe sNebula is an effective method to predict HLA-peptide binding and thus improve our understanding of the immune system. PMID:27558848

  20. 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.

  1. Potent inhibition of mandelate racemase by a fluorinated substrate-product analogue with a novel binding mode.

    Science.gov (United States)

    Nagar, Mitesh; Lietzan, Adam D; St Maurice, Martin; Bearne, Stephen L

    2014-02-25

    Mandelate racemase (MR) from Pseudomonas putida catalyzes the Mg(2+)-dependent 1,1-proton transfer that interconverts the enantiomers of mandelate. Because trifluorolactate is also a substrate of MR, we anticipated that replacing the phenyl rings of the competitive, substrate-product analogue inhibitor benzilate (Ki = 0.7 mM) with trifluoromethyl groups might furnish an inhibitor. Surprisingly, the substrate-product analogue 3,3,3-trifluoro-2-hydroxy-2-(trifluoromethyl)propanoate (TFHTP) was a potent competitive inhibitor [Ki = 27 ± 4 μM; cf. Km = 1.2 mM for both (R)-mandelate and (R)-trifluorolactate]. To understand the origins of this high binding affinity, we determined the X-ray crystal structure of the MR-TFHTP complex to 1.68 Å resolution. Rather than chelating the active site Mg(2+) with its glycolate moiety, like other ground state analogues, TFHTP exhibited a novel binding mode with the two trifluoromethyl groups closely packed against the 20s loop and the carboxylate bridging the two active site Brønsted acid-base catalysts Lys 166 and His 297. Recognizing that positioning a carboxylate between the Brønsted acid-base catalysts could yield an inhibitor, we showed that tartronate was a competitive inhibitor of MR (Ki = 1.8 ± 0.1 mM). The X-ray crystal structure of the MR-tartronate complex (1.80 Å resolution) revealed that the glycolate moiety of tartronate chelated the Mg(2+) and that the carboxylate bridged Lys 166 and His 297. Models of tartronate in monomers A and B of the crystal structure mimicked the binding orientations of (S)-mandelate and that anticipated for (R)-mandelate, respectively. For the latter monomer, the 20s loop appeared to be disordered, as it also did in the X-ray structure of the MR triple mutant (C92S/C264S/K166C) complexed with benzilate, which was determined to 1.89 Å resolution. These observations indicate that the 20s loop likely undergoes a significant conformational change upon binding (R)-mandelate. In general, our

  2. 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.

  3. Prediction of SAMPL3 Host-Guest Binding Affinities: Evaluating the Accuracy of Generalized Force-Fields

    OpenAIRE

    Muddana, Hari S.; Gilson, Michael K.

    2012-01-01

    We used the second-generation mining minima method (M2) to compute the binding affinities of the novel host-guest complexes in the SAMPL3 blind prediction challenge. The predictions were in poor agreement with experiment, and we conjectured that much of the error might derive from the force field, CHARMm with Vcharge charges. Repeating the calculations with other generalized force-fields led to no significant improvement, and we observed that the predicted affinities were highly sensitive to ...

  4. Mode I Fracture Toughness Prediction for Multiwalled-Carbon-Nanotube Reinforced Ceramics

    Energy Technology Data Exchange (ETDEWEB)

    Nguyen, Ba Nghiep; Henager, Charles H.

    2015-08-27

    This article develops a multiscale model to predict fracture toughness of multiwalled-carbon-nanotube (MWCNT) reinforced ceramics. The model bridges different scales from the scale of a MWCNT to that of a composite domain containing a macroscopic crack. From the nano, micro to meso scales, Eshelby-Mori-Tanaka models combined with a continuum damage mechanics approach are explored to predict the elastic damage behavior of the composite as a function of MWCNT volume fraction. MWCNTs are assumed to be randomly dispersed in a ceramic matrix subject to cracking under loading. A damage variable is used to describe matrix cracking that causes reduction of the elastic modulus of the matrix. This damage model is introduced in a modified boundary layer modeling approach to capture damage initiation and development at a tip of a pre-existing crack. Damage and fracture are captured only in a process window containing the crack tip under plane strain Mode I loading. The model is validated against the published experimental fracture toughness data for a MWCNT 3 mol% yttria stabilized zirconia composite system. In addition, crack resistance curves as a function of MWCNT content are predicted and fitted by a power law as observed in the experiments on zirconia.

  5. 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...

  6. 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.

  7. 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.

  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. 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 

  11. Fast DC Mode Prediction Scheme For Intra 4x4 Block In H.264/AVC Video Coding Standard

    Directory of Open Access Journals (Sweden)

    Tajdid UI Alam

    2012-09-01

    Full Text Available In this paper, the researchers proposed a new scheme for DC mode prediction in intra frame for 4X4 block. In this scheme, the upper and left neighboring pixels would be used to predict each of the pixels in the 4X4 block with different weight. The prediction equations for each position of the 4X4 block in DC mode would be static with fixed weighting coefficients. As a result, the computational time for intra frame would be decreased considerably with an increase in PSNR.

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

    NARCIS (Netherlands)

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

    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

  13. 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. PMID:25461542

  14. Accurate pan-specific prediction of peptide-MHC class II binding affinity with improved binding core identification

    DEFF Research Database (Denmark)

    Andreatta, Massimo; Karosiene, Edita; Rasmussen, Michael;

    2015-01-01

    A key event in the generation of a cellular response against malicious organisms through the endocytic pathway is binding of peptidic antigens by major histocompatibility complex class II (MHC class II) molecules. The bound peptide is then presented on the cell surface where it can be recognized ...

  15. 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

  16. 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.

  17. 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.

  18. 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.

  19. An Improved Selective Encryption for H.264 Video based on Intra Prediction Mode Scrambling

    Directory of Open Access Journals (Sweden)

    Jianguo Jiang

    2010-10-01

    Full Text Available Video encryption is becoming increasingly important as multimedia applications gain more and more popularity. With a focus on the widely-used H.264 video coding standard, various encryption algorithms based on the intra prediction mode have been developed while suffering limited scrambling space and inadequate security. In this paper, the existing encryption algorithms are first analyzed with respect to the perception performance, plaintext scrambling space and key security. An encryption algorithm is then proposed by taking into account key distribution and synchronization, leading to improved encryption effect. In contrast to the existing algorithms, experiment results have shown that the proposed algorithm achieved higher security while less impact on the code length and frame rate. In addition, the computational complexity is reduced which facilitates real-time video applications.

  20. 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

    is derived from a large compilation of quantitative HLA-DR binding events covering 14 of the more than 500 known HLA-DR alleles. Taking both peptide and HLA sequence information into account, the method can generalize and predict peptide binding also for HLA-DR molecules where experimental data is absent......-even in the absence of specific data for the particular molecule in question. Moreover, when compared to TEPITOPE, currently the only other publicly available prediction method aiming at providing broad HLA-DR allelic coverage, NetMHCIIpan performs equivalently for alleles included in the training of TEPITOPE while...... 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...

  1. aPPRove: An HMM-Based Method for Accurate Prediction of RNA-Pentatricopeptide Repeat Protein Binding Events

    Science.gov (United States)

    Harrison, Thomas; Ruiz, Jaime; Sloan, Daniel B.; Ben-Hur, Asa; Boucher, Christina

    2016-01-01

    Pentatricopeptide repeat containing proteins (PPRs) bind to RNA transcripts originating from mitochondria and plastids. There are two classes of PPR proteins. The P class contains tandem P-type motif sequences, and the PLS class contains alternating P, L and S type sequences. In this paper, we describe a novel tool that predicts PPR-RNA interaction; specifically, our method, which we call aPPRove, determines where and how a PLS-class PPR protein will bind to RNA when given a PPR and one or more RNA transcripts by using a combinatorial binding code for site specificity proposed by Barkan et al. Our results demonstrate that aPPRove successfully locates how and where a PPR protein belonging to the PLS class can bind to RNA. For each binding event it outputs the binding site, the amino-acid-nucleotide interaction, and its statistical significance. Furthermore, we show that our method can be used to predict binding events for PLS-class proteins using a known edit site and the statistical significance of aligning the PPR protein to that site. In particular, we use our method to make a conjecture regarding an interaction between CLB19 and the second intronic region of ycf3. The aPPRove web server can be found at www.cs.colostate.edu/~approve. PMID:27560805

  2. aPPRove: An HMM-Based Method for Accurate Prediction of RNA-Pentatricopeptide Repeat Protein Binding Events.

    Science.gov (United States)

    Harrison, Thomas; Ruiz, Jaime; Sloan, Daniel B; Ben-Hur, Asa; Boucher, Christina

    2016-01-01

    Pentatricopeptide repeat containing proteins (PPRs) bind to RNA transcripts originating from mitochondria and plastids. There are two classes of PPR proteins. The [Formula: see text] class contains tandem [Formula: see text]-type motif sequences, and the [Formula: see text] class contains alternating [Formula: see text], [Formula: see text] and [Formula: see text] type sequences. In this paper, we describe a novel tool that predicts PPR-RNA interaction; specifically, our method, which we call aPPRove, determines where and how a [Formula: see text]-class PPR protein will bind to RNA when given a PPR and one or more RNA transcripts by using a combinatorial binding code for site specificity proposed by Barkan et al. Our results demonstrate that aPPRove successfully locates how and where a PPR protein belonging to the [Formula: see text] class can bind to RNA. For each binding event it outputs the binding site, the amino-acid-nucleotide interaction, and its statistical significance. Furthermore, we show that our method can be used to predict binding events for [Formula: see text]-class proteins using a known edit site and the statistical significance of aligning the PPR protein to that site. In particular, we use our method to make a conjecture regarding an interaction between CLB19 and the second intronic region of ycf3. The aPPRove web server can be found at www.cs.colostate.edu/~approve. PMID:27560805

  3. 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.

  4. 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

  5. Avian wing proportions and flight styles: first step towards predicting the flight modes of mesozoic birds.

    Directory of Open Access Journals (Sweden)

    Xia Wang

    Full Text Available We investigated the relationship between wing element proportions and flight mode in a dataset of living avian species to provide a framework for making basic estimates of the range of flight styles evolved by Mesozoic birds. Our results show that feather length (f(prim and total arm length (ta (sum of the humerus, ulna and manus length ratios differ significantly between four flight style groups defined and widely used for living birds and as a result are predictive for fossils. This was confirmed using multivariate ordination analyses, with four wing elements (humerus, ulna/radius, manus, primary feathers, that discriminate the four broad flight styles within living birds. Among the variables tested, manus length is closely correlated with wing size, yet is the poorest predictor for flight style, suggesting that the shape of the bones in the hand wing is most important in determining flight style. Wing bone thickness (shape must vary with wing beat strength, with weaker forces requiring less bone. Finally, we show that by incorporating data from Mesozoic birds, multivariate ordination analyses can be used to predict the flight styles of fossils.

  6. 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.

  7. 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.

  8. 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

    2016-01-01

    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. PMID:27023588

  9. 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.

  10. 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

    2016-04-01

    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. PMID:27023588

  11. 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

  12. Pharmacophore-directed Homology Modeling and Molecular Dynamics Simulation of G Protein-coupled Receptor: Study of Possible Binding Modes of 5-HT2C Receptor Agonists

    Institute of Scientific and Technical Information of China (English)

    Zhili ZUO; Gang CHEN; Xiaomin LUO; Chummok PUAH; Weiliang ZHU; Kaixian CHEN; Hualiang JIANG

    2007-01-01

    A new pharmacophore-based modeling procedure, including homology modeling, pharmacophore study, flexible molecular docking, and long-time molecular dynamics (MD) simulations, was employed to construct the structure of the human 5-HT2C receptor and determine the characteristics of binding modes of 5-HT2C receptor agonists. An agonist-receptor complex has been constructed based on homology modeling and a pharmacophore hypothesis model based on some high active compounds. Then MD simulations of the ligand-receptor complex in an explicit membrane environment were carried out. The conformation of the 5-HT2C receptor during MD simulation was explored, and the stable binding modes of the studied agonist were determined. Flexible molecular docking of several structurally diverse agonists of the human 5-HT2C receptor was carried out, and the general binding modes of these agonists were investigated. According to the models presented in this work and the results of Flexi-Dock, the involvement of the amino acid residues Asp134,Ser138, Asn210, Asn331, Tyr358, Ile131, Ser 132, Val135, Thr139, Ile189, Va1202, Va1208, Leu209, Phe214,Va1215, Gly218, Ser219, Phe223, Trp324, Phe327, and Phe328 in agonist recognition was studied. The obtained binding modes of the human 5-HT2C receptor agonists have good agreement with the site-directed mutagenesis data and other studies.

  13. 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

  14. 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.

  15. Prediction of protein binding sites using physical and chemical descriptors and the support vector machine regression method

    Institute of Scientific and Technical Information of China (English)

    Sun Zhong-Hua; Jiang Fan

    2010-01-01

    In this paper a new continuous variable called core-ratio is defined to describe the probability for a residue to be in a binding site, thereby replacing the previous binary description of the interface residue using 0 and 1. So we can use the support vector machine regression method to fit the core-ratio value and predict the protein binding sites. We also design a new group of physical and chemical descriptors to characterize the binding sites. The new descriptors are more effective, with an averaging procedure used. Our test shows that much better prediction results can be obtained by the support vector regression (SVR) method than by the support vector classification method.

  16. 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.

  17. 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.

  18. Progress in analytical methods to predict and control azimuthal combustion instability modes in annular chambers

    OpenAIRE

    Bauerheim, Michaël; Nicoud, Franck; Poinsot, Thierry

    2016-01-01

    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 ...

  19. Computational analysis and prediction of the binding motif and protein interacting partners of the Abl SH3 domain.

    Directory of Open Access Journals (Sweden)

    Tingjun Hou

    2006-01-01

    Full Text Available Protein-protein interactions, particularly weak and transient ones, are often mediated by peptide recognition domains, such as Src Homology 2 and 3 (SH2 and SH3 domains, which bind to specific sequence and structural motifs. It is important but challenging to determine the binding specificity of these domains accurately and to predict their physiological interacting partners. In this study, the interactions between 35 peptide ligands (15 binders and 20 non-binders and the Abl SH3 domain were analyzed using molecular dynamics simulation and the Molecular Mechanics/Poisson-Boltzmann Solvent Area method. The calculated binding free energies correlated well with the rank order of the binding peptides and clearly distinguished binders from non-binders. Free energy component analysis revealed that the van der Waals interactions dictate the binding strength of peptides, whereas the binding specificity is determined by the electrostatic interaction and the polar contribution of desolvation. The binding motif of the Abl SH3 domain was then determined by a virtual mutagenesis method, which mutates the residue at each position of the template peptide relative to all other 19 amino acids and calculates the binding free energy difference between the template and the mutated peptides using the Molecular Mechanics/Poisson-Boltzmann Solvent Area method. A single position mutation free energy profile was thus established and used as a scoring matrix to search peptides recognized by the Abl SH3 domain in the human genome. Our approach successfully picked ten out of 13 experimentally determined binding partners of the Abl SH3 domain among the top 600 candidates from the 218,540 decapeptides with the PXXP motif in the SWISS-PROT database. We expect that this physical-principle based method can be applied to other protein domains as well.

  20. 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.

  1. 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

  2. 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.

  3. 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.

  4. 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.

  5. 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...

  6. 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.

  7. 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.

  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

    The identification of potential T-cell epitopes is important for development of new human or vetenary vaccines, both considering single protein/subunit vaccines, and for epitope/peptide vaccines as such. The highly diverse MHC class I alleles bind very different peptides, and accurate binding pre...... in situations where only very limited data are available for training....

  9. Predictions and Experimental Microstructural Characterization of High Strain Rate Failure Modes in Layered Aluminum Composites

    Science.gov (United States)

    Khanikar, Prasenjit

    Different aluminum alloys can be combined, as composites, for tailored dynamic applications. Most investigations pertaining to metallic alloy layered composites, however, have been based on quasi-static approaches. The dynamic failure of layered metallic composites, therefore, needs to be characterized in terms of strength, toughness, and fracture response. A dislocation-density based crystalline plasticity formulation, finite-element techniques, rational crystallographic orientation relations and a new fracture methodology were used to predict the failure modes associated with the high strain rate behavior of aluminum layered composites. Two alloy layers, a high strength alloy, aluminum 2195, and an aluminum alloy 2139, with high toughness, were modeled with representative microstructures that included precipitates, dispersed particles, and different grain boundary (GB) distributions. The new fracture methodology, based on an overlap method and phantom nodes, is used with a fracture criteria specialized for fracture on different cleavage planes. One of the objectives of this investigation, therefore, was to determine the optimal arrangements of the 2139 and 2195 aluminum alloys for a metallic layered composite that would combine strength, toughness and fracture resistance for high strain-rate applications. Different layer arrangements were investigated for high strain-rate applications, and the optimal arrangement was with the high toughness 2139 layer on the bottom, which provided extensive shear strain localization, and the high strength 2195 layer on the top for high strength resistance. The layer thickness of the bottom high toughness layer also affected the bending behavior of the roll-boned interface and the potential delamination of the layers. Shear strain localization, dynamic cracking and delamination were the mutually competing failure mechanisms for the layered metallic composite, and control of these failure modes can be optimized for high strain

  10. 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....

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

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

    OpenAIRE

    Marharyta Petukh; Minghui Li; Emil Alexov

    2015-01-01

    Author Summary Developing methods for accurate prediction of effects of amino acid substitutions on protein-protein affinity is important for both understanding disease-causing mechanism of missense mutations and guiding protein engineering. For both purposes, there is a need for accurate methods primarily based on first principle calculations, while being fast enough to handle large number of cases. Here we report a new method, the Single Amino Acid Mutation based change in Binding free Ener...

  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. The binding mode of Ni-(L-His)2 in NikA revealed by X-ray crystallography

    International Nuclear Information System (INIS)

    The ABC-type importer NikABCDE mediates nickel acquisition in Escherichia coli. The periplasmic nickel binding component NikA has a folding similar to that of the peptide transporter OppA and does not bind free nickel. Instead, we showed that the metal is tetra-coordinated by an organic tri-dentate molecule and His416. Conversely, it has been recently reported that NikA binds Ni-(L-His)2 and that addition of histidine increases the rate of nickel uptake in vivo. Here, we report the structure of NikA/Ni-(L-His)2 and show that histidine binding differs from peptide binding in OppA. The structure also confirms the central role of His416 in nickel binding. (authors)

  20. Predicting the Impact of Missense Mutations on Protein–Protein Binding Affinity

    OpenAIRE

    Li, Minghui; Petukh, Marharyta; Alexov, Emil; Panchenko, Anna R

    2014-01-01

    The crucial prerequisite for proper biological function is the protein’s ability to establish highly selective interactions with macromolecular partners. A missense mutation that alters the protein binding affinity may cause significant perturbations or complete abolishment of the function, potentially leading to diseases. The availability of computational methods to evaluate the impact of mutations on protein–protein binding is critical for a wide range of biomedical applications. Here, we r...

  1. Molecular modeling of the binding mode of chiral metal complexes A- and A-[Co(phen)2dppz]3+ with B-DNA

    Institute of Scientific and Technical Information of China (English)

    杨频; 韩大雄

    2000-01-01

    Molecular modeling methods have been applied to the structural characterization of the interaction between chiral metal complexes [Co(phen)2dppz]3+ (where phen = 1, 10-phenanthroline, dppz = dipyrido[3,2-a: 2’, 3’-c]phenazine) and the oligonucleotide (B-DNA fragment). The natures of two kinds of the binding modes, which are currently intense controversy, have been explored. Barton proposed that there is enantio-selective DMA binding by the octahedral complexes and intercalative access by these complexes from the major groove; but Norden suggested that both enantiomers bind extremely strongly to DNA from the minor groove without any noticeable enantio-selectivity. Our results support and extend structural models based upon Norden’s studies, and conflict with Barton’s model.

  2. Molecular modeling of the binding mode of chiral metal complexes △- and (A)-[Co(phen)2dppz]3+ with B-DNA

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Molecular modeling methods have been applied to the structural characterization of the interaction between chiral metal complexes [Co(phen)2dppz]3+ (where phen = 1, 10-phenanthroline, dppz = dipyrido[3,2-a: 2′, 3′-c]phenazine) and the oligonucleotide (B-DNA fragment). The natures of two kinds of the binding modes, which are currently intense controversy, have been explored. Barton proposed that there is enantio-selective DNA binding by the octahedral complexes and intercalative access by these complexes from the major groove; but Norden suggested that both enantiomers bind extremely strongly to DNA from the minor groove without any noticeable enantio-selectivity. Our results support and extend structural models based upon Norden's studies, and conflict with Barton's model.

  3. The utility of geometrical and chemical restraint information extracted from predicted ligand-binding sites in protein structure refinement.

    Science.gov (United States)

    Brylinski, Michal; Lee, Seung Yup; Zhou, Hongyi; Skolnick, Jeffrey

    2011-03-01

    Exhaustive exploration of molecular interactions at the level of complete proteomes requires efficient and reliable computational approaches to protein function inference. Ligand docking and ranking techniques show considerable promise in their ability to quantify the interactions between proteins and small molecules. Despite the advances in the development of docking approaches and scoring functions, the genome-wide application of many ligand docking/screening algorithms is limited by the quality of the binding sites in theoretical receptor models constructed by protein structure prediction. In this study, we describe a new template-based method for the local refinement of ligand-binding regions in protein models using remotely related templates identified by threading. We designed a Support Vector Regression (SVR) model that selects correct binding site geometries in a large ensemble of multiple receptor conformations. The SVR model employs several scoring functions that impose geometrical restraints on the Cα positions, account for the specific chemical environment within a binding site and optimize the interactions with putative ligands. The SVR score is well correlated with the RMSD from the native structure; in 47% (70%) of the cases, the Pearson's correlation coefficient is >0.5 (>0.3). When applied to weakly homologous models, the average heavy atom, local RMSD from the native structure of the top-ranked (best of top five) binding site geometries is 3.1Å (2.9Å) for roughly half of the targets; this represents a 0.1 (0.3)Å average improvement over the original predicted structure. Focusing on the subset of strongly conserved residues, the average heavy atom RMSD is 2.6Å (2.3Å). Furthermore, we estimate the upper bound of template-based binding site refinement using only weakly related proteins to be ∼2.6Å RMSD. This value also corresponds to the plasticity of the ligand-binding regions in distant homologues. The Binding Site Refinement (BSR

  4. Neighbourhood, Route and Workplace-Related Environmental Characteristics Predict Adults' Mode of Travel to Work

    OpenAIRE

    Dalton, Alice M; Jones, Andrew P.; Panter, Jenna R.; David Ogilvie

    2013-01-01

    Objective Commuting provides opportunities for regular physical activity which can reduce the risk of chronic disease. Commuters' mode of travel may be shaped by their environment, but understanding of which specific environmental characteristics are most important and might form targets for intervention is limited. This study investigated associations between mode choice and a range of objectively assessed environmental characteristics. Methods Participants in the Commuting and Health in Cam...

  5. Comparisons of Predicted Plasma Performance in ITER H-mode Plasmas with Various Mixes of External Heating

    International Nuclear Information System (INIS)

    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 χφ/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 χφ/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

  6. 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.

  7. Munc13-like skMLCK variants cannot mimic the unique calmodulin binding mode of Munc13 as evidenced by chemical cross-linking and mass spectrometry.

