WorldWideScience

Sample records for flexible protein docking

  1. AnchorDock for Blind Flexible Docking of Peptides to Proteins.

    Science.gov (United States)

    Slutzki, Michal; Ben-Shimon, Avraham; Niv, Masha Y

    2017-01-01

    Due to increasing interest in peptides as signaling modulators and drug candidates, several methods for peptide docking to their target proteins are under active development. The "blind" docking problem, where the peptide-binding site on the protein surface is unknown, presents one of the current challenges in the field. AnchorDock protocol was developed by Ben-Shimon and Niv to address this challenge.This protocol narrows the docking search to the most relevant parts of the conformational space. This is achieved by pre-folding the free peptide and by computationally detecting anchoring spots on the surface of the unbound protein. Multiple flexible simulated annealing molecular dynamics (SAMD) simulations are subsequently carried out, starting from pre-folded peptide conformations, constrained to the various precomputed anchoring spots.Here, AnchorDock is demonstrated using two known protein-peptide complexes. A PDZ-peptide complex provides a relatively easy case due to the relatively small size of the protein, and a typical peptide conformation and binding region; a more challenging example is a complex between USP7 N-term and a p53-derived peptide, where the protein is larger, and the peptide conformation and a binding site are generally assumed to be unknown. AnchorDock returned native-like solutions ranked first and third for the PDZ and USP7 complexes, respectively. We describe the procedure step by step and discuss possible modifications where applicable.

  2. Evaluation of the novel algorithm of flexible ligand docking with moveable target-protein atoms.

    Science.gov (United States)

    Sulimov, Alexey V; Zheltkov, Dmitry A; Oferkin, Igor V; Kutov, Danil C; Katkova, Ekaterina V; Tyrtyshnikov, Eugene E; Sulimov, Vladimir B

    2017-01-01

    We present the novel docking algorithm based on the Tensor Train decomposition and the TT-Cross global optimization. The algorithm is applied to the docking problem with flexible ligand and moveable protein atoms. The energy of the protein-ligand complex is calculated in the frame of the MMFF94 force field in vacuum. The grid of precalculated energy potentials of probe ligand atoms in the field of the target protein atoms is not used. The energy of the protein-ligand complex for any given configuration is computed directly with the MMFF94 force field without any fitting parameters. The conformation space of the system coordinates is formed by translations and rotations of the ligand as a whole, by the ligand torsions and also by Cartesian coordinates of the selected target protein atoms. Mobility of protein and ligand atoms is taken into account in the docking process simultaneously and equally. The algorithm is realized in the novel parallel docking SOL-P program and results of its performance for a set of 30 protein-ligand complexes are presented. Dependence of the docking positioning accuracy is investigated as a function of parameters of the docking algorithm and the number of protein moveable atoms. It is shown that mobility of the protein atoms improves docking positioning accuracy. The SOL-P program is able to perform docking of a flexible ligand into the active site of the target protein with several dozens of protein moveable atoms: the native crystallized ligand pose is correctly found as the global energy minimum in the search space with 157 dimensions using 4700 CPU ∗ h at the Lomonosov supercomputer.

  3. Incorporation of protein flexibility and conformational energy penalties in docking screens to improve ligand discovery

    Science.gov (United States)

    Fischer, Marcus; Coleman, Ryan G.; Fraser, James S.; Shoichet, Brian K.

    2014-07-01

    Proteins fluctuate between alternative conformations, which presents a challenge for ligand discovery because such flexibility is difficult to treat computationally owing to problems with conformational sampling and energy weighting. Here we describe a flexible docking method that samples and weights protein conformations using experimentally derived conformations as a guide. The crystallographically refined occupancies of these conformations, which are observable in an apo receptor structure, define energy penalties for docking. In a large prospective library screen, we identified new ligands that target specific receptor conformations of a cavity in cytochrome c peroxidase, and we confirm both ligand pose and associated receptor conformation predictions by crystallography. The inclusion of receptor flexibility led to ligands with new chemotypes and physical properties. By exploiting experimental measures of loop and side-chain flexibility, this method can be extended to the discovery of new ligands for hundreds of targets in the Protein Data Bank for which similar experimental information is available.

  4. Docking ligands into flexible and solvated macromolecules. 7. Impact of protein flexibility and water molecules on docking-based virtual screening accuracy.