    Directory of Open Access Journals (Sweden)

    Sabine Herbst

    Full Text Available Among the neuronal binding partners of calmodulin (CaM are Munc13 proteins as essential presynaptic regulators that play a key role in synaptic vesicle priming and are crucial for presynaptic short-term plasticity. Recent NMR structural investigations of a CaM/Munc13-1 peptide complex have revealed an extended structure, which contrasts the compact structures of most classical CaM/target complexes. This unusual binding mode is thought to be related to the presence of an additional hydrophobic anchor residue at position 26 of the CaM binding motif of Munc13-1, resulting in a novel 1-5-8-26 motif. Here, we addressed the question whether the 1-5-8-26 CaM binding motif is a Munc13-related feature or whether it can be induced in other CaM targets by altering the motif's core residues. For this purpose, we chose skeletal muscle myosin light chain kinase (skMLCK with a classical 1-5-8-14 CaM binding motif and constructed three skMLCK peptide variants mimicking Munc13-1, in which the hydrophobic anchor amino acid at position 14 was moved to position 26. Chemical cross-linking between CaM and skMLCK peptide variants combined with high-resolution mass spectrometry yielded insights into the peptides' binding modes. This structural comparison together with complementary binding data from surface plasmon resonance experiments revealed that skMLCK variants with an artificial 1-5-8-26 motif cannot mimic CaM binding of Munc13-1. Apparently, additional features apart from the spacing of the hydrophobic anchor residues are required to define the functional 1-5-8-26 motif of Munc13-1. We conclude that Munc13 proteins display a unique CaM binding behavior to fulfill their role as efficient presynaptic calcium sensors over broad range of Ca(2+ concentrations.

  8. 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

  9. 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.

  10. Combined molecular dynamics and continuum solvent approaches (MM-PBSA/GBSA) to predict noscapinoid binding to γ-tubulin dimer.

    Science.gov (United States)

    Suri, C; Naik, P K

    2015-06-01

    γ-tubulin plays crucial role in the nucleation and organization of microtubules during cell division. Recent studies have also indicated its role in the regulation of microtubule dynamics at the plus end of the microtubules. Moreover, γ-tubulin has been found to be over-expressed in many cancer types, such as carcinomas of the breast and glioblastoma multiforme. These studies have led to immense interest in the identification of chemical leads that might interact with γ-tubulin and disrupt its function in order to explore γ-tubulin as potential chemotherapeutic target. Recently a colchicine-interacting cavity was identified at the interface of γ-tubulin dimer that might also interact with other similar compounds. In the same direction we theoretically investigated binding of a class of compounds, noscapinoids (noscapine and its derivatives) at the interface of the γ-tubulin dimer. Molecular interaction of noscapine and two of its derivatives, amino-noscapine and bromo-noscapine, was investigated by molecular docking, molecular dynamics simulation and binding free energy calculation. All noscapinoids displayed stable interaction throughout simulation of 25 ns. The predictive binding free energy (ΔGbind) indicates that noscapinoids bind strongly with the γ-tubulin dimer. However, bromo-noscapine showed the best binding affinity (ΔGbind = -37.6 kcal/mol) followed by noscapine (ΔGbind = -29.85 kcal/mol) and amino-noscapine (ΔGbind = -23.99 kcal/mol) using the MM-PBSA method. Similarly using the MM-GBSA method, bromo-noscapine showed highest binding affinity (ΔGbind = -43.64 kcal/mol) followed by amino-noscapine (ΔGbind = -37.56 kcal/mol) and noscapine (ΔGbind = -34.57 kcal/mol). The results thus generate compelling evidence that these noscapinoids may hold great potential for preclinical and clinical evaluation. PMID:26274780

  11. Nuclear Factor 90 uses an ADAR2-like binding mode to recognize specific bases in dsRNA

    OpenAIRE

    Jayachandran, Uma; Grey, Heather; Cook, Atlanta

    2016-01-01

    Nuclear factors 90 and 45 (NF90 and NF45) form a protein complex involved in the posttranscriptional control of many genes in vertebrates. NF90 is a member of the dsRNA binding domain (dsRBD) family of proteins. RNA binding partners identified so far include elements in 3' untranslated regions of specific mRNAs and several noncoding RNAs. In NF90, a tandem pair of dsRBDs separated by a natively unstructured segment confers dsRNA binding activity. We determined a crystal structure of the tande...

  12. Nuclear factor 90 uses an ADAR2-like binding mode to recognize specific bases in dsRNA

    OpenAIRE

    Jayachandran, Uma; Grey, Heather; Cook, Atlanta

    2015-01-01

    Nuclear factors 90 and 45 (NF90 and NF45) form a protein complex involved in the post-transcriptional control of many genes in vertebrates. NF90 is a member of the dsRNA binding domain (dsRBD) family of proteins. RNA binding partners identified so far include elements in 3′ untranslated regions of specific mRNAs and several non-coding RNAs. In NF90, a tandem pair of dsRBDs separated by a natively unstructured segment confers dsRNA binding activity. We determined a crystal structure of the tan...

  13. Positron emission tomography displacement sensitivity: predicting binding potential change for positron emission tomography tracers based on their kinetic characteristics.

    Science.gov (United States)

    Morris, Evan D; Yoder, Karmen K

    2007-03-01

    There is great interest in positron emission tomography (PET) as a noninvasive assay of fluctuations in synaptic neurotransmitter levels, but questions remain regarding the optimal choice of tracer for such a task. A mathematical method is proposed for predicting the utility of any PET tracer as a detector of changes in the concentration of an endogenous competitor via displacement of the tracer (a.k.a., its 'vulnerability' to competition). The method is based on earlier theoretical work by Endres and Carson and by the authors. A tracer-specific predictor, the PET Displacement Sensitivity (PDS), is calculated from compartmental model simulations of the uptake and retention of dopaminergic radiotracers in the presence of transient elevations of dopamine (DA). The PDS predicts the change in binding potential (DeltaBP) for a given change in receptor occupancy because of binding by the endogenous competitor. Simulations were performed using estimates of tracer kinetic parameters derived from the literature. For D(2)/D(3) tracers, the calculated PDS indices suggest a rank order for sensitivity to displacement by DA as follows: raclopride (highest sensitivity), followed by fallypride, FESP, FLB, NMSP, and epidepride (lowest). Although the PDS takes into account the affinity constant for the tracer at the binding site, its predictive value cannot be matched by either a single equilibrium constant, or by any one rate constant of the model. Values for DeltaBP have been derived from published studies that employed comparable displacement paradigms with amphetamine and a D(2)/D(3) tracer. The values are in good agreement with the PDS-predicted rank order of sensitivity to displacement. PMID:16788713

  14. 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 ...

  15. Predictions of mixed mode interface crack growth using a cohesive zone model for ductile fracture

    DEFF Research Database (Denmark)

    Tvergaard, Viggo

    2004-01-01

    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......Special interface elements that account for ductile failure by the nucleation and growth of voids to coalescence are used to analyse crack growth. In these elements the stress component tangential to the interface is accounted for, as determined by the requirement of compatibility with the...

  16. 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.

  17. Ligand binding mode to duplex and triplex DNA assessed by combining electrospray tandem mass spectrometry and molecular modeling

    OpenAIRE

    Rosu, Frédéric; Nguyen, Chi-Hung; De Pauw, Edwin; Gabelica, Valérie

    2007-01-01

    In this paper, we report the analysis of seven benzopyridoindole and benzopyridoquinoxaline drugs binding to different duplex DNA and triple helical DNA, using an approach combining electrospray ionization mass spectrometry (ESI-MS), tandem mass spectrometry (MS/MS), and molecular modeling. The ligands were ranked according to the collision energy (CE(50)) necessary to dissociate 50% of the complex with the duplex or the triplex in tandem MS. To determine the probable ligand binding site and ...

  18. Streambed microstructure predicts evolution of development and life history mode in the plethodontid salamander Eurycea tynerensis

    Directory of Open Access Journals (Sweden)

    Bonett Ronald M

    2006-03-01

    Full Text Available Abstract Background Habitat variation strongly influences the evolution of developmentally flexible traits, and may drive speciation and diversification. The plethodontid salamander Eurycea tynerensis is endemic to the geologically diverse Ozark Plateau of south-central North America, and comprises both strictly aquatic paedomorphic populations (achieving reproductive maturity while remaining in the larval form and more terrestrial metamorphic populations. The switch between developmental modes has occurred many times, but populations typically exhibit a single life history mode. This unique system offers an opportunity to study the specific ecological circumstances under which alternate developmental and life history modes evolve. We use phylogenetic independent contrasts to test for relationships between a key microhabitat feature (streambed sediment and this major life history polymorphism. Results We find streambed microstructure (sediment particle size, type and degree of sorting to be highly correlated with life-history mode. Eurycea tynerensis is paedomorphic in streams containing large chert gravel, but metamorphoses in nearby streams containing poorly sorted, clastic material such as sandstone or siltstone. Conclusion Deposits of large chert gravel create loosely associated streambeds, which provide access to subsurface water during dry summer months. Conversely, streambeds composed of more densely packed sandstone and siltstone sediments leave no subterranean refuge when surface water dries, presumably necessitating metamorphosis and use of terrestrial habitats. This represents a clear example of the relationship between microhabitat structure and evolution of a major developmental and life history trait, and has broad implications for the role of localized ecological conditions on larger-scale evolutionary processes.

  19. Habit, information acquisition, and the prediction of travel mode choice behavior

    NARCIS (Netherlands)

    Verplanken, B.

    1996-01-01

    Three studies examined the role of habit in travel mode choices. Habit was measured by using mental representations of activities that may include the target behavior. Using behavioral process-tracing paradigms, it was found that habit attenuates not only the elaborateness of information acquisition

  20. 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...

  1. 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

    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 on the obse...

  2. Common mode EMI prediction and research in induction motor for electric vehicles

    Science.gov (United States)

    Gao, Yinhan; Wang, Juxian; Yang, Kaiyu; Wang, Tianhao; An, Zhanyang

    2015-02-01

    This paper presents an equivalent circuit of high frequency voltage-controlled switch model of IGBT, and a surge voltage absorption circuit as well. This model can not only significantly reduce the surge voltage, decrease EMI noise, but also obviously inhibit common mode voltage towards the DC power mains.

  3. Interplay between magnetism and energetics in Fe-Cr alloys from a predictive noncollinear magnetic tight-binding model

    Science.gov (United States)

    Soulairol, R.; Barreteau, C.; Fu, Chu-Chun

    2016-07-01

    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 to be particularly promising if the size difference between the alloying elements is rather small and the electronic properties prevail.

  4. 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...

  5. 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. PMID:26901629

  6. Revealing the binding modes and the unbinding of 14-3-3σ proteins and inhibitors by computational methods.

    Science.gov (United States)

    Hu, Guodong; Cao, Zanxia; Xu, Shicai; Wang, Wei; Wang, Jihua

    2015-01-01

    The 14-3-3σ proteins are a family of ubiquitous conserved eukaryotic regulatory molecules involved in the regulation of mitogenic signal transduction, apoptotic cell death, and cell cycle control. A lot of small-molecule inhibitors have been identified for 14-3-3 protein-protein interactions (PPIs). In this work, we carried out molecular dynamics (MD) simulations combined with molecular mechanics generalized Born surface area (MM-GBSA) method to study the binding mechanism between a 14-3-3σ protein and its eight inhibitors. The ranking order of our calculated binding free energies is in agreement with the experimental results. We found that the binding free energies are mainly from interactions between the phosphate group of the inhibitors and the hydrophilic residues. To improve the binding free energy of Rx group, we designed the inhibitor R9 with group R9 = 4-hydroxypheny. However, we also found that the binding free energy of inhibitor R9 is smaller than that of inhibitor R1. By further using the steer molecular dynamics (SMD) simulations, we identified a new hydrogen bond between the inhibitor R8 and residue Arg64 in the pulling paths. The information obtained from this study may be valuable for future rational design of novel inhibitors, and provide better structural understanding of inhibitor binding to 14-3-3σ proteins. PMID:26568041

  7. 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.

  8. Urinary liver-type fatty acid-binding protein predicts adverse outcomes in acute kidney injury

    OpenAIRE

    Ferguson, Michael A.; Vaidya, Vishal S.; Waikar, Sushrut S.; Collings, Fitz B.; Sunderland, Kelsey E.; Gioules, Costas J.; Bonventre, Joseph V.

    2009-01-01

    Acute kidney injury (AKI) is a common condition with significant associated morbidity and mortality. The insensitivity and non-specificity of traditional markers of renal dysfunction prevent timely diagnosis, estimation of the severity of renal injury, and the administration of possible therapeutic agents. Here, we determine the prognostic ability of urinary liver-type fatty acid-binding protein (L-FABP), and further characterize its sensitivity and specificity as a biomarker of AKI. Initial ...

  9. Seasonal difference in brain serotonin transporter binding predicts symptom severity in patients with seasonal affective disorder.

    Science.gov (United States)

    Mc Mahon, Brenda; Andersen, Sofie B; Madsen, Martin K; Hjordt, Liv V; Hageman, Ida; Dam, Henrik; Svarer, Claus; da Cunha-Bang, Sofi; Baaré, William; Madsen, Jacob; Hasholt, Lis; Holst, Klaus; Frokjaer, Vibe G; Knudsen, Gitte M

    2016-05-01

    Cross-sectional neuroimaging studies in non-depressed individuals have demonstrated an inverse relationship between daylight minutes and cerebral serotonin transporter; this relationship is modified by serotonin-transporter-linked polymorphic region short allele carrier status. We here present data from the first longitudinal investigation of seasonal serotonin transporter fluctuations in both patients with seasonal affective disorder and in healthy individuals. Eighty (11)C-DASB positron emission tomography scans were conducted to quantify cerebral serotonin transporter binding; 23 healthy controls with low seasonality scores and 17 patients diagnosed with seasonal affective disorder were scanned in both summer and winter to investigate differences in cerebral serotonin transporter binding across groups and across seasons. The two groups had similar cerebral serotonin transporter binding in the summer but in their symptomatic phase during winter, patients with seasonal affective disorder had higher serotonin transporter than the healthy control subjects (P = 0.01). Compared to the healthy controls, patients with seasonal affective disorder changed their serotonin transporter significantly less between summer and winter (P sex- (P = 0.02) and genotype- (P = 0.04) dependent. In the patients with seasonal affective disorder, the seasonal change in serotonin transporter binding was positively associated with change in depressive symptom severity, as indexed by Hamilton Rating Scale for Depression - Seasonal Affective Disorder version scores (P = 0.01). Our findings suggest that the development of depressive symptoms in winter is associated with a failure to downregulate serotonin transporter levels appropriately during exposure to the environmental stress of winter, especially in individuals with high predisposition to affective disorders.media-1vid110.1093/brain/aww043_video_abstractaww043_video_abstract. PMID:26994750

  10. Seasonal difference in brain serotonin transporter binding predicts symptom severity in patients with seasonal affective disorder

    DEFF Research Database (Denmark)

    Mc Mahon, Brenda; Andersen, Sofie B; Madsen, Martin K.;

    2016-01-01

    between summer and winter (P sex- (P = 0.02) and genotype- (P = 0.04) dependent. In the patients with seasonal affective disorder, the seasonal change in serotonin transporter binding was positively associated with change in depressive symptom...... to the environmental stress of winter, especially in individuals with high predisposition to affective disorders.media-1vid110.1093/brain/aww043_video_abstractaww043_video_abstract....

  11. Surface plasmon resonance imaging reveals multiple binding modes of Agrobacterium transformation mediator VirE2 to ssDNA.

    Science.gov (United States)

    Kim, Sanghyun; Zbaida, David; Elbaum, Michael; Leh, Hervé; Nogues, Claude; Buckle, Malcolm

    2015-07-27

    VirE2 is the major secreted protein of Agrobacterium tumefaciens in its genetic transformation of plant hosts. It is co-expressed with a small acidic chaperone VirE1, which prevents VirE2 oligomerization. After secretion into the host cell, VirE2 serves functions similar to a viral capsid in protecting the single-stranded transferred DNA en route to the nucleus. Binding of VirE2 to ssDNA is strongly cooperative and depends moreover on protein-protein interactions. In order to isolate the protein-DNA interactions, imaging surface plasmon resonance (SPRi) studies were conducted using surface-immobilized DNA substrates of length comparable to the protein-binding footprint. Binding curves revealed an important influence of substrate rigidity with a notable preference for poly-T sequences and absence of binding to both poly-A and double-stranded DNA fragments. Dissociation at high salt concentration confirmed the electrostatic nature of the interaction. VirE1-VirE2 heterodimers also bound to ssDNA, though by a different mechanism that was insensitive to high salt. Neither VirE2 nor VirE1-VirE2 followed the Langmuir isotherm expected for reversible monomeric binding. The differences reflect the cooperative self-interactions of VirE2 that are suppressed by VirE1. PMID:26044711

  12. 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...

  13. Development of classification model and QSAR model for predicting binding affinity of endocrine disrupting chemicals to human sex hormone-binding globulin.

    Science.gov (United States)

    Liu, Huihui; Yang, Xianhai; Lu, Rui

    2016-08-01

    Disturbing the transport process is a crucial pathway for endocrine disrupting chemicals (EDCs) to disrupt endocrine function. However, this mechanism has not gotten enough attention, compared with that of hormone receptors and synthetase up to now, especially for the sex hormone transport process. In this study, we selected sex hormone-binding globulin (SHBG) and EDCs as a model system and the relative competing potency of a chemical with testosterone binding to SHBG (log RBA) as the endpoints, to develop classification models and quantitative structure-activity relationship (QSAR) models. With the classification model, a satisfactory model with nR09, nR10 and RDF155v as the most relevant variables was screened. Statistic results indicated that the model had the sensitivity, specificity, accuracy of 86.4%, 80.0%, 84.4% and 85.7%, 87.5%, 86.2% for the training set and validation set, respectively, highlighting a high classification performance of the model. With the QSAR model, a satisfactory model with statistical parameters, specifically, an adjusted determination coefficient (Radj(2)) of 0.810, a root mean square error (RMSE) of 0.616, a leave-one-out cross-validation squared correlation coefficient (QLOO(2)) of 0.777, a bootstrap method (QBOOT(2)) of 0.756, an external validation coefficient (Qext(2)) of 0.544 and a RMSEext of 0.859, were obtained, which implied satisfactory goodness of fit, robustness and predictive ability. The applicability domain of the current model covers a large number of structurally diverse chemicals, especially a few classes of nonsteroidal compounds. PMID:27156209

  14. 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.

  15. 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

    of hydrogen/deuterium exchange mass spectrometry (HDX-MS) to characterize interactions of low affinity peptides with their cognate protein targets. The HDX-MS workflow was optimized to accurately detect low-affinity peptide-protein interactions by use of ion mobility, electron transfer dissociation, non...... of KDM4C, indicating distinct binding modes. In contrast, the perturbation site of another PD-selected peptide inhibiting the function of KDM1A maps to a GST-tag. Our results demonstrate that HDX-MS can validate and map weak peptide-protein interactions, and pave the way for understanding and optimizing...

  16. Prediction of striatal D2 receptor binding by DRD2/ANKK1 TaqIA allele status.

    Science.gov (United States)

    Eisenstein, Sarah A; Bogdan, Ryan; Love-Gregory, Latisha; Corral-Frías, Nadia S; Koller, Jonathan M; Black, Kevin J; Moerlein, Stephen M; Perlmutter, Joel S; Barch, Deanna M; Hershey, Tamara

    2016-10-01

    In humans, the A1 (T) allele of the dopamine (DA) D2 receptor/ankyrin repeat and kinase domain containing 1 (DRD2/ANKK1) TaqIA (rs1800497) single nucleotide polymorphism has been associated with reduced striatal DA D2/D3 receptor (D2/D3R) availability. However, radioligands used to estimate D2/D3R are displaceable by endogenous DA and are nonselective for D2R, leaving the relationship between TaqIA genotype and D2R specific binding uncertain. Using the positron emission tomography (PET) radioligand, (N-[(11) C]methyl)benperidol ([(11) C]NMB), which is highly selective for D2R over D3R and is not displaceable by endogenous DA, the current study examined whether DRD2/ANKK1 TaqIA genotype predicts D2R specific binding in two independent samples. Sample 1 (n = 39) was composed of obese and nonobese adults; sample 2 (n = 18) was composed of healthy controls, unmedicated individuals with schizophrenia, and siblings of individuals with schizophrenia. Across both samples, A1 allele carriers (A1+) had 5 to 12% less striatal D2R specific binding relative to individuals homozygous for the A2 allele (A1-), regardless of body mass index or diagnostic group. This reduction is comparable to previous PET studies of D2/D3R availability (10-14%). The pooled effect size for the difference in total striatal D2R binding between A1+ and A1- was large (0.84). In summary, in line with studies using displaceable D2/D3R radioligands, our results indicate that DRD2/ANKK1 TaqIA allele status predicts striatal D2R specific binding as measured by D2R-selective [(11) C]NMB. These findings support the hypothesis that DRD2/ANKK1 TaqIA allele status may modify D2R, perhaps conferring risk for certain disease states. PMID:27241797

  17. Prediction of binding affinity and efficacy of thyroid hormone receptor ligands using QSAR and structure-based modeling methods

    International Nuclear Information System (INIS)

    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 R2 = 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 (R2 = 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 prediction of both

  18. 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

  19. 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

  20. 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.

  1. 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...

  2. 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.

  3. 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

  4. 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.

  5. 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.

  6. Markov chain modelling of reliability analysis and prediction under mixed mode loading

    Science.gov (United States)

    Singh, Salvinder; Abdullah, Shahrum; Nik Mohamed, Nik Abdullah; Mohd Noorani, Mohd Salmi

    2015-03-01

    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.

  7. Transmission mode predicts specificity and interaction patterns in coral-Symbiodinium networks.

    Directory of Open Access Journals (Sweden)

    Nicholas S Fabina

    Full Text Available Most reef-building corals in the order Scleractinia depend on endosymbiotic algae in the genus Symbiodinium for energy and survival. Significant levels of taxonomic diversity in both partners result in numerous possible combinations of coral-Symbiodinium associations with unique functional characteristics. We created and analyzed the first coral-Symbiodinium networks utilizing a global dataset of interaction records from coral reefs in the tropical Indo-Pacific and Atlantic Oceans for 1991 to 2010. Our meta-analysis reveals that the majority of coral species and Symbiodinium types are specialists, but failed to detect any one-to-one obligate relationships. Symbiont specificity is correlated with a host's transmission mode, with horizontally transmitting corals being more likely to interact with generalist symbionts. Globally, Symbiodinium types tend to interact with only vertically or horizontally transmitting corals, and only a few generalist types are found with both. Our results demonstrate a strong correlation between symbiont specificity, symbiont transmission mode, and community partitioning. The structure and dynamics of these network interactions underlie the fundamental biological partnership that determines the condition and resilience of coral reef ecosystems.

  8. Predicting the response of aquatic invertebrates to stress using species traits and stressor mode of action

    NARCIS (Netherlands)

    Rubach, M.N.

    2010-01-01

    How much stress can one take? It depends, on the combination of your mental and physical characteristics (traits), but it’s hard to predict. Chemicals can have devastating effects on ecosystems and they can cause stress in animals and plants. Thus, their risk for ecosystem health needs to be assesse

  9. 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....

  10. 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...... with low estimated binding energies corresponded to relatively large RMS differences when aligned with the corresponding crystal structure. Secondly, the inhibitors were docked to their parent protein structures in which they were cocrystallized. In this case, there was a good correlation between low...

  11. Fast Intra and Inter Prediction Mode Decision of H.264/AVC for Medical Image Compression Based on Region of Interest

    Directory of Open Access Journals (Sweden)

    Mehdi Jafari

    2012-01-01

    Full Text Available This paper aims at applying H.264 in medical video compression applications and improving the H.264 Compression performance with better perceptual quality and low coding complexity. In order to achieve higher compression of medical video, while maintaining high image quality in the region of interest, with low coding complexity, here we propose a new model using H.264/AVC that uses lossless compression in the region of interest, and very high rate, lossy compression in other regions. This paper proposes a new method to achieve fast intra and inter prediction mode decision that is based on coarse macroblocks for intra and inter prediction mode decision of the background region and finer macroblocks for region of interest. Also the macroblocks of the background region are encoded with the maximum quantization parameter allowed by H.264/AVC in order to maximize the number of null coefficients. Experimental results show that the proposed algorithm achieves a higher compression rate on medical videos with a higher quality of region of interest with low coding complexity when compared to our previous algorithm and other standard algorithms reported in the literature.

  12. 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.

  13. 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.

  14. One target-two different binding modes: structural insights into gevokizumab and canakinumab interactions to interleukin-1β.

    Science.gov (United States)

    Blech, Michaela; Peter, Daniel; Fischer, Peter; Bauer, Margit M T; Hafner, Mathias; Zeeb, Markus; Nar, Herbert

    2013-01-01

    Interleukin-1β (IL-1β) is a key orchestrator in inflammatory and several immune responses. IL-1β exerts its effects through interleukin-1 receptor type I (IL-1RI) and interleukin-1 receptor accessory protein (IL-1RAcP), which together form a heterotrimeric signaling-competent complex. Canakinumab and gevokizumab are highly specific IL-1β monoclonal antibodies. Canakinumab is known to neutralize IL-1β by competing for binding to IL-1R and therefore blocking signaling by the antigen:antibody complex. Gevokizumab is claimed to be a regulatory therapeutic antibody that modulates IL-1β bioactivity by reducing the affinity for its IL-1RI:IL-1RAcP signaling complex. How IL-1β signaling is affected by both canakinumab and gevokizumab was not yet experimentally determined. We have analyzed the crystal structures of canakinumab and gevokizumab antibody binding fragment (Fab) as well as of their binary complexes with IL-1β. Furthermore, we characterized the epitopes on IL-1β employed by the antibodies by NMR epitope mapping studies. The direct comparison of NMR and X-ray data shows that the epitope defined by the crystal structure encompasses predominantly those residues whose NMR resonances are severely perturbed upon complex formation. The antigen:Fab co-structures confirm the previously identified key contact residues on IL-1β and provide insight into the mechanisms leading to their distinct modulation of IL-1β signaling. A significant steric overlap of the binding interfaces of IL-1R and canakinumab on IL-1β causes competitive inhibition of the association of IL-1β and its receptor. In contrast, gevokizumab occupies an allosteric site on IL-1β and complex formation results in a minor reduction of binding affinity to IL-1RI. This suggests two different mechanisms of IL-1β pathway attenuation. PMID:23041424

  15. Predictive Models for Halogen-bond Basicity of Binding Sites of Polyfunctional Molecules.

    Science.gov (United States)

    Glavatskikh, Marta; Madzhidov, Timur; Solov'ev, Vitaly; Marcou, Gilles; Horvath, Dragos; Graton, Jérôme; Le Questel, Jean-Yves; Varnek, Alexandre

    2016-02-01

    Halogen bonding (XB) strength assesses the ability of an electron-enriched group to be involved in complexes with polarizable electrophilic halogenated or diatomic halogen molecules. Here, we report QSPR models of XB of particular relevance for an efficient screening of large sets of compounds. The basicity is described by pKBI2 , the decimal logarithm of the experimental 1 : 1 (B : I2 ) complexation constant K of organic compounds (B) with diiodine (I2 ) as a reference halogen-bond donor in alkanes at 298 K. Modeling involved ISIDA fragment descriptors, using SVM and MLR methods on a set of 598 organic compounds. Developed models were then challenged to make predictions for an external test set of 11 polyfunctional compounds for which unambiguous assignment of the measured effective complexation constant to specific groups out of the putative acceptor sites is not granted. At this stage, developed models were used to predict pKBI2 of all putative acceptor sites, followed by an estimation of the predicted effective complexation constant using the ChemEqui program. The best consensus models perform well both in cross-validation (root mean squared error RMSE=0.39-0.47 logKBI2 units) and external predictions (RMSE=0.49). The SVM models are implemented on our website (http://infochim.u-strasbg.fr/webserv/VSEngine.html) together with the estimation of their applicability domain and an automatic detection of potential halogen-bond acceptor atoms. PMID:27491792

  16. 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

  17. 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.

  18. 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.

  19. Bispyrimidines as potent histamine H(4) receptor ligands: delineation of structure-activity relationships and detailed H(4) receptor binding mode.

    Science.gov (United States)

    Engelhardt, Harald; Schultes, Sabine; de Graaf, Chris; Nijmeijer, Saskia; Vischer, Henry F; Zuiderveld, Obbe P; Dobler, Julia; Stachurski, Katharina; Mayer, Moriz; Arnhof, Heribert; Scharn, Dirk; Haaksma, Eric E J; de Esch, Iwan J P; Leurs, Rob

    2013-06-13

    The basic methylpiperazine moiety is considered a necessary substructure for high histamine H4 receptor (H4R) affinity. This moiety is however also the metabolic hot spot for various classes of H4R ligands (e.g., indolcarboxamides and pyrimidines). We set out to investigate whether mildly basic 2-aminopyrimidines in combination with the appropriate linker can serve as a replacement for the methylpiperazine moiety. In the series of 2-aminopyrimidines, the introduction of an additional 2-aminopyrimidine moiety in combination with the appropriate linker lead to bispyrimidines displaying pKi values for binding the human H4R up to 8.2. Furthermore, the methylpiperazine replacement results in compounds with improved metabolic properties. The attempt to transfer the knowledge generated in the class of bispyrimidines to the indolecarboxamides failed. Combining the derived structure-activity relationships with homology modeling leads to new detailed insights in the molecular aspects of ligand-H4R binding in general and the binding mode of the described bispyrimidines in specific. PMID:23668417

  20. 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.

  1. Quantitative structure-property relationships modeling to predict in vitro and in vivo binding of drugs to the bile sequestrant, colesevelam (Welchol).

    Science.gov (United States)

    Walker, Joseph R; Brown, Karen; Rohatagi, Shashank; Bathala, Mohinder S; Xu, Chao; Wickremasingha, Prachi K; Salazar, Daniel E; Mager, Donald E

    2009-10-01

    Quantitative structure-property relationship (QSPR) models were developed to correlate physicochemical properties of structurally unrelated drugs with extent of in vitro binding to colesevelam, and predicted values were compared with drug exposure changes in vivo following coadministration. The binding of 17 drugs to colesevelam was determined by an in vitro dissolution drug-binding assay. Data from several clinical studies in healthy volunteers to support administration of colesevelam in diabetic patients were also collected along with existing in vivo literature data and compared with in vitro results. Steric, electronic, and hydrophobic descriptors were calculated for test compounds, and univariate and partial least squares regression approaches were used to derive QSPR models to evaluate which of the molecular descriptors correlated best with in vitro binding. A quadrant analysis evaluated the correlation between predicted/actual in vitro binding results and the in vivo data. The in vitro binding assay exhibited high sensitivity, identifying those compounds with a low probability of producing relevant in vivo drug interactions. Drug lipophilicity was identified as the primary determinant of in vitro binding to colesevelam by the final univariate and partial least squares models (R(2) = 0.69 and 0.98; Q(2) = 0.48 and 0.59). The in vitro assay and in silico models represent predictive tools that may allow investigators to conduct only informative clinical drug interaction studies with colesevelam.

  2. 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.

  3. Static and dynamic posterior cingulate cortex nodal topology of default mode network predicts attention task performance.

    Science.gov (United States)

    Lin, Pan; Yang, Yong; Jovicich, Jorge; De Pisapia, Nicola; Wang, Xiang; Zuo, Chun S; Levitt, James Jonathan

    2016-03-01

    Characterization of the default mode network (DMN) as a complex network of functionally interacting dynamic systems has received great interest for the study of DMN neural mechanisms. In particular, understanding the relationship of intrinsic resting-state DMN brain network with cognitive behaviors is an important issue in healthy cognition and mental disorders. However, it is still unclear how DMN functional connectivity links to cognitive behaviors during resting-state. In this study, we hypothesize that static and dynamic DMN nodal topology is associated with upcoming cognitive task performance. We used graph theory analysis in order to understand better the relationship between the DMN functional connectivity and cognitive behavior during resting-state and task performance. Nodal degree of the DMN was calculated as a metric of network topology. We found that the static and dynamic posterior cingulate cortex (PCC) nodal degree within the DMN was associated with task performance (Reaction Time). Our results show that the core node PCC nodal degree within the DMN was significantly correlated with reaction time, which suggests that the PCC plays a key role in supporting cognitive function. PMID:25904156

  4. 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.

  5. 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

  6. Time-Perception Network and Default Mode Network Are Associated with Temporal Prediction in a Periodic Motion Task.

    Science.gov (United States)

    Carvalho, Fabiana M; Chaim, Khallil T; Sanchez, Tiago A; de Araujo, Draulio B

    2016-01-01

    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 functional magnetic resonance imaging (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 (DMPFC), anterior cingulate cortex (ACC), and bilateral posterior cingulate cortex/precuneus (PCC/PC). It suggests that the DMN plays a role in processing contextually expected information and supports recent evidence that the DMN may

  7. The Crystal Structure of the C-Terminal Domain of the Salmonella enterica PduO Protein: An Old Fold with a New Heme-Binding Mode.

    Science.gov (United States)

    Ortiz de Orué Lucana, Darío; Hickey, Neal; Hensel, Michael; Klare, Johann P; Geremia, Silvano; Tiufiakova, Tatiana; Torda, Andrew E

    2016-01-01

    The two-domain protein PduO, involved in 1,2-propanediol utilization in the pathogenic Gram-negative bacterium Salmonella enterica is an ATP:Cob(I)alamin adenosyltransferase, but this is a function of the N-terminal domain alone. The role of its C-terminal domain (PduOC) is, however, unknown. In this study, comparative growth assays with a set of Salmonella mutant strains showed that this domain is necessary for effective in vivo catabolism of 1,2-propanediol. It was also shown that isolated, recombinantly-expressed PduOC binds heme in vivo. The structure of PduOC co-crystallized with heme was solved (1.9 Å resolution) showing an octameric assembly with four heme moieities. The four heme groups are highly solvent-exposed and the heme iron is hexa-coordinated with bis-His ligation by histidines from different monomers. Static light scattering confirmed the octameric assembly in solution, but a mutation of the heme-coordinating histidine caused dissociation into dimers. Isothermal titration calorimetry using the PduOC apoprotein showed strong heme binding (K d = 1.6 × 10(-7) M). Biochemical experiments showed that the absence of the C-terminal domain in PduO did not affect adenosyltransferase activity in vitro. The evidence suggests that PduOC:heme plays an important role in the set of cobalamin transformations required for effective catabolism of 1,2-propanediol. Salmonella PduO is one of the rare proteins which binds the redox-active metabolites heme and cobalamin, and the heme-binding mode of the C-terminal domain differs from that in other members of this protein family. PMID:27446048

  8. Structure of Chlorobium tepidum sepiapterin reductase complex reveals the novel substrate binding mode for stereospecific production of L-threo-tetrahydrobiopterin.

    Science.gov (United States)

    Supangat, Supangat; Seo, Kyung Hye; Choi, Yong Kee; Park, Young Shik; Son, Daeyoung; Han, Chang-deok; Lee, Kon Ho

    2006-01-27

    Sepiapterin reductase (SR) is involved in the last step of tetrahydrobiopterin (BH(4)) biosynthesis by reducing the di-keto group of 6-pyruvoyl tetrahydropterin. Chlorobium tepidum SR (cSR) generates a distinct BH(4) product, L-threo-BH(4) (6R-(1'S,2'S)-5,6,7,8-BH(4)), whereas animal enzymes produce L-erythro-BH(4) (6R-(1'R,2'S)-5,6,7,8-BH(4)) although it has high amino acid sequence similarities to the other animal enzymes. To elucidate the structural basis for the different reaction stereospecificities, we have determined the three-dimensional structures of cSR alone and complexed with NADP and sepiapterin at 2.1 and 1.7 A resolution, respectively. The overall folding of the cSR, the binding site for the cofactor NADP(H), and the positions of active site residues were quite similar to the mouse and the human SR. However, significant differences were found in the substrate binding region of the cSR. In comparison to the mouse SR complex, the sepiapterin in the cSR is rotated about 180 degrees around the active site and bound between two aromatic side chains of Trp-196 and Phe-99 so that its pterin ring is shifted to the opposite side, but its side chain position is not changed. The swiveled sepiapterin binding results in the conversion of the side chain configuration, exposing the opposite face for hydride transfer from NADPH. The different sepiapterin binding mode within the conserved catalytic architecture presents a novel strategy of switching the reaction stereospecificities in the same protein fold. PMID:16308317

  9. 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.

  10. Mannose binding lectin (MBL levels predict lung function decline in severe asthma

    Directory of Open Access Journals (Sweden)

    Ilonka. H. van Veen

    2006-12-01

    Full Text Available There is increasing evidence that activation of the complement system in asthma contributes to ongoing inflammation, tissue damage and airway remodeling. Mannose binding lectin (MBL is a pattern recognition molecule that serves as the key mediator of the lectin pathway of complement activation. MBL levels are genetically determined and vary widely amongst individuals. In the present study we hypothesized that high MBL levels in asthma are associated with increased loss of lung function over time, as a consequence of inflammatory tissue damage. We measured serum MBL levels by ELISA in 68 patients with severe asthma and prospectively determined the change in post-bronchodilator (pb FEV1 over a mean period of 5.7 years. The relationship between MBL and change in pbFEV1 (FEV1 was analysed using (multiple regression analysis and corrected for possible confounders (age, sex, age of onset, asthma duration, and pbFEV1. The median (range MBL level was 332 (10.8-3587 ng·ml–1. MBL was significantly associated with FEV1 (p<0.04. Patients with a high MBL level (332 ng·ml–1 had an increased risk of lung function decline compared to those with low MBL levels (OR (CI: 3.16 (1.14-8.79, p = 0.027; the excess decline being 42 ml·yr–1 (p = 0.01. We conclude that a high MBL level is associated with an increased decline in lung function in patients with severe asthma. MBL might provide a clue towards better understanding of the pathophysiology of ongoing inflammation and subsequent decline in lung function of patients with severe asthma.

  11. 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.

  12. Crystal structure and mutational study of RecOR provide insight into its mode of DNA binding.

    Science.gov (United States)

    Timmins, Joanna; Leiros, Ingar; McSweeney, Sean

    2007-07-11

    The crystal structure of the complex formed between Deinococcus radiodurans RecR and RecO (drRecOR) has been determined. In accordance with previous biochemical characterisation, the drRecOR complex displays a RecR:RecO molecular ratio of 2:1. The biologically relevant drRecOR entity consists of a heterohexamer in the form of two drRecO molecules positioned on either side of the tetrameric ring of drRecR, with their OB (oligonucleotide/oligosaccharide-binding) domains pointing towards the interior of the ring. Mutagenesis studies validated the protein-protein interactions observed in the crystal structure and allowed mapping of the residues in the drRecOR complex required for DNA binding. Furthermore, the preferred DNA substrate of drRecOR was identified as being 3'-overhanging DNA, as encountered at ssDNA-dsDNA junctions. Together these results suggest a possible mechanism for drRecOR recognition of stalled replication forks. PMID:17581636

  13. 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

    the polymorphic pocket residues in MHC molecules that are in close proximity to the peptide residue. For MHC molecules with known specificities, we established a library of pocket-residues and corresponding binding specificities. The binding specificity for a novel MHC molecule is calculated as the average...

  14. Prediction of Surface and pH-Specific Binding of Peptides to Metal and Oxide Nanoparticles

    Science.gov (United States)

    Heinz, Hendrik; Lin, Tzu-Jen; Emami, Fateme Sadat; Ramezani-Dakhel, Hadi; Naik, Rajesh; Knecht, Marc; Perry, Carole C.; Huang, Yu

    2015-03-01

    The mechanism of specific peptide adsorption onto metallic and oxidic nanostructures has been elucidated in atomic resolution using novel force fields and surface models in comparison to measurements. As an example, variations in peptide adsorption on Pd and Pt nanoparticles depending on shape, size, and location of peptides on specific bounding facets are explained. Accurate computational predictions of reaction rates in C-C coupling reactions using particle models derived from HE-XRD and PDF data illustrate the utility of computational methods for the rational design of new catalysts. On oxidic nanoparticles such as silica and apatites, it is revealed how changes in pH lead to similarity scores of attracted peptides lower than 20%, supported by appropriate model surfaces and data from adsorption isotherms. The results demonstrate how new computational methods can support the design of nanoparticle carriers for drug release and the understanding of calcification mechanisms in the human body.

  15. 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

  16. 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.

  17. 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.

  18. 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

  19. 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

    2016-08-01

    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. PMID:27427335

  20. 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

    2016-08-01

    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.

  1. Structural Insight into the DNA-Binding Mode of the Primosomal Proteins PriA, PriB, and DnaT

    Directory of Open Access Journals (Sweden)

    Yen-Hua Huang

    2014-01-01

    Full Text Available Replication restart primosome is a complex dynamic system that is essential for bacterial survival. This system uses various proteins to reinitiate chromosomal DNA replication to maintain genetic integrity after DNA damage. The replication restart primosome in Escherichia coli is composed of PriA helicase, PriB, PriC, DnaT, DnaC, DnaB helicase, and DnaG primase. The assembly of the protein complexes within the forked DNA responsible for reloading the replicative DnaB helicase anywhere on the chromosome for genome duplication requires the coordination of transient biomolecular interactions. Over the last decade, investigations on the structure and mechanism of these nucleoproteins have provided considerable insight into primosome assembly. In this review, we summarize and discuss our current knowledge and recent advances on the DNA-binding mode of the primosomal proteins PriA, PriB, and DnaT.

  2. DNABINDPROT: fluctuation-based predictor of DNA-binding residues within a network of interacting residues

    OpenAIRE

    Ozbek, Pemra; Soner, Seren; Erman, Burak; Haliloglu, Turkan

    2010-01-01

    DNABINDPROT is designed to predict DNA-binding residues, based on the fluctuations of residues in high-frequency modes by the Gaussian network model. The residue pairs that display high mean-square distance fluctuations are analyzed with respect to DNA binding, which are then filtered with their evolutionary conservation profiles and ranked according to their DNA-binding propensities. If the analyses are based on the exact outcome of fluctuations in the highest mode, using a conservation thre...

  3. Studies on 16α-Hydroxylation of Steroid Molecules and Regioselective Binding Mode in Homology-Modeled Cytochrome P450-2C11

    Science.gov (United States)

    Ali, Hamed I.; Yamada, Morio; Fujita, Yukihisa; Maeda, Mitsuko; Akaho, Eiichi

    2011-01-01

    We investigated the 16α-hydroxylation of steroid molecules and regioselective binding mode in homology-modeled cytochrome P450-2C11 to correlate the biological study with the computational molecular modeling. It revealed that there was a positive relationship between the observed inhibitory potencies and the binding free energies. Docking of steroid molecules into this homology-modeled CYP2C11 indicated that 16α-hydroxylation is favored with steroidal molecules possessing the following components, (1) a bent A-B ring configuration (5β-reduced), (2) C-3 α-hydroxyl group, (3) C-17β-acetyl group, and (4) methyl group at both the C-18 and C-19. These respective steroid components requirements were defined as the inhibitory contribution factor. Overall studies of the male rat CYP2C11 metabolism revealed that the above-mentioned steroid components requirements were essential to induce an effective inhibition of [3H]progesterone 16α-hydroxylation. As far as docking of homology-modeled CYP2C11 against investigated steroids is concerned, they are docked at the active site superimposed with flurbiprofen. It was also found that the distance between heme iron and C16α-H was between 4 to 6 Å and that the related angle was in the range of 180 ± 45°.

  4. 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.

  5. Insight into the binding mode and the structural features of the pyrimidine derivatives as human A2A adenosine receptor antagonists.

    Science.gov (United States)

    Zhang, Lihui; Liu, Tianjun; Wang, Xia; Wang, Jinan; Li, Guohui; Li, Yan; Yang, Ling; Wang, Yonghua

    2014-01-01

    The interaction of 278 monocyclic and bicyclic pyrimidine derivatives with human A2A adenosine receptor (AR) was investigated by employing molecular dynamics, thermodynamic analysis and three-dimensional quantitative structure-activity relationship (3D-QSAR) approaches. The binding analysis reveals that the pyrimidine derivatives are anchored in TM2, 3, 5, 6 and 7 of A2A AR by the aromatic stacking and hydrogen bonding interactions. The key residues involving Phe168, Glu169, and Asn253 stabilize the monocyclic and bicyclic cores of inhibitors. The thermodynamic analysis by molecular mechanics/Poisson Boltzmann surface area (MM-PBSA) approach also confirms the reasonableness of the binding modes. In addition, the ligand-/receptor-based comparative molecular similarity indices analysis (CoMSIA) models of high statistical significance were generated and the resulting contour maps correlate well with the structural features of the antagonists essential for high A2A AR affinity. A minor/bulky group with negative charge at C2/C6 of pyrimidine ring respectively enhances the activity for all these pyrimidine derivatives. Particularly, the higher electron density of the ring in the bicyclic derivatives, the more potent the antagonists. The obatined results might be helpful in rational design of novel candidate of A2A adenosine receptor antagonist for treatment of Parkinson's disease. PMID:23665268

  6. Studies on 16α-Hydroxylation of Steroid Molecules and Regioselective Binding Mode in Homology-Modeled Cytochrome P450-2C11

    Directory of Open Access Journals (Sweden)

    Hamed I. Ali

    2011-01-01

    Full Text Available We investigated the 16α-hydroxylation of steroid molecules and regioselective binding mode in homology-modeled cytochrome P450-2C11 to correlate the biological study with the computational molecular modeling. It revealed that there was a positive relationship between the observed inhibitory potencies and the binding free energies. Docking of steroid molecules into this homology-modeled CYP2C11 indicated that 16α-hydroxylation is favored with steroidal molecules possessing the following components, (1 a bent A-B ring configuration (5β-reduced, (2 C-3 α-hydroxyl group, (3 C-17β-acetyl group, and (4 methyl group at both the C-18 and C-19. These respective steroid components requirements were defined as the inhibitory contribution factor. Overall studies of the male rat CYP2C11 metabolism revealed that the above-mentioned steroid components requirements were essential to induce an effective inhibition of [3H]progesterone 16α-hydroxylation. As far as docking of homology-modeled CYP2C11 against investigated steroids is concerned, they are docked at the active site superimposed with flurbiprofen. It was also found that the distance between heme iron and C16α-H was between 4 to 6 Å and that the related angle was in the range of 180±45∘.

  7. Structures of mammalian ER α-glucosidase II capture the binding modes of broad-spectrum iminosugar antivirals.

    Science.gov (United States)

    Caputo, Alessandro T; Alonzi, Dominic S; Marti, Lucia; Reca, Ida-Barbara; Kiappes, J L; Struwe, Weston B; Cross, Alice; Basu, Souradeep; Lowe, Edward D; Darlot, Benoit; Santino, Angelo; Roversi, Pietro; Zitzmann, Nicole

    2016-08-01

    The biosynthesis of enveloped viruses depends heavily on the host cell endoplasmic reticulum (ER) glycoprotein quality control (QC) machinery. This dependency exceeds the dependency of host glycoproteins, offering a window for the targeting of ERQC for the development of broad-spectrum antivirals. We determined small-angle X-ray scattering (SAXS) and crystal structures of the main ERQC enzyme, ER α-glucosidase II (α-GluII; from mouse), alone and in complex with key ligands of its catalytic cycle and antiviral iminosugars, including two that are in clinical trials for the treatment of dengue fever. The SAXS data capture the enzyme's quaternary structure and suggest a conformational rearrangement is needed for the simultaneous binding of a monoglucosylated glycan to both subunits. The X-ray structures with key catalytic cycle intermediates highlight that an insertion between the +1 and +2 subsites contributes to the enzyme's activity and substrate specificity, and reveal that the presence of d-mannose at the +1 subsite renders the acid catalyst less efficient during the cleavage of the monoglucosylated substrate. The complexes with iminosugar antivirals suggest that inhibitors targeting a conserved ring of aromatic residues between the α-GluII +1 and +2 subsites would have increased potency and selectivity, thus providing a template for further rational drug design. PMID:27462106

  8. Dual binding mode of antithyroid drug methimazole to mammalian heme peroxidases - structural determination of the lactoperoxidase-methimazole complex at 1.97 Å resolution.

    Science.gov (United States)

    Singh, Rashmi Prabha; Singh, Avinash; Sirohi, Harsh Vardhan; Singh, Amit Kumar; Kaur, Punit; Sharma, Sujata; Singh, Tej P

    2016-07-01

    Lactoperoxidase (LPO, EC 1.11.1.7) is a member of the mammalian heme peroxidase family which also includes thyroid peroxidase (TPO). These two enzymes have a sequence homology of 76%. The structure of LPO is known but not that of TPO. In order to determine the mode of binding of antithyroid drugs to thyroid peroxidase, we have determined the crystal structure of LPO complexed with an antithyroid drug, methimazole (MMZ) at 1.97 Å resolution. LPO was isolated from caprine colostrum, purified to homogeneity and crystallized with 20% poly(ethylene glycol)-3350. Crystals of LPO were soaked in a reservoir solution containing MMZ. The structure determination showed the presence of two crystallographically independent molecules in the asymmetric unit. Both molecules contained one molecule of MMZ, but with different orientations. MMZ was held tightly between the heme moiety on one side and the hydrophobic parts of the side chains of Arg255, Glu258, and Leu262 on the opposite side. The back of the cleft contained the side chains of Gln105 and His109 which also interacted with MMZ. In both orientations, MMZ had identical buried areas and formed a similar number of interactions. It appears that the molecules of MMZ can enter the substrate-binding channel of LPO in two opposite orientations. But once they reach the distal heme pocket, their orientations are frozen due to equally tight packing of MMZ in both orientations. This is a novel example of an inhibitor binding to an enzyme with two orientations at the same site with nearly equal occupancies. PMID:27398304

  9. 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

    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...

  10. Mutational analysis of a predicted zinc-binding motif in the 26-kilodalton protein encoded by the vaccinia virus A2L gene: correlation of zinc binding with late transcriptional transactivation activity.

    OpenAIRE

    Keck, J G; Feigenbaum, F; B. Moss

    1993-01-01

    Transient transfection assays indicated that A2L is one of three vaccinia virus intermediate genes that are required for the transcriptional transactivation of viral late genes. We have expressed the A2L open reading frame in Escherichia coli and shown by blotting experiments that the 26-kDa protein binds zinc, a property predicted by the presence of a CX2CX13CX2C zinc finger motif. The specificity for zinc binding was demonstrated by competition with other metals. The role of the sequence mo...

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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

  16. 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.

  17. 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. PMID:27378005

  18. 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.

  19. 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...... is of functional significance. The MHC class I allomorphs from house sparrow and tree sparrow, species that diverged 10 million years ago (MYA), had overlapping peptide-binding specificities, and these similarities across species were also confirmed in phylogenetic analyses based on amino acid sequences. Notably......, 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...

  20. 基于FPGA的AVS帧内预测电路设计%FPGA-based design of intra mode prediction in AVS video encoder

    Institute of Scientific and Technical Information of China (English)

    李文军; 王祖强; 徐辉; 张贞雷

    2013-01-01

    提出了一种AVS高清视频编码器帧内预测模块硬件结构.通过对AVS帧内预测各个预测模式的分析,设计了帧内预测编码流水线结构和模式预测运算单元电路.根据各预测模式的编码运算关系,合理安排流水线结构,采用8 bit数据并行流水处理,实现了高清视频帧内预测实时编码.将除Plane模式之外的其他预测模式采用同一硬件电路来实现,对运算比较复杂的Plane模式单独设计了硬件结构,节省了硬件资源.%In this paper,a hardware architecture of AVS HD intra predictor is proposed.After the analysis of each prediction mode,a pipeline of the intra prediction encoder and the hardware of processing element are designed.According to the relationship of each prediction mode,the pipeline is reasonable organized.The encoder can encode 8 pixels in one cycle and realize the HD video sequences real-time encoding.All of the prediction modes but Plane mode are implied in the same hardware circuit and the Plane mode is implied in a different hardware,which saves the hardware resources.The design improves the usage of the hardware.

  1. Improving the performance of the PLB index for ligand-binding site prediction using dihedral angles and the solvent-accessible surface area.

    Science.gov (United States)

    Cao, Chen; Xu, Shutan

    2016-01-01

    Protein ligand-binding site prediction is highly important for protein function determination and structure-based drug design. Over the past twenty years, dozens of computational methods have been developed to address this problem. Soga et al. identified ligand cavities based on the preferences of amino acids for the ligand-binding site (RA) and proposed the propensity for ligand binding (PLB) index to rank the cavities on the protein surface. However, we found that residues exhibit different RAs in response to changes in solvent exposure. Furthermore, previous studies have suggested that some dihedral angles of amino acids in specific regions of the Ramachandran plot are preferred at the functional sites of proteins. Based on these discoveries, the amino acid solvent-accessible surface area and dihedral angles were combined with the RA and PLB to obtain two new indexes, multi-factor RA (MF-RA) and multi-factor PLB (MF-PLB). MF-PLB, PLB and other methods were tested using two benchmark databases and two particular ligand-binding sites. The results show that MF-PLB can improve the success rate of PLB for both ligand-bound and ligand-unbound structures, particularly for top choice prediction. PMID:27619067

  2. Geological predictions for the long-term isolation of radioactive waste based on extrapolating uniform mode and rate of crustal movements

    International Nuclear Information System (INIS)

    Long-term predictions of geological and tectonic disturbances are key issues for the safety assessment of radioactive waste disposal, especially on the Japanese Islands. Geological predictions of disturbances should be performed by extrapolating uniform mode and rate of crustal movements under the current framework. Multiple lines of geological evidence in Japan strongly suggest that the present mode of tectonics began during the late Pliocene to early Quaternary, and was fully developed by the middle Pleistocene. The uplift rates of mountains in Japan are determined to have been approximately constant until the middle Pleistocene based on simulations of temporal changes in mean altitude developed under concurrent tectonics and denudation processes. The onset of the neotectonic mode of deformation was probably triggered by the initiation of the eastward movement of the Amur Plate and the collision of the Izu block with central Honshu. The uncertainty of predictions beyond steady-state crustal deformation would, in general, increase for long-term predictions using the extrapolation procedure. Consequently, future geological and tectonic disturbances in Japan can be estimated with relatively high reliability for the next 100,000 years. (author)

  3. [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. PMID:23233989

  4. Predictive modelling of the impact of argon injection on H-mode plasmas in JET with the RITM code

    Energy Technology Data Exchange (ETDEWEB)

    Unterberg, B [Institut fuer Plasmaphysik, Forschungszentrum Juelich GmbH, Ass. Euratom-FZ Juelich, D-52425 Juelich (Germany); Kalupin, D [Institut fuer Plasmaphysik, Forschungszentrum Juelich GmbH, Ass. Euratom-FZ Juelich, D-52425 Juelich (Germany); Tokar' , M Z [Institut fuer Plasmaphysik, Forschungszentrum Juelich GmbH, Ass. Euratom-FZ Juelich, D-52425 Juelich (Germany); Corrigan, G [EURATOM UKAEA Fusion Association, Culham Science Centre, Abingdon, Oxon OX14 3DB (United Kingdom); Dumortier, P [Laboratory for Plasma Physics, Ass. Euratom-Belgian State, Koninklijke Militaire School-Ecole Royale Militaire, B-1000 Brussels (Belgium); Huber, A [Institut fuer Plasmaphysik, Forschungszentrum Juelich GmbH, Ass. Euratom-FZ Juelich, D-52425 Juelich (Germany); Jachmich, S [Laboratory for Plasma Physics, Ass. Euratom-Belgian State, Koninklijke Militaire School-Ecole Royale Militaire, B-1000 Brussels (Belgium); Kempenaars, M [FOM-Instituut voor Plasmafysica ' Rijnhuizen' , Ass. Euratom-FOM, PO Box 1207, 3430 BE Nieuwegein (Netherlands); Kreter, A [Institut fuer Plasmaphysik, Forschungszentrum Juelich GmbH, Ass. Euratom-FZ Juelich, D-52425 Juelich (Germany); Messiaen, A M [Laboratory for Plasma Physics, Ass. Euratom-Belgian State, Koninklijke Militaire School-Ecole Royale Militaire, B-1000 Brussels (Belgium); Monier-Garbet, P [Ass. Euratom-CEA, DRFC, CEA Cadarache, St Paul lez Durance (France); Ongena, J [Laboratory for Plasma Physics, Ass. Euratom-Belgian State, Koninklijke Militaire School-Ecole Royale Militaire, B-1000 Brussels (Belgium); Puiatti, M E [Associazione Euratom-ENEA sulla Fusione, Consorzio RFX, Padova (Italy); Valisa, M [Associazione Euratom-ENEA sulla Fusione, Consorzio RFX, Padova (Italy); Hellermann, M von [FOM-Instituut voor Plasmafysica ' Rijnhuizen' , Ass. Euratom-FOM, PO Box 1207, 3430 BE Nieuwegein(Netherlands)

    2004-05-01

    Self-consistent modelling of energy and particle transport of the plasma background and impurities has been performed with the code RITM for argon seeded high density H-mode plasmas in JET. The code can reproduce both the profiles in the plasma core and the structure of the edge pedestal. The impact of argon on core transport is found to be small; in particular, no significant change in confinement is observed in both experimental and modelling results. The same transport model, which has been used to reproduce density peaking in the radiative improved mode in TEXTOR, reveals a flat density profile in Ar seeded JET H-mode plasmas in agreement with the experimental observations. This behaviour is attributed to the rather flat profile of the safety factor in the bulk of H-mode discharges.

  5. The Relative Importance of Family History, Gender, Mode of Onset, and Age at Onset in Predicting Clinical Features of First-Episode Psychotic Disorders.

    Science.gov (United States)

    Compton, Michael T; Berez, Chantal; Walker, Elaine F

    2014-11-01

    Objective: Family history of psychosis, gender, mode of onset, and age at onset are considered prognostic factors important to clinicians evaluating first-episode psychosis; yet, clinicians have little guidance as to how these four factors differentially predict early-course substance abuse, symptomatology, and functioning. We conducted a "head-to-head comparison" of these four factors regarding their associations with key clinical features at initial hospitalization. We also assessed potential interactions between gender and family history with regard to age at onset of psychosis and symptom severity.Methods: Consecutively admitted first-episode patients (n=334) were evaluated in two studies that rigorously assessed a number of early-course variables. Associations among variables of interest were examined using Pearson correlations, ÷2 tests, Student's t-tests, and 2x2 factorial analyses of variance.Results: Substance (nicotine, alcohol, and cannabis) abuse and positive symptom severity were predicted only by male gender. Negative symptom severity and global functioning impairments were predicted by earlier age at onset of psychosis. General psychopathology symptom severity was predicted by both mode of onset and age at onset. Interaction effects were not observed with regard to gender and family history in predicting age at onset or symptom severity.Conclusions: The four prognostic features have differential associations with substance abuse, domains of symptom severity, and global functioning. Gender and age at onset of psychosis appear to be more predictive of clinical features at the time of initial evaluation (and thus presumably longer-term outcomes) than the presence of a family history of psychosis and a more gradual mode of onset. PMID:25367167

  6. 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...... 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...

  7. 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.

  8. DAT versus D2 receptor binding in the rat striatum: l-DOPA-induced motor activity is better predicted by reuptake than release of dopamine.

    Science.gov (United States)

    Nikolaus, Susanne; Beu, Markus; Angelica De Souza Silva, Maria; Huston, Joseph P; Hautzel, Hubertus; Antke, Christina; Müller, Hans-Wilhelm

    2016-09-01

    The reuptake and release of dopamine (DA) can be estimated using in vivo imaging methods by assessing the competition between endogenous DA and an administered exogenous DA transporter (DAT) and D2 receptor (D2 R) radioligand, respectively. The aim of this study was to investigate the comparative roles of DA release vs DA reuptake in the rat striatum with small animal SPECT in relation to l-DOPA-induced behaviors. DAT and D2 R binding, together with behavioral measures, were obtained in 99 rats in response to treatment with either 5 or 10 mg/kg l-DOPA or vehicle. The behavioral parameters included the distance travelled, and durations and frequencies of ambulation, sitting, rearing, head-shoulder motility, and grooming. Data were subjected to a cluster analysis and to a multivariate principal component analysis. The highest DAT binding (i.e., the lowest DA reuptake) was associated with the highest, and the lowest DAT binding (i.e., the highest DA reuptake) was associated with the lowest motor/exploratory activity. The highest and the lowest D2 R binding (i.e., the lowest and the highest DA release, respectively) were merely associated with the second highest and second lowest levels of motor/exploratory activity. These findings indicate that changes in DA reuptake in response to fluctuating DA levels offer a better prediction of motor activity than the release of DA into the synaptic cleft. This dissociation, as reflected by in vivo DAT and D2 R binding data, may be accounted for by the regulatory sensitization meachnisms that occur at D2 R binding sites in response to altered levels of DA. Synapse 70:369-377, 2016. © 2016 Wiley Periodicals, Inc. PMID:27164322

  9. 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

  10. Rhodopsin TM6 Can Interact with Two Separate and Distinct Sites on Arrestin: Evidence for Structural Plasticity and Multiple Docking Modes in Arrestin–Rhodopsin Binding

    OpenAIRE

    Sinha, Abhinav; Jones Brunette, Amber M.; Fay, Jonathan F.; Schafer, Christopher T.; Farrens, David L.

    2014-01-01

    Various studies have implicated the concave surface of arrestin in the binding of the cytosolic surface of rhodopsin. However, specific sites of contact between the two proteins have not previously been defined in detail. Here, we report that arrestin shares part of the same binding site on rhodopsin as does the transducin Gα subunit C-terminal tail, suggesting binding of both proteins to rhodopsin may share some similar underlying mechanisms. We also identify two areas of contact between the...

  11. NetMHCpan, a method for quantitative predictions of peptide binding to any HLA-A and -B locus protein of known sequence

    DEFF Research Database (Denmark)

    Nielsen, Morten; Lundegaard, Claus; Blicher, Thomas;

    2007-01-01

    surpassed 1500. Characterizing the specificity of each separately would be a major undertaking. PRINCIPAL FINDINGS: Here, we have drawn on a large database of known peptide-HLA-I interactions to develop a bioinformatics method, which takes both peptide and HLA sequence information into account, and...... generates quantitative predictions of the affinity of any peptide-HLA-I interaction. Prospective experimental validation of peptides predicted to bind to previously untested HLA-I molecules, cross-validation, and retrospective prediction of known HIV immune epitopes and endogenous presented peptides, all...... provide new basic insights into HLA structure-function relationships. The method is available at http://www.cbs.dtu.dk/services/NetMHCpan....

  12. 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.

  13. 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.

  14. Predicting treatment response in Schizophrenia: the role of stratal and frontal dopamine D2/D3 receptor binding potential

    DEFF Research Database (Denmark)

    Wulff, Sanne; Nørbak-Emig, Henrik; Nielsen, Mette Ødegaard;

    2014-01-01

    the ligand [123]IBZM (123labeled iodbenzamid) to examine the binding potential (BP) of dopamine D2/D3 receptors in striatum. Patients were treated with amisulpride for six weeks. In the EPIcohort we included 25 patients. The ligand [123I]epidepride was used for quantification of extrastriatal dopamine D2/D3...

  15. 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;

    structural Magnetic Resonance Imaging, SPECT and PANSS. In the IBZMcohort we included 26 patients. We used the ligand [123]IBZM (123labeled iodbenzamid) to examine the binding potential (BP) of dopamine D2/D3 receptors in striatum. Patients were treated with amisulpride for six weeks. In the EPIcohort we...

  16. 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

  17. 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.

  18. 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...

  19. 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.

  20. 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.

  1. Structural Studies of Soybean Calmodulin Isoform 4 Bound to the Calmodulin-binding Domain of Tobacco Mitogen-activated Protein Kinase Phosphatase-1 Provide Insights into a Sequential Target Binding Mode*

    OpenAIRE

    Ishida, Hiroaki; Rainaldi, Mario; Vogel, Hans J.

    2009-01-01

    The calcium regulatory protein calmodulin (CaM) binds in a calcium-dependent manner to numerous target proteins. The calmodulin-binding domain (CaMBD) region of Nicotiana tabacum MAPK phosphatase has an amino acid sequence that does not resemble the CaMBD of any other known Ca2+-CaM-binding proteins. Using a unique fusion protein strategy, we have been able to obtain a high resolution solution structure of the complex of soybean Ca2+-CaM4 (SCaM4) and this CaMBD. Complete isotope labeling of b...

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

    OpenAIRE

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

    2016-01-01

    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 endo...

  3. In Silico Prediction of Estrogen Receptor Subtype Binding Affinity and Selectivity Using Statistical Methods and Molecular Docking with 2-Arylnaphthalenes and 2-Arylquinolines

    Directory of Open Access Journals (Sweden)

    Yonghua Wang

    2010-09-01

    Full Text Available Over the years development of selective estrogen receptor (ER ligands has been of great concern to researchers involved in the chemistry and pharmacology of anticancer drugs, resulting in numerous synthesized selective ER subtype inhibitors. In this work, a data set of 82 ER ligands with ERα and ERβ inhibitory activities was built, and quantitative structure-activity relationship (QSAR methods based on the two linear (multiple linear regression, MLR, partial least squares regression, PLSR and a nonlinear statistical method (Bayesian regularized neural network, BRNN were applied to investigate the potential relationship of molecular structural features related to the activity and selectivity of these ligands. For ERα and ERβ, the performances of the MLR and PLSR models are superior to the BRNN model, giving more reasonable statistical properties (ERα: for MLR, Rtr2 = 0.72, Qte2 = 0.63; for PLSR, Rtr2 = 0.92, Qte2 = 0.84. ERβ: for MLR, Rtr2 = 0.75, Qte2 = 0.75; for PLSR, Rtr2 = 0.98, Qte2 = 0.80. The MLR method is also more powerful than other two methods for generating the subtype selectivity models, resulting in Rtr2 = 0.74 and Qte2 = 0.80. In addition, the molecular docking method was also used to explore the possible binding modes of the ligands and a relationship between the 3D-binding modes and the 2D-molecular structural features of ligands was further explored. The results show that the binding affinity strength for both ERα and ERβ is more correlated with the atom fragment type, polarity, electronegativites and hydrophobicity. The substitutent in position 8 of the naphthalene or the quinoline plane and the space orientation of these two planes contribute the most to the subtype selectivity on the basis of similar hydrogen bond interactions between binding ligands and both ER subtypes. The QSAR models built together with the docking procedure should be of great advantage for screening and designing ER ligands with improved affinity

  4. Resting-State Glutamate and GABA Concentrations Predict Task-Induced Deactivation in the Default Mode Network

    OpenAIRE

    Hu, Yuzheng; Chen, Xi; Gu, Hong; Yang, Yihong

    2013-01-01

    Deactivation of the human brain's default mode network (DMN) is regarded as suppression of endogenous activity to support exogenous task-related processes. This phenomenon has important functional relevance and insufficient DMN deactivation has been implicated in several neuropsychiatric disorders. However, the neurochemical mechanism of the DMN′s deactivation remains largely unknown. In the present study, we test the hypothesis that the major excitatory and inhibitory neurotransmitters, glut...

  5. Toxicity challenges in environmental chemicals: Prediction of human plasma protein binding through quantitative structure-activity relationship (QSAR) models

    Science.gov (United States)

    The present study explores the merit of utilizing available pharmaceutical data to construct a quantitative structure-activity relationship (QSAR) for prediction of the fraction of a chemical unbound to plasma protein (Fub) in environmentally relevant compounds. Independent model...

  6. Fuzzy Sliding Mode Observer with Grey Prediction for the Estimation of the State-of-Charge of a Lithium-Ion Battery

    Directory of Open Access Journals (Sweden)

    Daehyun Kim

    2015-11-01

    Full Text Available We propose a state-of-charge (SOC estimation method for Li-ion batteries that combines a fuzzy sliding mode observer (FSMO with grey prediction. Unlike the existing methods based on a conventional first-order sliding mode observer (SMO and an adaptive gain SMO, the proposed method eliminates chattering in SOC estimation. In this method, which uses a fuzzy inference system, the gains of the SMO are adjusted according to the predicted future error and present estimation error of the terminal voltage. To forecast the future error value, a one-step-ahead terminal voltage prediction is obtained using a grey predictor. The proposed estimation method is validated through two types of discharge tests (a pulse discharge test and a random discharge test. The SOC estimation results are compared to the results of the conventional first-order SMO-based and the adaptive gain SMO-based methods. The experimental results show that the proposed method not only reduces chattering, but also improves estimation accuracy.

  7. Validation of Atmospheric Dynamics (VADY) - representation of circulation types/dynamical modes in the decadal-prediction model system of MPI-ESM

    Science.gov (United States)

    Lang, Benjamin; Jacobeit, Jucundus; Beck, Christoph; Philipp, Andreas

    2016-04-01

    The climate research program "Medium-range Climate Predictions" (MiKlip), funded by the Federal Ministry of Education and Research in Germany (BMBF), has the aim to improve a climate model system (MPI-ESM) in such a way that it can provide reliable decadal predictions of climate, including extreme weather events. A substantial part of the development process is a comprehensive model validation. Within MiKlip, it includes comparisons of model simulations and observations in order to allow statements about the performance of the model and to give particular recommendations for the further development of the model. The research project "Validation of Atmospheric Dynamics" (VADY), conducted by the cooperation partners "Institute of Geography at the University of Augsburg" (IGUA) and the "German Aerospace Centre" (DLR), contributes to model validation within MiKlip with a special focus on atmospheric waves (DLR) and circulation dynamics (IGUA). Within the framework of VADY, DLR validates the representation of atmospheric waves on different levels and scales based on suitable activity indices (e.g. the so-called large-scale dynamical activity index (LDAI), which is a measure for the activity of planetary waves). The focus of IGUA is on the model validation with respect to the representation of atmospheric circulation types, dynamical modes and the teleconnectivity of the atmospheric circulation. The present contribution provides results of the model validation concerning circulation types/dynamical modes. Results are shown for both the frequency of occurrence and internal characteristics (e. g. persistence or intensity), and for different classification methods (e. g. based on PCA or clustering techniques). The representation of circulation types/dynamical modes will be compared for different generations of the MPI-ESM decadal-prediction model (baseline0, baseline1, prototype) in order to clarify both advances and limitations in the development of the model. Furthermore

  8. Design of Potential Bisubstrate Inhibitors against Mycobacterium tuberculosis (Mtb) 1-Deoxy-D-Xylulose 5-Phosphate Reductoisomerase (Dxr)—Evidence of a Novel Binding Mode

    OpenAIRE

    San Jose, Géraldine; Jackson, Emily R.; Uh, Eugene; Johny, Chinchu; Haymond, Amanda; Lundberg, Lindsay; Pinkham, Chelsea; Kehn-Hall, Kylene; Boshoff, Helena I.; Couch, Robin D.; Dowd, Cynthia S.

    2013-01-01

    In most bacteria, the nonmevalonate pathway is used to synthesize isoprene units. Dxr, the second step in the pathway, catalyzes the NADPH-dependent reductive isomerization of 1-deoxy-D-xylulose-5-phosphate (DXP) to 2-C-methyl-D-erythritol-4-phosphate (MEP). Dxr is inhibited by natural products fosmidomycin and FR900098, which bind in the DXP binding site. These compounds, while potent inhibitors of Dxr, lack whole cell activity against Mycobacterium tuberculosis (Mtb) due to their polarity. ...

  9. Spectroscopic investigations on the complexation of Cm(III) and Eu(III) with organic model ligands and their binding mode in human urine (in vitro)

    International Nuclear Information System (INIS)

    In case of incorporation, trivalent actinides (An(III)) and lanthanides (Ln(III)) pose a serious health risk to humans. An(III) are artificial, highly radioactive elements which are mainly produced during the nuclear fuel cycle in nuclear power plants. Via hazardous accidents or nonprofessional storage of radioactive waste, they can be released in the environment and enter the human food chain. In contrast, Ln(III) are nonradioactive, naturally occurring elements with multiple applications in technique and medicine. Consequently it is possible that humans get in contact and incorporate both, An(III) and Ln(III). Therefore, it is of particular importance to elucidate the behaviour of these elements in the human body. While macroscopic processes such as distribution, accumulation and excretion are studied quite well, knowledge about the chemical binding form (speciation) of An(III) and Ln(III) in various body fluids is still sparse. In the present work, for the first time, the speciation of Cm(III) and Eu(III) in natural human urine (in vitro) has been investigated spectroscopically and the formed complex identified. For this purpose, also basic investigations on the complex formation of Cm(III) and Eu(III) in synthetic model urine as well as with the urinary relevant, organic model ligands urea, alanine, phenylalanine, threonine and citrate have been performed and the previously unknown complex stability constants determined. Finally, all experimental results were compared to literature data and predictions calculated by thermodynamic modelling. Since both, Cm(III) and Eu(III), exhibit unique luminescence properties, particularly the suitability of time-resolved laser-induced fluorescence spectroscopy (TRLFS) could be demonstrated as a method to investigate these metal ions in untreated, complex biofluids. The results of this work provide new scientific findings on the biochemical reactions of An(III) and Ln(III) in human body fluids on a molecular scale and

  10. Murine hyperglycemic vasculopathy and cardiomyopathy: whole-genome gene expression analysis predicts cellular targets and regulatory networks influenced by mannose binding lectin

    Directory of Open Access Journals (Sweden)

    Chenhui eZou

    2012-02-01

    Full Text Available Hyperglycemia, in the absence of type 1 or 2 diabetes, is an independent risk factor for cardiovascular disease. We have previously demonstrated a central role for mannose binding lectin (MBL-mediated cardiac dysfunction in acute hyperglycemic mice. In this study, we applied whole genome microarray data analysis to investigate MBL’s role in systematic gene expression changes. The data predict possible intracellular events taking place in multiple cellular compartments such as enhanced insulin signaling pathway sensitivity, promoted mitochondrial respiratory function, improved cellular energy expenditure and protein quality control, improved cytoskeleton structure and facilitated intracellular trafficking, all of which may contribute to the organismal health of MBL null mice against acute hyperglycemia. Our data show a tight association between gene expression profile and tissue function which might be a very useful tool in predicting cellular targets and regulatory networks connected with in vivo observations, providing clues for further mechanistic studies.

  11. Urinary Liver-Type Fatty Acid-Binding Protein Predicts Progression to Nephropathy in Type 1 Diabetic Patients

    OpenAIRE

    Nielsen, Stine Elkjaer; Sugaya, Takeshi; Hovind, Peter; Baba, Tsuneharu; Parving, Hans-Henrik; Rossing, Peter

    2010-01-01

    OBJECTIVE 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 of progression to micro- and macroalbuminuria in type 1 diabetes. RESEARCH DESIGN AND METHODS From an inception cohort of 277 patients, u-LFABP, adjusted for urinary creatinine (enzyme-li...

  12. Monitoring of Urinary L-Type Fatty Acid-Binding Protein Predicts Histological Severity of Acute Kidney Injury

    OpenAIRE

    Negishi, Kousuke; Noiri, Eisei; DOI, Kent; Maeda-Mamiya, Rui; Sugaya, Takeshi; Portilla, Didier; Fujita, Toshiro

    2009-01-01

    The present study aimed to evaluate whether levels of urinary L-type fatty acid-binding protein (L-FABP) could be used to monitor histological injury in acute kidney injury (AKI) induced by cis-platinum (CP) injection and ischemia reperfusion (IR). Different degrees of AKI severity were induced by several renal insults (CP dose and ischemia time) in human L-FABP transgenic mice. Renal histological injury scores increased with both CP dose and ischemic time. In CP-induced AKI, urinary L-FABP l...

  13. High-Throughput Melanin-Binding Affinity and In Silico Methods to Aid in the Prediction of Drug Exposure in Ocular Tissue.

    Science.gov (United States)

    Reilly, John; Williams, Sarah L; Forster, Cornelia J; Kansara, Viral; End, Peter; Serrano-Wu, Michael H

    2015-12-01

    Drugs possessing the ability to bind to melanin-rich tissue, such as the eye, are linked with higher ocular exposure, and therefore have the potential to affect the efficacy and safety profiles of therapeutics. A high-throughput melanin chromatographic affinity assay has been developed and validated, which has allowed the rapid melanin affinity assessment for a large number of compounds. Melanin affinity of compounds can be quickly assigned as low, medium, or high melanin binders. A high-throughput chromatographic method has been developed and fully validated to assess melanin affinity of pharmaceuticals and has been useful in predicting ocular tissue distribution in vivo studies. The high-throughput experimental approach has also allowed for a specific training set of 263 molecules for a quantitative structure-affinity relationships (QSAR) method to be developed, which has also been shown to be a predictor of ocular tissue exposure. Previous studies have reported the development of in silico QSAR models based on training sets of relatively small and mostly similar compounds; this model covers a broader range of melanin-binding affinities than what has been previously published and identified several physiochemical descriptors to be considered in the design of compounds where melanin-binding modulation is desired.

  14. BRCA-Monet: a breast cancer specific drug treatment mode-of-action network for treatment effective prediction using large scale microarray database

    OpenAIRE

    Ma, Chifeng; Chen, Hung-I Harry; Flores, Mario; Huang, Yufei; Chen, Yidong

    2013-01-01

    Background Connectivity map (cMap) is a recent developed dataset and algorithm for uncovering and understanding the treatment effect of small molecules on different cancer cell lines. It is widely used but there are still remaining challenges for accurate predictions. Method Here, we propose BRCA-MoNet, a network of drug mode of action (MoA) specific to breast cancer, which is constructed based on the cMap dataset. A drug signature selection algorithm fitting the characteristic of cMap data, ...

  15. Prediction and validation of protein–protein interactors from genome-wide DNA-binding data using a knowledge-based machine-learning approach

    Science.gov (United States)

    Homan, Bernou; Mohamed, Stephanie; Harvey, Richard P.; Bouveret, Romaric

    2016-01-01

    The ability to accurately predict the DNA targets and interacting cofactors of transcriptional regulators from genome-wide data can significantly advance our understanding of gene regulatory networks. NKX2-5 is a homeodomain transcription factor that sits high in the cardiac gene regulatory network and is essential for normal heart development. We previously identified genomic targets for NKX2-5 in mouse HL-1 atrial cardiomyocytes using DNA-adenine methyltransferase identification (DamID). Here, we apply machine learning algorithms and propose a knowledge-based feature selection method for predicting NKX2-5 protein : protein interactions based on motif grammar in genome-wide DNA-binding data. We assessed model performance using leave-one-out cross-validation and a completely independent DamID experiment performed with replicates. In addition to identifying previously described NKX2-5-interacting proteins, including GATA, HAND and TBX family members, a number of novel interactors were identified, with direct protein : protein interactions between NKX2-5 and retinoid X receptor (RXR), paired-related homeobox (PRRX) and Ikaros zinc fingers (IKZF) validated using the yeast two-hybrid assay. We also found that the interaction of RXRα with NKX2-5 mutations found in congenital heart disease (Q187H, R189G and R190H) was altered. These findings highlight an intuitive approach to accessing protein–protein interaction information of transcription factors in DNA-binding experiments. PMID:27683156

  16. HADDOCK2P2I : A biophysical model for predicting the binding affinity of protein-protein interaction inhibitors

    NARCIS (Netherlands)

    Kastritis, Panagiotis L.; Garcia Lopes Maia Rodrigues, João; Bonvin, Alexandre M J J

    2014-01-01

    The HADDOCK score, a scoring function for both protein-protein and protein-nucleic acid modeling, has been successful in selecting near-native docking poses in a variety of cases, including those of the CAPRI blind prediction experiment. However, it has yet to be optimized for small molecules, and i

  17. Identification and Validation of Novel Hedgehog-Responsive Enhancers Predicted by Computational Analysis of Ci/Gli Binding Site Density.

    Directory of Open Access Journals (Sweden)

    Katherine Gurdziel

    Full Text Available The Hedgehog (Hh signaling pathway directs a multitude of cellular responses during embryogenesis and adult tissue homeostasis. Stimulation of the pathway results in activation of Hh target genes by the transcription factor Ci/Gli, which binds to specific motifs in genomic enhancers. In Drosophila, only a few enhancers (patched, decapentaplegic, wingless, stripe, knot, hairy, orthodenticle have been shown by in vivo functional assays to depend on direct Ci/Gli regulation. All but one (orthodenticle contain more than one Ci/Gli site, prompting us to directly test whether homotypic clustering of Ci/Gli binding sites is sufficient to define a Hh-regulated enhancer. We therefore developed a computational algorithm to identify Ci/Gli clusters that are enriched over random expectation, within a given region of the genome. Candidate genomic regions containing Ci/Gli clusters were functionally tested in chicken neural tube electroporation assays and in transgenic flies. Of the 22 Ci/Gli clusters tested, seven novel enhancers (and the previously known patched enhancer were identified as Hh-responsive and Ci/Gli-dependent in one or both of these assays, including: Cuticular protein 100A (Cpr100A; invected (inv, which encodes an engrailed-related transcription factor expressed at the anterior/posterior wing disc boundary; roadkill (rdx, the fly homolog of vertebrate Spop; the segment polarity gene gooseberry (gsb; and two previously untested regions of the Hh receptor-encoding patched (ptc gene. We conclude that homotypic Ci/Gli clustering is not sufficient information to ensure Hh-responsiveness; however, it can provide a clue for enhancer recognition within putative Hedgehog target gene loci.

  18. Full-f Neoclassical Simulations toward a Predictive Model for H-mode Pedestal Ion Energy, Particle and Momentum Transport

    Energy Technology Data Exchange (ETDEWEB)

    Battaglia, D. J. [PPPL; Boedo, J. A. [University of California San Diego; Burrell, K. H. [General Atomics; Chang, C. S. [PPPL; Canik, J. M. [ORNL; deGrassie, J. S. [General Atomics; Gerhardt, S. P. [PPPL; Grierson, B. A. [General Atomics; Groebner, R. J. [General Atomics; Maingi, Rajesh [PPPL; Smith, S. P. [General Atomics

    2014-09-01

    Energy and particle transport rates are decoupled in the H-mode edge since the ion thermal transport rate is primarily set by the neoclassical transport of the deuterium ions in the tail of the thermal energy distribution, while the net particle transport rate is set by anomalous transport of the colder bulk ions. Ion orbit loss drives the energy distributions away from Maxwellian, and describes the anisotropy, poloidal asymmetry and local minimum near the separatrix observed in the Ti profile. Non-Maxwellian distributions also drive large intrinsic edge flows, and the interaction of turbulence at the top of the pedestal with the intrinsic edge flow can generate an intrinsic core torque. The primary driver of the radial electric field (Er) in the pedestal and scrapeoff layer (SOL) are kinetic neoclassical effects, such as ion orbit loss of tail ions and parallel electron loss to the divertor. This paper describes the first multi-species kinetic neoclassical transport calculations for ELM-free H-mode pedestal and scrape-off layer on DIII-D using XGC0, a 5D full-f particle-in-cell drift-kinetic solver with self-consistent neutral recycling and sheath potentials. Quantitative agreement between the flux-driven simulation and the experimental electron density, impurity density and orthogonal measurements of impurity temperature and flow profiles is achieved by adding random-walk particle diffusion to the guiding-center drift motion. This interpretative technique quantifies the role of neoclassical, anomalous and neutral transport to the overall pedestal structure, and consequently illustrates the importance of including kinetic effects self-consistently in transport calculations around transport barriers.

  19. Predicting promiscuous antigenic T cell epitopes of Mycobacterium tuberculosis mymA operon proteins binding to MHC Class I and Class II molecules.

    Science.gov (United States)

    Saraav, Iti; Pandey, Kirti; Sharma, Monika; Singh, Swati; Dutta, Prasun; Bhardwaj, Anshu; Sharma, Sadhna

    2016-10-01

    Limited efficacy of Bacillus Calmette-Guérin vaccine has raised the need to explore other immunogenic candidates to develop an effective vaccine against Mycobacterium tuberculosis (Mtb). Both CD4+ and CD8+ T cells play a critical role in host immunity to Mtb. Infection of macrophages with Mtb results in upregulation of mymA operon genes thereby suggesting their importance as immune targets. In the present study, after exclusion of self-peptides mymA operon proteins of Mtb were analyzed in silico for the presence of Human Leukocyte Antigen (HLA) Class I and Class II binding peptides using Bioinformatics and molecular analysis section, NetMHC 3.4, ProPred and Immune epitope database software. Out of 56 promiscuous epitopes obtained, 41 epitopes were predicted to be antigenic for MHC Class I. In MHC Class II, out of 336 promiscuous epitopes obtained, 142 epitopes were predicted to be antigenic. The comparative bioinformatics analysis of mymA operon proteins found Rv3083 to be the best vaccine candidate. Molecular docking was performed with the most antigenic peptides of Rv3083 (LASGAASVV with alleles HLA-B51:01, HAATSGTLI with HLA-A02, IVTATGLNI and EKIHYGLKVNTA with HLA-DRB1_01:01) to study the structural basis for recognition of peptides by various HLA molecules. The software binding prediction was validated by the obtained molecular docking score of peptide-HLA complex. These peptides can be further investigated for their immunological relevance in patients of tuberculosis using major histocompatibility complex tetramer approach. PMID:27389362

  20. Semi-quantitative predictions for the Polish parliamentary elections (October 25, 2015) based on the Emotion/Information/Opinion mode

    CERN Document Server

    Sobkowicz, Pawel

    2015-01-01

    Based on an agent based model of opinion changes, described in detail in a recent paper (\\arXiv:1507.00126), we attempt to predict, three months in advance, the range of possible results of the Polish parliamentary elections, scheduled for October 25, 2015. The model reproduces semi-quantitatively the poll results for the three parties which dominated the recent presidential elections and allows estimation of some variations of the electoral propaganda campaigns by the parties.

  1. Integrative genomic analyses of the RNA-binding protein, RNPC1, and its potential role in cancer prediction.

    Science.gov (United States)

    Ding, Zhiming; Yang, Hai-Wei; Xia, Tian-Song; Wang, Bo; Ding, Qiang

    2015-08-01

    The RNA binding motif protein 38 (RBM38, also known as RNPC1) plays a pivotal role in regulating a wide range of biological processes, from cell proliferation and cell cycle arrest to cell myogenic differentiation. It was originally recognized as an oncogene, and was frequently found to be amplified in prostate, ovarian and colorectal cancer, chronic lymphocytic leukemia, colon carcinoma, esophageal cancer, dog lymphomas and breast cancer. In the present study, the complete RNPC1 gene was identified in a number of vertebrate genomes, suggesting that RNPC1 exists in all types of vertebrates, including fish, amphibians, birds and mammals. In the different genomes, the gene had a similar 4 exon/3 intron organization, and all the genetic loci were syntenically conserved. The phylogenetic tree demonstrated that the RNPC1 gene from the mammalian, bird, reptile and teleost lineage formed a species-specific cluster. A total of 34 functionally relevant single nucleotide polymorphisms (SNPs), including 14 SNPs causing missense mutations, 8 exonic splicing enhancer SNPs and 12 SNPs causing nonsense mutations, were identified in the human RNPC1 gene. RNPC1 was found to be expressed in bladder, blood, brain, breast, colorectal, eye, head and neck, lung, ovarian, skin and soft tissue cancer. In 14 of the 94 tests, an association between RNPC1 gene expression and cancer prognosis was observed. We found that the association between the expression of RNPC1 and prognosis varied in different types of cancer, and even in the same type of cancer from the different databases used. This suggests that the function of RNPC1 in these tumors may be multidimensional. The sex determining region Y (SRY)-box 5 (Sox5), runt-related transcription factor 3 (RUNX3), CCAAT displacement protein 1 (CUTL1), v-rel avian reticuloendotheliosis viral oncogene homolog (Rel)A, peroxisome proliferator-activated receptor γ isoform 2 (PPARγ2) and activating transcription factor 6 (ATF6) regulatory

  2. Design of Potential Bisubstrate Inhibitors against Mycobacterium tuberculosis (Mtb) 1-Deoxy-D-Xylulose 5-Phosphate Reductoisomerase (Dxr)-Evidence of a Novel Binding Mode.

    Science.gov (United States)

    San Jose, Géraldine; Jackson, Emily R; Uh, Eugene; Johny, Chinchu; Haymond, Amanda; Lundberg, Lindsay; Pinkham, Chelsea; Kehn-Hall, Kylene; Boshoff, Helena I; Couch, Robin D; Dowd, Cynthia S

    2013-07-01

    In most bacteria, the nonmevalonate pathway is used to synthesize isoprene units. Dxr, the second step in the pathway, catalyzes the NADPH-dependent reductive isomerization of 1-deoxy-D-xylulose-5-phosphate (DXP) to 2-C-methyl-D-erythritol-4-phosphate (MEP). Dxr is inhibited by natural products fosmidomycin and FR900098, which bind in the DXP binding site. These compounds, while potent inhibitors of Dxr, lack whole cell activity against Mycobacterium tuberculosis (Mtb) due to their polarity. Our goal was to use the Mtb Dxr-fosmidomycin co-crystal structure to design bisubstrate ligands to bind to both the DXP and NADPH sites. Such compounds would be expected to demonstrate improved whole cell activity due to increased lipophilicity. Two series of compounds were designed and synthesized. Compounds from both series inhibited Mtb Dxr. The most potent compound (8) has an IC50 of 17.8 µM. Analysis shows 8 binds to Mtb Dxr via a novel, non-bisubstrate mechanism. Further, the diethyl ester of 8 inhibits Mtb growth making this class of compounds interesting lead molecules in the search for new antitubercular agents. PMID:23914289

  3. Oxygen equilibria and ligand binding kinetics of erythrocruorins from two burrowing polychaetes of different modes of life, Marphysa sanguinea and Diopatra cuprea

    DEFF Research Database (Denmark)

    Weber, Roy E.; Bonaventura, J.; Sullivan, B.;

    1978-01-01

    Oxygen equilibria, ligand-binding kinetics and some other physicochemical properties are reported for erythrocruorins of two intertidal polychaetes:Marphysa sanguinea, which inhabits simple, relatively stagnant burrows, andDiopatra cuprea, which inhabits impermeable, parchment-like tubes that are...

  4. Prediction

    CERN Document Server

    Sornette, Didier

    2010-01-01

    This chapter first presents a rather personal view of some different aspects of predictability, going in crescendo from simple linear systems to high-dimensional nonlinear systems with stochastic forcing, which exhibit emergent properties such as phase transitions and regime shifts. Then, a detailed correspondence between the phenomenology of earthquakes, financial crashes and epileptic seizures is offered. The presented statistical evidence provides the substance of a general phase diagram for understanding the many facets of the spatio-temporal organization of these systems. A key insight is to organize the evidence and mechanisms in terms of two summarizing measures: (i) amplitude of disorder or heterogeneity in the system and (ii) level of coupling or interaction strength among the system's components. On the basis of the recently identified remarkable correspondence between earthquakes and seizures, we present detailed information on a class of stochastic point processes that has been found to be particu...

  5. Performance prediction and flow analysis in the vaned distributor of a pump turbine under low flow rate in pump mode

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    The main goal of this work is to investigate the possible different flow patterns existing in pump turbine under off-design conditions in pump mode. Numerical simulations by solving the Navier-Stokes equation, coupled with the "SST k-ω" turbulence model, were carried out. Flow characteristics were assumed to be stalled in the appropriate region of ?ow rate levels of Q/QD=0.15–0.61. The simulation result was compared with experimental data and they showed good agreement. Consequently, velocity fields in three axial locations in stay vanes and guide vanes were analysed in details. It was shown that "jet-wake" flow pattern exists near the band, which changes little in the whole shape with flow rate increasing; to the middle location of vanes, reverse flow begins to appear on the interface between the runner and guide vanes, which will disappear gradually as the flow rate increases; massive reverse flow is captured near the crown, whose intensity will be weakened as the flow rate increases. Ultimately, it was found that the special head-flow profile can be ascribed to the special hydraulic loss characteristics of the stay vanes and guide vanes.

  6. Prediction of CL-20 chemical degradation pathways, theoretical and experimental evidence for dependence on competing modes of reaction

    Energy Technology Data Exchange (ETDEWEB)

    Qasim, Mohammad M.; Fredrickson, Herbert L.; Honea, P.; Furey, John; Leszczynski, Jerzy; Okovytyy, S.; Szecsody, Jim E.; Kholod, Y.

    2005-10-01

    Highest occupied and lowest unoccupied molecular orbital energies, formation energies, bond lengths and FTIR spectra all suggest competing CL-20 degradation mechanisms. This second of two studies investigates recalcitrant, toxic, aromatic CL-20 intermediates that absorb from 370 to 430 nm. Our earlier study (Struct. Chem., 15, 2004) revealed that these intermediates were formed at high OH- concentrations via the chemically preferred pathway of breaking the C-C bond between the two cyclopentanes, thereby eliminating nitro groups, forming conjugated π bonds, and resulting in a pyrazine three-ring aromatic intermediate. In attempting to find and make dominant a more benign CL-20 transformation pathway, this current research validates hydroxylation results from both studies and examines CL-20 transformations via photo-induced free radical reactions. This article discusses CL-20 competing modes of degradation revealed through: computational calculation; UV/VIS and SF spectroscopy following alkaline hydrolysis; and photochemical irradiation to degrade CL-20 and its byproducts at their respective wavelengths of maximum absorption.

  7. Prediction of CL-20 chemical degradation pathways, theoretical and experimental evidence for dependence on competing modes of reaction.

    Science.gov (United States)

    Qasim, M; Fredrickson, H; Honea, P; Furey, J; Leszczynski, J; Okovytyy, S; Szecsody, J; Kholod, Y

    2005-10-01

    Highest occupied and lowest unoccupied molecular orbital energies, formation energies, bond lengths and FTIR spectra all suggest competing CL-20 degradation mechanisms. This second of two studies investigates recalcitrant, toxic, aromatic CL-20 intermediates that absorb from 370 to 430 nm. Our earlier study (Struct. Chem., 15, 2004) revealed that these intermediates were formed at high OH(-) concentrations via the chemically preferred pathway of breaking the C-C bond between the two cyclopentanes, thereby eliminating nitro groups, forming conjugated pi bonds, and resulting in a pyrazine three-ring aromatic intermediate. In attempting to find and make dominant a more benign CL-20 transformation pathway, this current research validates hydroxylation results from both studies and examines CL-20 transformations via photo-induced free radical reactions. This article discusses CL-20 competing modes of degradation revealed through: computational calculation; UV/VIS and SF spectroscopy following alkaline hydrolysis; and photochemical irradiation to degrade CL-20 and its byproducts at their respective wavelengths of maximum absorption. PMID:16272046

  8. Field-Evolved Mode 1 Resistance of the Fall Armyworm to Transgenic Cry1Fa-Expressing Corn Associated with Reduced Cry1Fa Toxin Binding and Midgut Alkaline Phosphatase Expression.

    Science.gov (United States)

    Jakka, Siva R K; Gong, Liang; Hasler, James; Banerjee, Rahul; Sheets, Joel J; Narva, Kenneth; Blanco, Carlos A; Jurat-Fuentes, Juan L

    2015-12-04

    Insecticidal protein genes from the bacterium Bacillus thuringiensis (Bt) are expressed by transgenic Bt crops (Bt crops) for effective and environmentally safe pest control. The development of resistance to these insecticidal proteins is considered the most serious threat to the sustainability of Bt crops. Resistance in fall armyworm (Spodoptera frugiperda) populations from Puerto Rico to transgenic corn producing the Cry1Fa insecticidal protein resulted, for the first time in the United States, in practical resistance, and Bt corn was withdrawn from the local market. In this study, we used a field-collected Cry1Fa corn-resistant strain (456) of S. frugiperda to identify the mechanism responsible for field-evolved resistance. Binding assays detected reduced Cry1Fa, Cry1Ab, and Cry1Ac but not Cry1Ca toxin binding to midgut brush border membrane vesicles (BBMV) from the larvae of strain 456 compared to that from the larvae of a susceptible (Ben) strain. This binding phenotype is descriptive of the mode 1 type of resistance to Bt toxins. A comparison of the transcript levels for putative Cry1 toxin receptor genes identified a significant downregulation (>90%) of a membrane-bound alkaline phosphatase (ALP), which translated to reduced ALP protein levels and a 75% reduction in ALP activity in BBMV from 456 compared to that of Ben larvae. We cloned and heterologously expressed this ALP from susceptible S. frugiperda larvae and demonstrated that it specifically binds with Cry1Fa toxin. This study provides a thorough mechanistic description of field-evolved resistance to a transgenic Bt crop and supports an association between resistance and reduced Cry1Fa toxin binding and levels of a putative Cry1Fa toxin receptor, ALP, in the midguts of S. frugiperda larvae.

  9. Field-Evolved Mode 1 Resistance of the Fall Armyworm to Transgenic Cry1Fa-Expressing Corn Associated with Reduced Cry1Fa Toxin Binding and Midgut Alkaline Phosphatase Expression.

    Science.gov (United States)

    Jakka, Siva R K; Gong, Liang; Hasler, James; Banerjee, Rahul; Sheets, Joel J; Narva, Kenneth; Blanco, Carlos A; Jurat-Fuentes, Juan L

    2016-02-01

    Insecticidal protein genes from the bacterium Bacillus thuringiensis (Bt) are expressed by transgenic Bt crops (Bt crops) for effective and environmentally safe pest control. The development of resistance to these insecticidal proteins is considered the most serious threat to the sustainability of Bt crops. Resistance in fall armyworm (Spodoptera frugiperda) populations from Puerto Rico to transgenic corn producing the Cry1Fa insecticidal protein resulted, for the first time in the United States, in practical resistance, and Bt corn was withdrawn from the local market. In this study, we used a field-collected Cry1Fa corn-resistant strain (456) of S. frugiperda to identify the mechanism responsible for field-evolved resistance. Binding assays detected reduced Cry1Fa, Cry1Ab, and Cry1Ac but not Cry1Ca toxin binding to midgut brush border membrane vesicles (BBMV) from the larvae of strain 456 compared to that from the larvae of a susceptible (Ben) strain. This binding phenotype is descriptive of the mode 1 type of resistance to Bt toxins. A comparison of the transcript levels for putative Cry1 toxin receptor genes identified a significant downregulation (>90%) of a membrane-bound alkaline phosphatase (ALP), which translated to reduced ALP protein levels and a 75% reduction in ALP activity in BBMV from 456 compared to that of Ben larvae. We cloned and heterologously expressed this ALP from susceptible S. frugiperda larvae and demonstrated that it specifically binds with Cry1Fa toxin. This study provides a thorough mechanistic description of field-evolved resistance to a transgenic Bt crop and supports an association between resistance and reduced Cry1Fa toxin binding and levels of a putative Cry1Fa toxin receptor, ALP, in the midguts of S. frugiperda larvae. PMID:26637593

  10. Monitoring of urinary L-type fatty acid-binding protein predicts histological severity of acute kidney injury.

    Science.gov (United States)

    Negishi, Kousuke; Noiri, Eisei; Doi, Kent; Maeda-Mamiya, Rui; Sugaya, Takeshi; Portilla, Didier; Fujita, Toshiro

    2009-04-01

    The present study aimed to evaluate whether levels of urinary L-type fatty acid-binding protein (L-FABP) could be used to monitor histological injury in acute kidney injury (AKI) induced by cis-platinum (CP) injection and ischemia reperfusion (IR). Different degrees of AKI severity were induced by several renal insults (CP dose and ischemia time) in human L-FABP transgenic mice. Renal histological injury scores increased with both CP dose and ischemic time. In CP-induced AKI, urinary L-FABP levels increased exponentially even in the lowest dose group as early as 2 hours, whereas blood urea nitrogen (BUN) levels increased at 48 hours. In IR-induced AKI, BUN levels increased only in the 30-minute ischemia group 24 hours after reperfusion; however, urinary L-FABP levels increased more than 100-fold, even in the 5-minute ischemia group after 1 hour. In both AKI models, urinary L-FABP levels showed a better correlation with final histological injury scores and glomerular filtration rates measured by fluorescein isothiocyanate-labeled inulin injection than with levels of BUN and urinary N-acetyl-D-glucosaminidase, especially at earlier time points. Receiver operating characteristic curve analysis demonstrated that urinary L-FABP was superior to other biomarkers for the detection of significant histological injuries and functional declines. In conclusion, urinary L-FABP levels are better suited to allow the accurate and earlier detection of both histological and functional insults in ischemic and nephrotoxin-induced AKI compared with conventional renal markers.

  11. IGF-1 receptor and IGF binding protein-3 might predict prognosis of patients with resectable pancreatic cancer

    International Nuclear Information System (INIS)

    The present study aimed to elucidate the clinicopathologic role of insulin-like growth factor-1 receptor (IGF1R) and IGF binding protein-3 (IGFBP3) in patients with pancreatic cancer. The function of IGFBP3 is controversial, because both inhibition and facilitation of the action of IGF as well as IGF-independent effects have been reported. In this study, IGF1R and IGFBP3 expression was examined, and their potential roles as prognostic markers in patients with pancreatic cancer were evaluated. Clinicopathological features of 122 patients with curatively resected pancreatic cancer were retrospectively reviewed, and expression of IGF1R and IGFBP3 was immunohistochemically analyzed. Expression of IGF1R and IGFBP3 was observed in 50 (41.0%) and 37 (30.3%) patients, respectively. IGF1R expression was significantly associated with histological grade (p = 0.037). IGFBP3 expression had a significant association with tumor location (p = 0.023), and a significant inverse association with venous invasion (p = 0.037). Tumors with IGF1R-positive and IGFBP3-negative expression (n = 32) were significantly frequently Stage II and III (p = 0.011). The prognosis for IGF1R positive patients was significantly poorer than that for IGF1R negative patients (p = 0.0181). IGFBP3 protein expression did not correlate significantly with patient survival. The subset of patients with both positive IGF1R and negative IGFBP3 had worse overall survival (8.8 months versus 12.6 months, respectively, p < 0.001). IGF1R signaling might be associated with tumor aggressiveness, and IGFBP3 might show antiproliferative effects in pancreatic cancer. Both high IGF1R expression and low IGFBP3 expression represent useful prognostic markers for patients with curatively resected pancreatic cancer

  12. Tore Supra Contribution to Experimental Prediction of the Power Flux to the Limiter in the ITER Start-up Mode

    International Nuclear Information System (INIS)

    Full text: This paper reports on the experimental programme run on Tore Supra, taking advantage of its limiter plasma edge, to gain more confidence in the prediction of the power flux to the start-up limiter in ITER. A scaling law for the value of parallel power flux q|| at the last closed flux surface, and its e-folding length λq in the scrape-off layer is proposed in limiter configuration. It finds a different dependence on macroscopic plasma parameters than the scaling presently used for ITER tile shaping. For example, at constant power flowing into the scrape-off layer the measured λq decreases with density, whereas the ITER scaling law predicts the opposite behaviour. The method that is used combines Langmuir probe, retarding field analyzer measurements, and power balance analysis. Using this method, it is found that strong secondary electron emission dominates the physics of power transmission to the wall. It results that the ion power flux is much smaller than expected, most of the power being carried by electrons. Nonetheless, the power decay length scaling found using this method is similar to standard Langmuir probe analysis because q|| is dominated by the J|| profile. In addition to this, for very high electron densities (up to a factor 1.4 above the Greenwald value) a steady-state highly radiating regime is observed, minimising the heat load on the limiter. This regime is investigated through a dedicated set of edge diagnostics, including Langmuir probes and spatially resolved VUV spectroscopy on the limiter. (author)

  13. The structure of tubulin-binding cofactor A from Leishmania major infers a mode of association during the early stages of microtubule assembly

    Energy Technology Data Exchange (ETDEWEB)

    Barrack, Keri L.; Fyfe, Paul K.; Hunter, William N., E-mail: w.n.hunter@dundee.ac.uk [University of Dundee, Dow Street, Dundee DD1 5EH, Scotland (United Kingdom)

    2015-04-21

    The structure of a tubulin-binding cofactor from L. major is reported and compared with yeast, plant and human orthologues. Tubulin-binding cofactor A (TBCA) participates in microtubule formation, a key process in eukaryotic biology to create the cytoskeleton. There is little information on how TBCA might interact with β-tubulin en route to microtubule biogenesis. To address this, the protozoan Leishmania major was targeted as a model system. The crystal structure of TBCA and comparisons with three orthologous proteins are presented. The presence of conserved features infers that electrostatic interactions that are likely to involve the C-terminal tail of β-tubulin are key to association. This study provides a reagent and template to support further work in this area.

  14. Structural and Enzymatic Analyses Reveal the Binding Mode of a Novel Series of Francisella tularensis Enoyl Reductase (FabI) Inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Mehboob, Shahila; Hevener, Kirk E.; Truong, Kent; Boci, Teuta; Santarsiero, Bernard D.; Johnson, Michael E. (UIC)

    2012-10-10

    Because of structural and mechanistic differences between eukaryotic and prokaryotic fatty acid synthesis enzymes, the bacterial pathway, FAS-II, is an attractive target for the design of antimicrobial agents. We have previously reported the identification of a novel series of benzimidazole compounds with particularly good antibacterial effect against Francisella tularensis, a Category A biowarfare pathogen. Herein we report the crystal structure of the F. tularensis FabI enzyme in complex with our most active benzimidazole compound bound with NADH. The structure reveals that the benzimidazole compounds bind to the substrate site in a unique conformation that is distinct from the binding motif of other known FabI inhibitors. Detailed inhibition kinetics have confirmed that the compounds possess a novel inhibitory mechanism that is unique among known FabI inhibitors. These studies could have a strong impact on future antimicrobial design efforts and may reveal new avenues for the design of FAS-II active antibacterial compounds.

  15. 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

    have previously been suggested based on molecular docking guided by structure-activity relationship (SAR) data; however, none of these have been verified by in vitro experiments. EXPERIMENTAL APPROACH: Heterologous (125) I-12G5-competition binding and functional assays (inhibition of CXCL12-mediated...... suggested from previous SAR studies. Furthermore, insights into the mechanism for CXCR4 activation by CXCL12 were gained. The combined findings will facilitate future design of novel CXCR4 antagonists....

  16. Crystal structure of enoyl-acyl carrier protein reductase (FabK) from Streptococcus pneumoniae reveals the binding mode of an inhibitor.

    Science.gov (United States)

    Saito, Jun; Yamada, Mototsugu; Watanabe, Takashi; Iida, Maiko; Kitagawa, Hideo; Takahata, Sho; Ozawa, Tomohiro; Takeuchi, Yasuo; Ohsawa, Fukuichi

    2008-04-01

    Enoyl-acyl carrier protein (ACP) reductases are critical for bacterial type II fatty acid biosynthesis and thus are attractive targets for developing novel antibiotics. We determined the crystal structure of enoyl-ACP reductase (FabK) from Streptococcus pneumoniae at 1.7 A resolution. There was one dimer per asymmetric unit. Each subunit formed a triose phosphate isomerase (TIM) barrel structure, and flavin mononucleotide (FMN) was bound as a cofactor in the active site. The overall structure was similar to the enoyl-ACP reductase (ER) of fungal fatty acid synthase and to 2-nitropropane dioxygenase (2-ND) from Pseudomonas aeruginosa, although there were some differences among these structures. We determined the crystal structure of FabK in complex with a phenylimidazole derivative inhibitor to envision the binding site interactions. The crystal structure reveals that the inhibitor binds to a hydrophobic pocket in the active site of FabK, and this is accompanied by induced-fit movements of two loop regions. The thiazole ring and part of the ureido moiety of the inhibitor are involved in a face-to-face pi-pi stacking interaction with the isoalloxazine ring of FMN. The side-chain conformation of the proposed catalytic residue, His144, changes upon complex formation. Lineweaver-Burk plots indicate that the inhibitor binds competitively with respect to NADH, and uncompetitively with respect to crotonoyl coenzyme A. We propose that the primary basis of the inhibitory activity is competition with NADH for binding to FabK, which is the first step of the two-step ping-pong catalytic mechanism. PMID:18305197

  17. Design and synthesis of BODIPY-clickate based Hg(2+) sensors: the effect of triazole binding mode with Hg(2+) on signal transduction.

    Science.gov (United States)

    Vedamalai, Mani; Kedaria, Dhaval; Vasita, Rajesh; Mori, Shigeki; Gupta, Iti

    2016-02-14

    BODIPY-clickates, F1 and F2, for the detection of Hg(2+) have been designed, synthesized and characterized. Both F1 and F2 showed hyperchromic shifts in the UV-visible spectra in response to increasing Hg(2+) concentrations. Hg(2+) ion binding caused perturbation of the emission quenching process and chelation induced enhanced bathochromic emission of F1 and F2 to 620 nm and 660 nm, respectively. Job's plot clearly indicated that the binding ratio of F1 and F2 with Hg(2+) was 1 : 1. The NMR titration of BODIPY-clickates with Hg(2+) confirmed that aromatic amines and triazoles were involved in the binding event. Furthermore, HRMS data of F1-Hg(2+) and F2-Hg(2+) supported the formation of mercury complexes of BODIPY-clickates. The dissociation constant for the interaction between fluorescent probes F1 and F2 with Hg(2+) was found to be 24.4 ± 5.1 μM and 22.0 ± 3.9 μM, respectively. The Hg(2+) ion induced fluorescence enhancement was almost stable in a pH range of 5 to 8. Having less toxicity to live cells, both the probes were successfully used to map the Hg(2+) ions in live A549 cells. PMID:26743311

  18. In situ study of binding of copper by fulvic acid: comparison of differential absorbance data and model predictions.

    Science.gov (United States)

    Yan, Mingquan; Dryer, Deborah; Korshin, Gregory V; Benedetti, Marc F

    2013-02-01

    This study examined the binding of copper(II) by Suwannee River fulvic acid (SRFA) using the method of differential absorbance that was used at environmentally-relevant concentrations of copper and SRFA. The pH- and metal-differential spectra were processed via numeric deconvolution to establish commonalities seen in the changes of absorbance caused by deprotonation of SRFA and its interactions with copper(II) ions. Six Gaussian bands were determined to be present in both the pH- and Cu-differential spectra. Their maxima were located, in the order of increasing wavelengths at 208 nm, 242 nm, 276 nm, 314 nm, 378 nm and 551 nm. The bands with these maxima were denoted as A0, A1, A2, A3, A4 and A5, respectively. Properties of these bands were compared with those existing in the spectra of model compounds such as sulfosalicylic acid (SSA), tannic acid (TA), and polystyrenesulfonic acid-co-maleic acid (PSMA). While none of the features observed in differential spectra of the model compound were identical to those present in the case of SRFA, Gaussian bands A1, A3 and possibly A2 were concluded to be largely attributable to a combination of responses of salicylic- and polyhydroxyphenolic groups. In contrast, bands A4 and A5 were detected in the differential spectra of SRFA only. Their nature remains to be elucidated. To examine correlations between the amount of copper(II) bound by SRFA and changes of its absorbance, differential absorbances measured at indicative wavelengths 250 nm and 400 nm were compared with the total amount of SRFA-bound copper estimated based on Visual MINTEQ calculations. This examination showed that the differential absorbances of SRFA in a wide range of pH values and copper concentrations were strongly correlated with the concentration of SRFA-bound copper. The approach presented in this study can be used to generate in situ information concerning the nature of functional groups in humic substances engaged in interactions with metals ions. This

  19. 基于宏块模式预测的时域错误隐藏算法%Temporal Error Concealment Algorithm Based on Macroblock Mode Prediction

    Institute of Scientific and Technical Information of China (English)

    朱冰莲; 刘剑东

    2009-01-01

    Aiming at the problem that the compressed video stream will inevitable be corrupted because of the wireless channel errors, which may degrade the reconstructed image quality, this paper presents an efficient temporal error concealment method which based on improved border-matching function and flexible macroblock mode of H.264 video standard. It utilizes the relativity between lost macroblock and other surrounding macroblocks to predict the block mode, and estimates the motion vector of the lost macroblock depending on the block mode. Simulation results under 3GPP/3GPP2 wireless channel show the proposed method performs better quality than other approaches with the same RTP packet loss rate.%针对压缩视频码流在无线信道传输过程中由于数据丢失或错误面导致的重构图像质量的问题,提出一种时域错误隐藏方法.在对边界匹配函数改进的基础上,根据H.264视频标准具有灵活的宏块分割模式的特点,利用受损宏块与其周围宏块的相关性预测分块模式进行运动矢量估计.实验结果表明,在相同的RTP包丢失率情况下,该算法与其他算法相比,能恢复出更高质量的图像.

  20. Optical binding of cylinder photonic molecules in the near-field of partially coherent fluctuating Gaussian Schell model sources. A coherent mode representation

    CERN Document Server

    Auñón, Juan Miguel; Nieto-Vesperinas, Manuel

    2014-01-01

    We present a theory and computation method of radiation pressure from partially coherent light by establishing a coherent mode representation of the radiation forces. This is illustrated with the near field emitted from a Gaussian Schell model source, mechanically acting on a single cylinder with magnetodielectric behavior, or on a photonic molecule constituted by a pair of such cylinders. Thus after studying the force produced by a single particle, we address the effects of the spatial coherence on the bonding and anti-bonding states of two particles. The coherence length manifests the critical limitation of the contribution of evanescent modes to the scattered fields, and hence to the nature and strength of the electromagnetic fores, even when electric and/or magnetic partial wave resonances are excited.

  1. ProClusEnsem: Predicting membrane protein types by fusing different modes of pseudo amino acid composition

    KAUST Repository

    Wang, Jingyan

    2012-05-01

    Knowing the type of an uncharacterized membrane protein often provides a useful clue in both basic research and drug discovery. With the explosion of protein sequences generated in the post genomic era, determination of membrane protein types by experimental methods is expensive and time consuming. It therefore becomes important to develop an automated method to find the possible types of membrane proteins. In view of this, various computational membrane protein prediction methods have been proposed. They extract protein feature vectors, such as PseAAC (pseudo amino acid composition) and PsePSSM (pseudo position-specific scoring matrix) for representation of protein sequence, and then learn a distance metric for the KNN (K nearest neighbor) or NN (nearest neighbor) classifier to predicate the final type. Most of the metrics are learned using linear dimensionality reduction algorithms like Principle Components Analysis (PCA) and Linear Discriminant Analysis (LDA). Such metrics are common to all the proteins in the dataset. In fact, they assume that the proteins lie on a uniform distribution, which can be captured by the linear dimensionality reduction algorithm. We doubt this assumption, and learn local metrics which are optimized for local subset of the whole proteins. The learning procedure is iterated with the protein clustering. Then a novel ensemble distance metric is given by combining the local metrics through Tikhonov regularization. The experimental results on a benchmark dataset demonstrate the feasibility and effectiveness of the proposed algorithm named ProClusEnsem. © 2012 Elsevier Ltd.

  2. Strong overtones modes in inelastic electron tunneling spectroscopy with cross-conjugated molecules: a prediction from theory.

    Science.gov (United States)

    Lykkebo, Jacob; Gagliardi, Alessio; Pecchia, Alessandro; Solomon, Gemma C

    2013-10-22

    Cross-conjugated molecules are known to exhibit destructive quantum interference, a property that has recently received considerable attention in single-molecule electronics. Destructive quantum interference can be understood as an antiresonance in the elastic transmission near the Fermi energy and leading to suppressed levels of elastic current. In most theoretical studies, only the elastic contributions to the current are taken into account. In this paper, we study the inelastic contributions to the current in cross-conjugated molecules and find that while the inelastic contribution to the current is larger than for molecules without interference, the overall behavior of the molecule is still dominated by the quantum interference feature. Second, an ongoing challenge for single molecule electronics is understanding and controlling the local geometry at the molecule-surface interface. With this in mind, we investigate a spectroscopic method capable of providing insight into these junctions for cross-conjugated molecules: inelastic electron tunneling spectroscopy (IETS). IETS has the advantage that the molecule interface is probed directly by the tunneling current. Previously, it has been thought that overtones are not observable in IETS. Here, overtones are predicted to be strong and, in some cases, the dominant spectroscopic features. We study the origin of the overtones and find that the interference features in these molecules are the key ingredient. The interference feature is a property of the transmission channels of the π system only, and consequently, in the vicinity of the interference feature, the transmission channels of the σ system and the π system become equally transmissive. This allows for scattering between the different transmission channels, which serves as a pathway to bypass the interference feature. A simple model calculation is able to reproduce the results obtained from atomistic calculations, and we use this to interpret these findings

  3. Tyrosine 105 and threonine 212 at outermost substrate binding subsites -6 and +4 control substrate specificity, oligosaccharide cleavage patterns, and multiple binding modes of barley alpha-amylase 1

    DEFF Research Database (Denmark)

    Bak-Jensen, K.S.; André, G.; Gottschalk, T.E.;

    2004-01-01

    in plant alpha-amylases whereas Thr(212) varies in these and related enzymes. Compared with wild-type AMY1, the subsite -6 mutant Y105A has 140, 15, and activity (k(cat)/K-m) on starch, amylose DP17, and 2-chloro-4-nitrophenyl β-D-maltoheptaoside, whereas T212Y at subsite +4 has 32, 370, and 90......% activity, respectively. Thus engineering of aromatic stacking interactions at the ends of the 10-subsite long binding cleft affects activity very differently, dependent on the substrate. Y105A dominates in dual subsite -6/+4 [Y105A/T212(Y/W)] AMY1 mutants having almost retained and low activity on starch......The role in activity of outer regions in the substrate binding cleft in alpha-amylases is illustrated by mutational analysis of Tyr(105) and Thr(212) localized at subsites - 6 and +4 ( substrate cleavage occurs between subsites -1 and +1) in barley alpha-amylase 1 (AMY1). Tyr(105) is conserved...

  4. Investigation of the mode of binding of a novel series of N-benzyl-4-heteroaryl-1-(phenylsulfonyl)piperazine-2-carboxamides to the hepatitis C virus polymerase

    Energy Technology Data Exchange (ETDEWEB)

    Gentles, Robert G.; Sheriff, Steven; Beno, Brett R.; Wan, Changhong; Kish, Kevin; Ding, Min; Zheng, Xiaofan; Chupak, Louis; Poss, Michael A.; Witmer, Mark R.; Morin, Paul; Wang, Ying-Kai; Rigat, Karen; Lemm, Julie; Voss, Stacey; Liu, Mengping; Pelosi, Lenore; Roberts, Susan B.; Gao, Min; Kadow, John F. (BMS)

    2013-11-20

    Structure based rationales for the activities of potent N-benzyl-4-heteroaryl-1-(phenylsulfonyl)piperazine-2-carboxamide inhibitors of the hepatitis C viral polymerase are described herein. These compounds bind to the hepatitis C virus non-structural protein 5B (NS5B), and co-crystal structures of select examples from this series with NS5B are reported. Comparison of co-crystal structures of a potent analog with both NS5B genotype 1a and genotype 1b provides a possible explanation for the genotype-selectivity observed with this compound class and suggests opportunities for the further optimization of the series.

  5. Genetic Analysis of the Mode of Interplay between an ATPase Subunit and Membrane Subunits of the Lipoprotein-Releasing ATP-Binding Cassette Transporter LolCDE†

    OpenAIRE

    Ito, Yasuko; Matsuzawa, Hitomi; Matsuyama, Shin-ichi; Narita, Shin-ichiro; Tokuda, Hajime

    2006-01-01

    The LolCDE complex, an ATP-binding cassette (ABC) transporter, releases lipoproteins from the inner membrane, thereby initiating lipoprotein sorting to the outer membrane of Escherichia coli. The LolCDE complex is composed of two copies of an ATPase subunit, LolD, and one copy each of integral membrane subunits LolC and LolE. LolD hydrolyzes ATP on the cytoplasmic side of the inner membrane, while LolC and/or LolE recognize and release lipoproteins anchored to the periplasmic leaflet of the i...

  6. Prediction of altered 3'- UTR miRNA-binding sites from RNA-Seq data: the swine leukocyte antigen complex (SLA as a model region.

    Directory of Open Access Journals (Sweden)

    Marie-Laure Endale Ahanda

    Full Text Available THE SLA (swine leukocyte antigen, MHC: SLA genes are the most important determinants of immune, infectious disease and vaccine response in pigs; several genetic associations with immunity and swine production traits have been reported. However, most of the current knowledge on SLA is limited to gene coding regions. MicroRNAs (miRNAs are small molecules that post-transcriptionally regulate the expression of a large number of protein-coding genes in metazoans, and are suggested to play important roles in fine-tuning immune mechanisms and disease responses. Polymorphisms in either miRNAs or their gene targets may have a significant impact on gene expression by abolishing, weakening or creating miRNA target sites, possibly leading to phenotypic variation. We explored the impact of variants in the 3'-UTR miRNA target sites of genes within the whole SLA region. The combined predictions by TargetScan, PACMIT and TargetSpy, based on different biological parameters, empowered the identification of miRNA target sites and the discovery of polymorphic miRNA target sites (poly-miRTSs. Predictions for three SLA genes characterized by a different range of sequence variation provided proof of principle for the analysis of poly-miRTSs from a total of 144 M RNA-Seq reads collected from different porcine tissues. Twenty-four novel SNPs were predicted to affect miRNA-binding sites in 19 genes of the SLA region. Seven of these genes (SLA-1, SLA-6, SLA-DQA, SLA-DQB1, SLA-DOA, SLA-DOB and TAP1 are linked to antigen processing and presentation functions, which is reminiscent of associations with disease traits reported for altered miRNA binding to MHC genes in humans. An inverse correlation in expression levels was demonstrated between miRNAs and co-expressed SLA targets by exploiting a published dataset (RNA-Seq and small RNA-Seq of three porcine tissues. Our results support the resource value of RNA-Seq collections to identify SNPs that may lead to altered mi

  7. Prediction of altered 3'- UTR miRNA-binding sites from RNA-Seq data: the swine leukocyte antigen complex (SLA) as a model region.

    Science.gov (United States)

    Endale Ahanda, Marie-Laure; Fritz, Eric R; Estellé, Jordi; Hu, Zhi-Liang; Madsen, Ole; Groenen, Martien A M; Beraldi, Dario; Kapetanovic, Ronan; Hume, David A; Rowland, Robert R R; Lunney, Joan K; Rogel-Gaillard, Claire; Reecy, James M; Giuffra, Elisabetta

    2012-01-01

    THE SLA (swine leukocyte antigen, MHC: SLA) genes are the most important determinants of immune, infectious disease and vaccine response in pigs; several genetic associations with immunity and swine production traits have been reported. However, most of the current knowledge on SLA is limited to gene coding regions. MicroRNAs (miRNAs) are small molecules that post-transcriptionally regulate the expression of a large number of protein-coding genes in metazoans, and are suggested to play important roles in fine-tuning immune mechanisms and disease responses. Polymorphisms in either miRNAs or their gene targets may have a significant impact on gene expression by abolishing, weakening or creating miRNA target sites, possibly leading to phenotypic variation. We explored the impact of variants in the 3'-UTR miRNA target sites of genes within the whole SLA region. The combined predictions by TargetScan, PACMIT and TargetSpy, based on different biological parameters, empowered the identification of miRNA target sites and the discovery of polymorphic miRNA target sites (poly-miRTSs). Predictions for three SLA genes characterized by a different range of sequence variation provided proof of principle for the analysis of poly-miRTSs from a total of 144 M RNA-Seq reads collected from different porcine tissues. Twenty-four novel SNPs were predicted to affect miRNA-binding sites in 19 genes of the SLA region. Seven of these genes (SLA-1, SLA-6, SLA-DQA, SLA-DQB1, SLA-DOA, SLA-DOB and TAP1) are linked to antigen processing and presentation functions, which is reminiscent of associations with disease traits reported for altered miRNA binding to MHC genes in humans. An inverse correlation in expression levels was demonstrated between miRNAs and co-expressed SLA targets by exploiting a published dataset (RNA-Seq and small RNA-Seq) of three porcine tissues. Our results support the resource value of RNA-Seq collections to identify SNPs that may lead to altered miRNA regulation patterns.

  8. Effective transcription factor binding site prediction using a combination of optimization, a genetic algorithm and discriminant analysis to capture distant interactions

    Directory of Open Access Journals (Sweden)

    Merkulova Tatyana I

    2007-12-01

    Full Text Available Abstract Background Reliable transcription factor binding site (TFBS prediction methods are essential for computer annotation of large amount of genome sequence data. However, current methods to predict TFBSs are hampered by the high false-positive rates that occur when only sequence conservation at the core binding-sites is considered. Results To improve this situation, we have quantified the performance of several Position Weight Matrix (PWM algorithms, using exhaustive approaches to find their optimal length and position. We applied these approaches to bio-medically important TFBSs involved in the regulation of cell growth and proliferation as well as in inflammatory, immune, and antiviral responses (NF-κB, ISGF3, IRF1, STAT1, obesity and lipid metabolism (PPAR, SREBP, HNF4, regulation of the steroidogenic (SF-1 and cell cycle (E2F genes expression. We have also gained extra specificity using a method, entitled SiteGA, which takes into account structural interactions within TFBS core and flanking regions, using a genetic algorithm (GA with a discriminant function of locally positioned dinucleotide (LPD frequencies. To ensure a higher confidence in our approach, we applied resampling-jackknife and bootstrap tests for the comparison, it appears that, optimized PWM and SiteGA have shown similar recognition performances. Then we applied SiteGA and optimized PWMs (both separately and together to sequences in the Eukaryotic Promoter Database (EPD. The resulting SiteGA recognition models can now be used to search sequences for BSs using the web tool, SiteGA. Analysis of dependencies between close and distant LPDs revealed by SiteGA models has shown that the most significant correlations are between close LPDs, and are generally located in the core (footprint region. A greater number of less significant correlations are mainly between distant LPDs, which spanned both core and flanking regions. When SiteGA and optimized PWM models were applied

  9. Crystal Structure of Cockroach Allergen Bla g 2, an Unusual Zinc Binding Aspartic Protease with a Novel Mode of Self-inhibition

    Energy Technology Data Exchange (ETDEWEB)

    Gustchina, Alla; Li, Mi; Wunschmann, Sabina; Chapman, Martin D.; Pomes, Anna; Wlodawer, Alexander (INDOOR Bio.); (NIH)

    2010-07-19

    The crystal structure of Bla g 2 was solved in order to investigate the structural basis for the allergenic properties of this unusual protein. This is the first structure of an aspartic protease in which conserved glycine residues, in two canonical DTG triads, are substituted by different amino acid residues. Another unprecedented feature revealed by the structure is the single phenylalanine residue insertion on the tip of the flap, with the side-chain occupying the S1 binding pocket. This and other important amino acid substitutions in the active site region of Bla g 2 modify the interactions in the vicinity of the catalytic aspartate residues, increasing the distance between them to {approx}4 {angstrom} and establishing unique direct contacts between the flap and the catalytic residues. We attribute the absence of substantial catalytic activity in Bla g 2 to these unusual features of the active site. Five disulfide bridges and a Zn-binding site confer stability to the protein, which may contribute to sensitization at lower levels of exposure than other allergens.

  10. Interactions of L-3,5,3'-Triiodothyronine [corrected], Allopregnanolone, and Ivermectin with the GABAA Receptor: Evidence for Overlapping Intersubunit Binding Modes.

    Directory of Open Access Journals (Sweden)

    Thomas Westergard

    Full Text Available Structural mechanisms of modulation of γ-aminobutyric acid (GABA type A receptors by neurosteroids and hormones remain unclear. The thyroid hormone L-3,5,3'-triiodothyronine (T3 inhibits GABAA receptors at micromolar concentrations and has common features with neurosteroids such as allopregnanolone (ALLOP. Here we use functional experiments on α2β1γ2 GABAA receptors expressed in Xenopus oocytes to detect competitive interactions between T3 and an agonist (ivermectin, IVM with a crystallographically determined binding site at subunit interfaces in the transmembrane domain of a homologous receptor (glutamate-gated chloride channel, GluCl. T3 and ALLOP also show competitive effects, supporting the presence of both a T3 and ALLOP binding site at one or more subunit interfaces. Molecular dynamics (MD simulations over 200 ns are used to investigate the dynamics and energetics of T3 in the identified intersubunit sites. In these simulations, T3 molecules occupying all intersubunit sites (with the exception of the α-β interface display numerous energetically favorable conformations with multiple hydrogen bonding partners, including previously implicated polar/acidic sidechains and a structurally conserved deformation in the M1 backbone.

  11. The X-Ray Structure of the Ligand-Free Antibiotic Ristocetin-A Reveals the Role of the Monomer/Dimer Equilibrium in Its Binding Mode

    Directory of Open Access Journals (Sweden)

    Thierry Prangé

    2016-01-01

    Full Text Available Ristocetin-A belongs to the group of the glycoheptapeptide antibiotics. The sulfate salt of ristocetin-A was crystallized in the P21 monoclinic space group with a homodimer in the asymmetric unit. The two subunits are linked back-to-back like the other members of the family via four peptide bonds forming a twisted β-sheet and exposing the binding pockets to the exterior. The two tetrasaccharide parts of this ligand-free antibiotic are in the anti/anti orientations contrary to what was found in the mono- and diliganded ristocetin-A/-(D-Ala-D-Ala complexes in which the two tetrasaccharides of the dimer are syn/anti. The ligand-free dimer shows however some conformational differences between the two subunits, particularly in the terminal arabinose leading to one extended and one bent conformation of the tetrasaccharide moiety. Comparison between this structure and the two available mono- and diliganded structures confirms that the anti/anti to syn/anti flipping of the tetrasaccharide is a key step in the binding to the D-Ala-D-Ala-containing target sequence and cannot proceed without displacement of the monomer/dimer equilibrium.

  12. Molecular Models of STAT5A Tetramers Complexed to DNA Predict Relative Genome-Wide Frequencies of the Spacing between the Two Dimer Binding Motifs of the Tetramer Binding Sites.

    Science.gov (United States)

    Sathyanarayana, Bangalore K; Li, Peng; Lin, Jian-Xin; Leonard, Warren J; Lee, Byungkook

    2016-01-01

    STAT proteins bind DNA as dimers and tetramers to control cellular development, differentiation, survival, and expansion. The tetramer binding sites are comprised of two dimer-binding sites repeated in tandem. The genome-wide distribution of the spacings between the dimer binding sites shows a distinctive, non-random pattern. Here, we report on estimating the feasibility of building possible molecular models of STAT5A tetramers bound to a DNA double helix with all possible spacings between the dimer binding sites. We found that the calculated feasibility estimates correlated well with the experimentally measured frequency of tetramer-binding sites. This suggests that the feasibility of forming the tetramer complex was a major factor in the evolution of this DNA sequence variation. PMID:27537504

  13. Investigating the impacts of DNA binding mode and sequence on thermodynamic quantities and water exchange values for two small molecule drugs.

    Science.gov (United States)

    Kenney, Rachael M; Buxton, Katherine E; Glazier, Samantha

    2016-09-01

    Doxorubicin and nogalamycin are antitumor antibiotics that interact with DNA via intercalation and threading mechanisms, respectively. Because the importance of water, particularly its impact on entropy changes, has been established in other biological processes, we investigated the role of water in these two drug-DNA binding events. We used the osmotic stress method to calculate the number of water molecules exchanged (Δnwater), and isothermal titration calorimetry to measure Kbinding, ΔH, and ΔS for two synthetic DNAs, poly(dA·dT) and poly(dG·dC), and calf thymus DNA (CT DNA). For nogalamycin, Δnwater0 for CT DNA and Δnwaterenthalpy changes were always negative, but net entropy changes depended on the drug. The effect of water exchange on the overall sign of entropy change appears to be smaller than other contributions.

  14. The structure of the exopolyphsophatase (PPX) from Escherchia coli O157:H7 suggests a binding mode for long polyphosphate chains

    Energy Technology Data Exchange (ETDEWEB)

    Rangarajan,E.; Nadeau, G.; Li, Y.; Wagner, J.; Hung, M.; Schrag, J.; Cygler, M.; Matte, A.

    2006-01-01

    Polyphosphate (polyP) is a linear polymer consisting of tens to hundreds of phosphate molecules joined together by high-energy anhydride bonds. These polymers are found in virtually all prokaryotic and eukaryotic cells and perform many functions; prominent among them are the responses to many stresses. Polyphosphate is synthesized by polyP kinase (PPK), using the terminal phosphate of ATP as the substrate, and degraded to inorganic phosphate by both endo- and exopolyphosphatases. Here we report the crystal structure and analysis of the polyphosphate phosphatase PPX from Escherichia coli O157:H7 refined at 2.2 Angstroms resolution. PPX is made of four domains. Domains I and II display structural similarity with one another and share the ribonuclease-H-like fold. Domain III bears structural similarity to the N-terminal, HD domain of SpoT. Domain IV, the smallest domain, has structural counterparts in cold-shock associated RNA-binding proteins but is of unknown function in PPX. The putative PPX active site is located at the interface between domains I and II. In the crystal structure of PPX these two domains are close together and represent the 'closed' state. Comparison with the crystal structure of PPX/GPPA from Aquifex aeolicus reveals close structural similarity between domains I and II of the two enzymes, with the PPX/GPPA representing an 'open' state. A striking feature of the dimer is a deep S-shaped canyon extending along the dimer interface and lined with positively charged residues. The active site region opens to this canyon. We postulate that this is a likely site of polyP binding.

  15. Urinary Tissue Inhibitor of Metalloproteinase-2 (TIMP-2) • Insulin-Like Growth Factor-Binding Protein 7 (IGFBP7) Predicts Adverse Outcome in Pediatric Acute Kidney Injury

    Science.gov (United States)

    Westhoff, Jens H.; Tönshoff, Burkhard; Waldherr, Sina; Pöschl, Johannes; Teufel, Ulrike; Westhoff, Timm H.; Fichtner, Alexander

    2015-01-01

    Background The G1 cell cycle inhibitors tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) have been identified as promising biomarkers for the prediction of adverse outcomes including renal replacement therapy (RRT) and mortality in critically ill adult patients who develop acute kidney injury (AKI). However, the prognostic value of urinary TIMP-2 and IGFBP7 in neonatal and pediatric AKI for adverse outcome has not been investigated yet. Methods The product of the urinary concentration of TIMP-2 and IGFBP7 ([TIMP-2]•[IGFBP7]) was assessed by a commercially available immunoassay (NephroCheck™) in a prospective cohort study in 133 subjects aged 0–18 years including 46 patients with established AKI according to pRIFLE criteria, 27 patients without AKI (non-AKI group I) and 60 apparently healthy neonates and children (non-AKI group II). AKI etiologies were: dehydration/hypovolemia (n = 7), hemodynamic instability (n = 7), perinatal asphyxia (n = 9), septic shock (n = 7), typical hemolytic-uremic syndrome (HUS; n = 5), interstitial nephritis (n = 5), vasculitis (n = 4), nephrotoxic injury (n = 1) and renal vein thrombosis (n = 1). Results When AKI patients were classified into pRIFLE criteria, 6/46 (13%) patients fulfilled the criteria for the category “Risk”, 13/46 (28%) for “Injury”, 26/46 (57%) for “Failure” and 1/46 (2%) for “Loss”. Patients in the “Failure” stage had a median 3.7-fold higher urinary [TIMP-2]•[IGFBP7] compared to non-AKI subjects (P<0.001). When analyzed for AKI etiology, highest [TIMP-2]•[IGFBP7] values were found in patients with septic shock (P<0.001 vs. non-AKI I+II). Receiver operating characteristic (ROC) curve analyses in the AKI group revealed good performance of [TIMP-2]•[IGFBP7] in predicting 30-day (area under the curve (AUC) 0.79; 95% CI, 0.61–0.97) and 3-month mortality (AUC 0.84; 95% CI, 0.67–0.99) and moderate performance in predicting RRT

  16. Urinary Tissue Inhibitor of Metalloproteinase-2 (TIMP-2 • Insulin-Like Growth Factor-Binding Protein 7 (IGFBP7 Predicts Adverse Outcome in Pediatric Acute Kidney Injury.

    Directory of Open Access Journals (Sweden)

    Jens H Westhoff

    Full Text Available The G1 cell cycle inhibitors tissue inhibitor of metalloproteinase-2 (TIMP-2 and insulin-like growth factor-binding protein 7 (IGFBP7 have been identified as promising biomarkers for the prediction of adverse outcomes including renal replacement therapy (RRT and mortality in critically ill adult patients who develop acute kidney injury (AKI. However, the prognostic value of urinary TIMP-2 and IGFBP7 in neonatal and pediatric AKI for adverse outcome has not been investigated yet.The product of the urinary concentration of TIMP-2 and IGFBP7 ([TIMP-2]•[IGFBP7] was assessed by a commercially available immunoassay (NephroCheck™ in a prospective cohort study in 133 subjects aged 0-18 years including 46 patients with established AKI according to pRIFLE criteria, 27 patients without AKI (non-AKI group I and 60 apparently healthy neonates and children (non-AKI group II. AKI etiologies were: dehydration/hypovolemia (n = 7, hemodynamic instability (n = 7, perinatal asphyxia (n = 9, septic shock (n = 7, typical hemolytic-uremic syndrome (HUS; n = 5, interstitial nephritis (n = 5, vasculitis (n = 4, nephrotoxic injury (n = 1 and renal vein thrombosis (n = 1.When AKI patients were classified into pRIFLE criteria, 6/46 (13% patients fulfilled the criteria for the category "Risk", 13/46 (28% for "Injury", 26/46 (57% for "Failure" and 1/46 (2% for "Loss". Patients in the "Failure" stage had a median 3.7-fold higher urinary [TIMP-2]•[IGFBP7] compared to non-AKI subjects (P<0.001. When analyzed for AKI etiology, highest [TIMP-2]•[IGFBP7] values were found in patients with septic shock (P<0.001 vs. non-AKI I+II. Receiver operating characteristic (ROC curve analyses in the AKI group revealed good performance of [TIMP-2]•[IGFBP7] in predicting 30-day (area under the curve (AUC 0.79; 95% CI, 0.61-0.97 and 3-month mortality (AUC 0.84; 95% CI, 0.67-0.99 and moderate performance in predicting RRT (AUC 0.67; 95% CI, 0.50-0.84.This study shows that urinary [TIMP

  17. Predictive Effects of Urinary Liver-Type Fatty Acid–Binding Protein for Deteriorating Renal Function and Incidence of Cardiovascular Disease in Type 2 Diabetic Patients Without Advanced Nephropathy

    OpenAIRE

    Araki, Shin-ichi; Haneda, Masakazu; Koya, Daisuke; Sugaya, Takeshi; Isshiki, Keiji; Kume, Shinji; Kashiwagi, Atsunori; Uzu, Takashi; Maegawa, Hiroshi

    2013-01-01

    OBJECTIVE To improve prognosis, it is important to predict the incidence of renal failure and cardiovascular disease in type 2 diabetic patients before the progression to advanced nephropathy. We investigated the predictive effects of urinary liver-type fatty acid–binding protein (L-FABP), which is associated with renal tubulointerstitial damage, in renal and cardiovascular prognosis. RESEARCH DESIGN AND METHODS Japanese type 2 diabetic patients (n = 618) with serum creatinine ≤1.0 mg/dL and ...

  18. Delineating binding modes of Gal/GalNAc and structural elements of the molecular recognition of tumor-associated mucin glycopeptides by the human macrophage galactose-type lectin.

    Science.gov (United States)

    Marcelo, Filipa; Garcia-Martin, Fayna; Matsushita, Takahiko; Sardinha, João; Coelho, Helena; Oude-Vrielink, Anneloes; Koller, Christiane; André, Sabine; Cabrita, Eurico J; Gabius, Hans-Joachim; Nishimura, Shin-Ichiro; Jiménez-Barbero, Jesús; Cañada, F Javier

    2014-12-01

    The human macrophage galactose-type lectin (MGL) is a key physiological receptor for the carcinoma-associated Tn antigen (GalNAc-α-1-O-Ser/Thr) in mucins. NMR and modeling-based data on the molecular recognition features of synthetic Tn-bearing glycopeptides by MGL are presented. Cognate epitopes on the sugar and matching key amino acids involved in the interaction were identified by saturation transfer difference (STD) NMR spectroscopy. Only the amino acids close to the glycosylation site in the peptides are involved in lectin contact. Moreover, control experiments with non-glycosylated MUC1 peptides unequivocally showed that the sugar residue is essential for MGL binding, as is Ca(2+) . NMR data were complemented with molecular dynamics simulations and Corcema-ST to establish a 3D view on the molecular recognition process between Gal, GalNAc, and the Tn-presenting glycopeptides and MGL. Gal and GalNAc have a dual binding mode with opposite trend of the main interaction pattern and the differences in affinity can be explained by additional hydrogen bonds and CH-π contacts involving exclusively the NHAc moiety.

  19. Elucidation of the CCR1- and CCR5-binding modes of MIP-1α by application of an NMR spectra reconstruction method to the transferred cross-saturation experiments

    Energy Technology Data Exchange (ETDEWEB)

    Yoshiura, Chie; Ueda, Takumi; Kofuku, Yutaka; Matsumoto, Masahiko; Okude, Junya; Kondo, Keita; Shiraishi, Yutaro; Shimada, Ichio, E-mail: shimada@iw-nmr.f.u-tokyo.ac.jp [The University of Tokyo, Graduate School of Pharmaceutical Sciences (Japan)

    2015-12-15

    C–C chemokine receptor 1 (CCR1) and CCR5 are involved in various inflammation and immune responses, and regulate the progression of the autoimmune diseases differently. However, the number of residues identified at the binding interface was not sufficient to clarify the differences in the CCR1- and CCR5-binding modes to MIP-1α, because the NMR measurement time for CCR1 and CCR5 samples was limited to 24 h, due to their low stability. Here we applied a recently developed NMR spectra reconstruction method, Conservation of experimental data in ANAlysis of FOuRier, to the amide-directed transferred cross-saturation experiments of chemokine receptors, CCR1 and CCR5, embedded in lipid bilayers of the reconstituted high density lipoprotein, and MIP-1α. Our experiments revealed that the residues on the N-loop and β-sheets of MIP-1α are close to both CCR1 and CCR5, and those in the C-terminal helix region are close to CCR5. These results suggest that the genetic influence of the single nucleotide polymorphisms of MIP-1α that accompany substitution of residues in the C-terminal helix region, E57 and V63, would provide clues toward elucidating how the CCR5–MIP-1α interaction affects the progress of autoimmune diseases.

  20. Elucidation of the CCR1- and CCR5-binding modes of MIP-1α by application of an NMR spectra reconstruction method to the transferred cross-saturation experiments.

    Science.gov (United States)

    Yoshiura, Chie; Ueda, Takumi; Kofuku, Yutaka; Matsumoto, Masahiko; Okude, Junya; Kondo, Keita; Shiraishi, Yutaro; Shimada, Ichio

    2015-12-01

    C-C chemokine receptor 1 (CCR1) and CCR5 are involved in various inflammation and immune responses, and regulate the progression of the autoimmune diseases differently. However, the number of residues identified at the binding interface was not sufficient to clarify the differences in the CCR1- and CCR5-binding modes to MIP-1α, because the NMR measurement time for CCR1 and CCR5 samples was limited to 24 h, due to their low stability. Here we applied a recently developed NMR spectra reconstruction method, Conservation of experimental data in ANAlysis of FOuRier, to the amide-directed transferred cross-saturation experiments of chemokine receptors, CCR1 and CCR5, embedded in lipid bilayers of the reconstituted high density lipoprotein, and MIP-1α. Our experiments revealed that the residues on the N-loop and β-sheets of MIP-1α are close to both CCR1 and CCR5, and those in the C-terminal helix region are close to CCR5. These results suggest that the genetic influence of the single nucleotide polymorphisms of MIP-1α that accompany substitution of residues in the C-terminal helix region, E57 and V63, would provide clues toward elucidating how the CCR5-MIP-1α interaction affects the progress of autoimmune diseases.

  1. Structures of CaV2 Ca2+/CaM-IQ Domain Complexes Reveal Binding Modes That Underlie Calcium-Dependent Inactivation And Facilitation

    International Nuclear Information System (INIS)

    Calcium influx drives two opposing voltage-activated calcium channel (CaV) self-modulatory processes: calcium-dependent inactivation (CDI) and calcium-dependent facilitation (CDF). Specific Ca2+/calmodulin (Ca2+/CaM) lobes produce CDI and CDF through interactions with the CaVα1 subunit IQ domain. Curiously, Ca2+/CaM lobe modulation polarity appears inverted between CaV1s and CaV2s. Here, we present crystal structures of CaV2.1, CaV2.2, and CaV2.3 Ca2+/CaM-IQ domain complexes. All display binding orientations opposite to CaV1.2 with a physical reversal of the CaM lobe positions relative to the IQ α-helix. Titration calorimetry reveals lobe competition for a high-affinity site common to CaV1 and CaV2 IQ domains that is occupied by the CDI lobe in the structures. Electrophysiological experiments demonstrate that the N-terminal CaV2 Ca2+/C-lobe anchors affect CDF. Together, the data unveil the remarkable structural plasticity at the heart of CaV feedback modulation and indicate that CaV1 and CaV2 IQ domains bear a dedicated CDF site that exchanges Ca2+/CaM lobe occupants

  2. Studies on the mode of action of calciferol. XIII. Development of a radioimmunoassay for vitamin D-dependent chick intestinal calcium-binding protein and tissue distribution

    International Nuclear Information System (INIS)

    A RIA for chick intestinal calcium-binding protein (CaBP) has been developed with a sensitivity of 1 ng. The antiserum was generated in rabbits injected with highly purified vitamin D-dependent chick intestinal CaBP. The assay employs the double antibody technique, and 125I-labeled CaBP was prepared using chloramine T. Low molecular weight peptide hormones and normal rabbit, rat, and human serum proteins show no cross-reactivity in the assay. Measurements of chick intestinal and kidney CaBP by RIA showed a good correlation with measurements of CaBP by the radial immunodiffusion method. The assay is reproducible (interassay variability, 16.3%) and precise (intraassay variability, 4.0%). The concentration of immunoreactive CaBP (iCaBP) in chick serum (2.7 ng/ml serum) can now be measured as early as 8 h after the administration of 6.5 nmol 1,25-dihydroxyvitamin D3; a maximum of 11 ng/ml is reached at 20 h. The level of CaBP in chick serum was found to be dependent on the dose of vitamin D3 or 1,25-dihydroxyvitamin D3 administered to the animal

  3. Studies on the mode of action of calciferol. XIII. Development of a radioimmunoassay for vitamin D-dependent chick intestinal calcium-binding protein and tissue distribution

    Energy Technology Data Exchange (ETDEWEB)

    Christakos, S.; Friedlander, E.J.; Frandsen, B.R.; Norman, A.W.

    1979-05-01

    A RIA for chick intestinal calcium-binding protein (CaBP) has been developed with a sensitivity of 1 ng. The antiserum was generated in rabbits injected with highly purified vitamin D-dependent chick intestinal CaBP. The assay employs the double antibody technique, and /sup 125/I-labeled CaBP was prepared using chloramine T. Low molecular weight peptide hormones and normal rabbit, rat, and human serum proteins show no cross-reactivity in the assay. Measurements of chick intestinal and kidney CaBP by RIA showed a good correlation with measurements of CaBP by the radial immunodiffusion method. The assay is reproducible (interassay variability, 16.3%) and precise (intraassay variability, 4.0%). The concentration of immunoreactive CaBP (iCaBP) in chick serum (2.7 ng/ml serum) can now be measured as early as 8 h after the administration of 6.5 nmol 1,25-dihydroxyvitamin D/sub 3/; a maximum of 11 ng/ml is reached at 20 h. The level of CaBP in chick serum was found to be dependent on the dose of vitamin D/sub 3/ or 1,25-dihydroxyvitamin D/sub 3/ administered to the animal.

  4. Exploring the strength, mode, dynamics, and kinetics of binding interaction of a cationic biological photosensitizer with DNA: implication on dissociation of the drug-DNA complex via detergent sequestration.

    Science.gov (United States)

    Paul, Bijan Kumar; Guchhait, Nikhil

    2011-10-20

    The present study aims at exploring a detailed characterization of the binding interaction of a promising cancer cell photosensitizer, harmane (HM), with DNA extracted from herring sperm. The polarity-sensitive prototropic transformation of HM, a naturally occurring, fluorescent, drug-binding alkaloid, β-carboline, is remarkably modified upon interaction with DNA and is manifested through significant modulations on the absorption and emission profiles of HM. From the series of studies undertaken in the present program, for example, absorption; steady-state emission; the effect of chaotrope (urea); iodide ion-induced steady-state fluorescence quenching; circular dichroism (CD); and helix melting from absorption spectroscopy; the mode of binding of HM into the DNA helix has been substantiated to be principally intercalative. Concomitantly, a discernible dependence of the photophysics of the DNA-bound drug on the medium ionic strength indicates that electrostatic attraction should not be ignored in the interaction. Efforts have also been delivered to delineate the dynamical aspects of the interaction, such as modulation in time-resolved fluorescence decay and rotational relaxation dynamics of the drug within the DNA environment. In view of the prospective biological applications of HM, the issue of facile dissociation of intercalated HM from the DNA helix also comprises a crucial prerequisite for the functioning as an effective therapeutic agent. In this context, our results imply that the concept of detergent-sequestered dissociation of the drug from the drug-DNA complex can be a prospective strategy through an appropriate choice of the detergent molecule. The utility of the present work resides in exploring the potential applicability of the fluorescence property of HM for studying its interactions with a relevant biological target, for example, DNA. In addition, the methods and techniques used in the present work can also be exploited to study the interaction of

  5. Performance of the TPSS Functional on Predicting Core Level Binding Energies of Main Group Elements Containing Molecules: A Good Choice for Molecules Adsorbed on Metal Surfaces.

    Science.gov (United States)

    Pueyo Bellafont, Noèlia; Viñes, Francesc; Illas, Francesc

    2016-01-12

    Here we explored the performance of Hartree-Fock (HF), Perdew-Burke-Ernzerhof (PBE), and Tao-Perdew-Staroverov-Scuseria (TPSS) functionals in predicting core level 1s binding energies (BEs) and BE shifts (ΔBEs) for a large set of 68 molecules containing a wide variety of functional groups for main group elements B → F and considering up to 185 core levels. A statistical analysis comparing with X-ray photoelectron spectroscopy (XPS) experiments shows that BEs estimations are very accurate, TPSS exhibiting the best performance. Considering ΔBEs, the three methods yield very similar and excellent results, with mean absolute deviations of ∼0.25 eV. When considering relativistic effects, BEs deviations drop approaching experimental values. So, the largest mean percentage deviation is of 0.25% only. Linear trends among experimental and estimated values have been found, gaining offsets with respect to ideality. By adding relativistic effects to offsets, HF and TPSS methods underestimate experimental values by solely 0.11 and 0.05 eV, respectively, well within XPS chemical precision. TPSS is posed as an excellent choice for the characterization, by XPS, of molecules on metal solid substrates, given its suitability in describing metal substrates bonds and atomic and/or molecular orbitals.

  6. A possible scenario for the fragile-to-strong dynamic crossover predicted by the extended mode-coupling theory for glass transition

    Energy Technology Data Exchange (ETDEWEB)

    Chong, S-H [Institute for Molecular Science, Okazaki 444-8585 (Japan); Chen, S-H [Department of Nuclear Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139 (United States); Mallamace, F, E-mail: chong@ims.ac.j [Dipartimento di Fisica, Universita di Messina and IRCCS Neurolesi ' Bonino-Pulejo' , I-98166 Messina (Italy)

    2009-12-16

    It is argued that the extended mode-coupling theory for glass transition predicts a dynamic crossover in the alpha-relaxation time and in the self-diffusion constant as a general implication of the structure of its equations of motion. This crossover occurs near the critical temperature T{sub c} of the idealized version of the theory, and is caused by the change in the dynamics from the one determined by the cage effect to that dominated by hopping processes. When combined with a model for the hopping kernel deduced from the dynamical theory for diffusion-jump processes, the dynamic crossover can be identified as the fragile-to-strong crossover (FSC) in which the alpha-relaxation time and the self-diffusion constant cross over from a non-Arrhenius to an Arrhenius behavior. Since the present theory does not resort to the existence of the so-called Widom line, to which the FSC in confined water has been attributed, it provides a possible explanation of the FSC observed in a variety of glass-forming systems in which the existence of the Widom line is unlikely. In addition, the present theory predicts that the Stokes-Einstein relation (SER) breaks down in different ways on the fragile and strong sides of the FSC, in agreement with the experimental observation in confined water. It is also demonstrated that the violation of the SER in both the fragile and strong regions can be fitted reasonably well by a single fractional relation with an empirical exponent of 0.85.

  7. An Unexpected Mode Of Binding Defines BMS948 as A Full Retinoic Acid Receptor β (RARβ, NR1B2 Selective Agonist.

    Directory of Open Access Journals (Sweden)

    Eswarkumar Nadendla

    Full Text Available Retinoic acid is an important regulator of cell differentiation which plays major roles in embryonic development and tissue remodeling. The biological action of retinoic acid is mediated by three nuclear receptors denoted RARα, β and γ. Multiple studies support that RARβ possesses functional characteristics of a tumor suppressor and indeed, its expression is frequently lost in neoplastic tissues. However, it has been recently reported that RARβ could also play a role in mammary gland tumorigenesis, thus demonstrating the important but yet incompletely understood function of this receptor in cancer development. As a consequence, there is a great need for RARβ-selective agonists and antagonists as tools to facilitate the pharmacological analysis of this protein in vitro and in vivo as well as for potential therapeutic interventions. Here we provide experimental evidences that the novel synthetic retinoid BMS948 is an RARβ-selective ligand exhibiting a full transcriptional agonistic activity and activating RARβ as efficiently as the reference agonist TTNPB. In addition, we solved the crystal structures of the RARβ ligand-binding domain in complex with BMS948 and two related compounds, BMS641 and BMS411. These structures provided a rationale to explain how a single retinoid can be at the same time an RARα antagonist and an RARβ full agonist, and revealed the structural basis of partial agonism. Finally, in addition to revealing that a flip by 180° of the amide linker, that usually confers RARα selectivity, accounts for the RARβ selectivity of BMS948, the structural analysis uncovers guidelines for the rational design of RARβ-selective antagonists.

  8. Revised stability constant, spectroscopic properties and binding mode of Zn(II) to FluoZin-3, the most common zinc probe in life sciences.

    Science.gov (United States)

    Marszałek, I; Krężel, A; Goch, W; Zhukov, I; Paczkowska, I; Bal, W

    2016-08-01

    2-[2-[2-[2-[bis(carboxylatomethyl)amino]-5-methoxyphenoxy]ethoxy]-4-(2,7-difluoro-3-oxido-6-oxo-4a,9a-dihydroxanthen-9-yl)anilino]acetate (FluoZin-3) is used very broadly in life sciences as intra- and extracellular Zn(II) sensor selective for Zn(II) over Co(II), Ca(II) and Mg(II) ions at their physiological concentrations. It has been used for determination of relative and absolute levels of exchangeable Zn(II) in cells and extracellular fluids. Despite its popularity, the knowledge of its acid/base and Zn(II) coordination abilities and of its spectroscopic properties remained very limited. Also the published conditional dissociation constant ((C)Kd) values at pH7.4 are slightly discrepant, (15nM or 8.9nM). In this work we determined the (C)Kd for Zn(II) complexation by FluoZin-3 at pH7.4 with nitrilotriacetic acid (NTA) as competitor using two independent methods: fluorimetry and UV-Vis spectroscopy. For the first time, we investigated FluoZin-3 alone and complexed with Zn(II) in the wide range of pH, determining the total of eight pKa values from fluorescence spectra and from various regions of UV-Vis spectra. The validated values of (C)Kd (9.1±0.4nM; -log (C)Kd=8.04) and of the absolute (pH-independent) stability constant log βZnL (8.16±0.05) were provided by fluorescence spectroscopy experiments performed at 1μM concentrations. Our experiments demonstrated that both of aminocarboxylate moieties of FluoZin-3 bind the Zn(II) ion synergistically. PMID:27216451

  9. Structures of Ca(V) Ca**2+/CaM-IQ Domain Complexes Reveal Binding Modes That Underlie Calcium-Dependent Inactivation And Facilitation

    Energy Technology Data Exchange (ETDEWEB)

    Kim, E.Y.; Rumpf, C.H.; Fujiwara, Y.; Cooley, E.S.; Petegem, F.Van; Minor, D.L., Jr.

    2009-05-20

    Calcium influx drives two opposing voltage-activated calcium channel (Ca{sub V}) self-modulatory processes: calcium-dependent inactivation (CDI) and calcium-dependent facilitation (CDF). Specific Ca{sup 2+}/calmodulin (Ca{sup 2+}/CaM) lobes produce CDI and CDF through interactions with the Ca{sub V}{alpha}{sub 1} subunit IQ domain. Curiously, Ca{sup 2+}/CaM lobe modulation polarity appears inverted between Ca{sub V}1s and Ca{sub V}2s. Here, we present crystal structures of Ca{sub V}2.1, Ca{sub V}2.2, and Ca{sub V}2.3 Ca{sup 2+}/CaM-IQ domain complexes. All display binding orientations opposite to Ca{sub V}1.2 with a physical reversal of the CaM lobe positions relative to the IQ {alpha}-helix. Titration calorimetry reveals lobe competition for a high-affinity site common to Ca{sub V}1 and Ca{sub V}2 IQ domains that is occupied by the CDI lobe in the structures. Electrophysiological experiments demonstrate that the N-terminal Ca{sub V}2 Ca{sup 2+}/C-lobe anchors affect CDF. Together, the data unveil the remarkable structural plasticity at the heart of Ca{sub V} feedback modulation and indicate that Ca{sub V}1 and Ca{sub V}2 IQ domains bear a dedicated CDF site that exchanges Ca{sup 2+}/CaM lobe occupants.

  10. Stoichiometry and Affinity of Thioflavin T Binding to Sup35p Amyloid Fibrils.

    Science.gov (United States)

    Sulatskaya, Anna I; Kuznetsova, Irina M; Belousov, Mikhail V; Bondarev, Stanislav A; Zhouravleva, Galina A; Turoverov, Konstantin K

    2016-01-01

    In this work two modes of binding of the fluorescent probe thioflavin T to yeast prion protein Sup35p amyloid fibrils were revealed by absorption spectrometry of solutions prepared by equilibrium microdialysis. These binding modes exhibited significant differences in binding affinity and stoichiometry. Moreover, the absorption spectrum and the molar extinction coefficient of the dye bound in each mode were determined. The fluorescence quantum yield of the dye bound in each mode was determined via a spectrofluorimetric study of the same solutions in which the recorded fluorescence intensity was corrected for the primary inner filter effect. As previously predicted, the existence of one of the detected binding modes may be due to the incorporation of the dye into the grooves along the fiber axis perpendicular to the β-sheets of the fibrils. It was assumed that the second type of binding with higher affinity may be due to the existence of ThT binding sites that are localized to areas where amyloid fibrils are clustered.

  11. NetMHCpan-3.0; improved prediction of binding to MHC class I molecules integrating information from multiple receptor and peptide length datasets

    DEFF Research Database (Denmark)

    Nielsen, Morten; Andreatta, Massimo

    2016-01-01

    Background: Binding of peptides to MHC class I molecules (MHC-I) is essential for antigen presentation to cytotoxic T-cells.Results: Here, we demonstrate how a simple alignment step allowing insertions and deletions in a pan-specific MHC-I binding machine-learning model enables combining informat......Background: Binding of peptides to MHC class I molecules (MHC-I) is essential for antigen presentation to cytotoxic T-cells.Results: Here, we demonstrate how a simple alignment step allowing insertions and deletions in a pan-specific MHC-I binding machine-learning model enables combining...

  12. Binding leverage as a molecular basis for allosteric regulation.

    Directory of Open Access Journals (Sweden)

    Simon Mitternacht

    2011-09-01

    Full Text Available Allosteric regulation involves conformational transitions or fluctuations between a few closely related states, caused by the binding of effector molecules. We introduce a quantity called binding leverage that measures the ability of a binding site to couple to the intrinsic motions of a protein. We use Monte Carlo simulations to generate potential binding sites and either normal modes or pairs of crystal structures to describe relevant motions. We analyze single catalytic domains and multimeric allosteric enzymes with complex regulation. For the majority of the analyzed proteins, we find that both catalytic and allosteric sites have high binding leverage. Furthermore, our analysis of the catabolite activator protein, which is allosteric without conformational change, shows that its regulation involves other types of motion than those modulated at sites with high binding leverage. Our results point to the importance of incorporating dynamic information when predicting functional sites. Because it is possible to calculate binding leverage from a single crystal structure it can be used for characterizing proteins of unknown function and predicting latent allosteric sites in any protein, with implications for drug design.

  13. Prediction of the Occurrence of the ADP-binding βαβ-fold in Proteins, Using an Amino Acid Sequence Fingerprint

    NARCIS (Netherlands)

    Wierenga, Rik K.; Terpstra, Peter; Hol, Wim G.J.

    1986-01-01

    An amino acid sequence "fingerprint” has been derived that can be used to test if a particular sequence will fold into a βαβ-unit with ADP-binding properties. It was deduced from a careful analysis of the known three-dimensional structures of ADP-binding βαβ-folds. This fingerprint is in fact a set

  14. A modern approach for epitope prediction: identification of foot-and-mouth disease virus peptides binding bovine leukocyte antigen (BoLA) class I molecules

    Science.gov (United States)

    Major histocompatibility complex (MHC) class I molecules regulate adaptive immune responses through the presentation of antigenic peptides to CD8positive T-cells. Polymorphisms in the peptide binding region of class I molecules determine peptide binding affinity and stability during antigen presenta...

  15. Pressure fluctuation prediction in pump mode using large eddy simulation and unsteady Reynolds-averaged Navier–Stokes in a pump–turbine

    Directory of Open Access Journals (Sweden)

    De-You Li

    2016-06-01

    Full Text Available For pump–turbines, most of the instabilities couple with high-level pressure fluctuations, which are harmful to pump–turbines, even the whole units. In order to understand the causes of pressure fluctuations and reduce their amplitudes, proper numerical methods should be chosen to obtain the accurate results. The method of large eddy simulation with wall-adapting local eddy-viscosity model was chosen to predict the pressure fluctuations in pump