    Science.gov (United States)

    Therrien, Eric; Weill, Nathanael; Tomberg, Anna; Corbeil, Christopher R; Lee, Devin; Moitessier, Nicolas

    2014-11-24

    The use of predictive computational methods in the drug discovery process is in a state of continual growth. Over the last two decades, an increasingly large number of docking tools have been developed to identify hits or optimize lead molecules through in-silico screening of chemical libraries to proteins. In recent years, the focus has been on implementing protein flexibility and water molecules. Our efforts led to the development of Fitted first reported in 2007 and further developed since then. In this study, we wished to evaluate the impact of protein flexibility and occurrence of water molecules on the accuracy of the Fitted docking program to discriminate active compounds from inactive compounds in virtual screening (VS) campaigns. For this purpose, a total of 171 proteins cocrystallized with small molecules representing 40 unique enzymes and receptors as well as sets of known ligands and decoys were selected from the Protein Data Bank (PDB) and the Directory of Useful Decoys (DUD), respectively. This study revealed that implementing displaceable crystallographic or computationally placed particle water molecules and protein flexibility can improve the enrichment in active compounds. In addition, an informed decision based on library diversity or research objectives (hit discovery vs lead optimization) on which implementation to use may lead to significant improvements.

  5. ReFlexIn: a flexible receptor protein-ligand docking scheme evaluated on HIV-1 protease.

    Directory of Open Access Journals (Sweden)

    Simon Leis

    Full Text Available For many targets of pharmaceutical importance conformational changes of the receptor protein are relevant during the ligand binding process. A new docking approach, ReFlexIn (Receptor Flexibility by Interpolation, that combines receptor flexibility with the computationally efficient potential grid representation of receptor molecules has been evaluated on the retroviral HIV-1 (Human Immunodeficiency Virus 1 protease system. An approximate inclusion of receptor flexibility is achieved by using interpolation between grid representations of individual receptor conformations. For the retroviral protease the method was tested on an ensemble of protease structures crystallized in the presence of different ligands and on a set of structures obtained from morphing between the unbound and a ligand-bound protease structure. Docking was performed on ligands known to bind to the protease and several non-binders. For the binders the ReFlexIn method yielded in almost all cases ligand placements in similar or closer agreement with experiment than docking to any of the ensemble members without degrading the discrimination with respect to non-binders. The improved docking performance compared to docking to rigid receptors allows for systematic virtual screening applications at very small additional computational cost.

  6. Rosetta Ligand docking with flexible XML protocols.

    Science.gov (United States)

    Lemmon, Gordon; Meiler, Jens

    2012-01-01

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

  7. Docking to flexible nicotinic acetylcholine receptors

    DEFF Research Database (Denmark)

    Sander, Tommy; Bruun, Anne T; Balle, Thomas

    2010-01-01

    Computational docking to nicotinic acetylcholine receptors (nAChRs) and other members of the Cys-loop receptor family is complicated by the flexibility of the so-called C-loop. As observed in the large number of published crystal structures of the acetylcholine binding protein (AChBP), a structural...

  8. SwarmDock and the Use of Normal Modes in Protein-Protein Docking

    Directory of Open Access Journals (Sweden)

    Paul A. Bates

    2010-09-01

    Full Text Available Here is presented an investigation of the use of normal modes in protein-protein docking, both in theory and in practice. Upper limits of the ability of normal modes to capture the unbound to bound conformational change are calculated on a large test set, with particular focus on the binding interface, the subset of residues from which the binding energy is calculated. Further, the SwarmDock algorithm is presented, to demonstrate that the modelling of conformational change as a linear combination of normal modes is an effective method of modelling flexibility in protein-protein docking.

  9. AnchorDock: Blind and Flexible Anchor-Driven Peptide Docking.

    Science.gov (United States)

    Ben-Shimon, Avraham; Niv, Masha Y

    2015-05-05

    The huge conformational space stemming from the inherent flexibility of peptides is among the main obstacles to successful and efficient computational modeling of protein-peptide interactions. Current peptide docking methods typically overcome this challenge using prior knowledge from the structure of the complex. Here we introduce AnchorDock, a peptide docking approach, which automatically targets the docking search to the most relevant parts of the conformational space. This is done by precomputing the free peptide's structure and by computationally identifying anchoring spots on the protein surface. Next, a free peptide conformation undergoes anchor-driven simulated annealing molecular dynamics simulations around the predicted anchoring spots. In the challenging task of a completely blind docking test, AnchorDock produced exceptionally good results (backbone root-mean-square deviation ≤ 2.2Å, rank ≤15) for 10 of 13 unbound cases tested. The impressive performance of AnchorDock supports a molecular recognition pathway that is driven via pre-existing local structural elements. Copyright © 2015 Elsevier Ltd. All rights reserved.

  10. Docking of flexible ligands to flexible receptors in solution by molecular dynamics simulation

    NARCIS (Netherlands)

    Mangoni, R; Roccatano, D; Di Nola, A

    1999-01-01

    In this paper, a method of simulating the docking of small flexible ligands to flexible receptors in water is reported. The method is based on molecular dynamics simulations and is an extension of an algorithm previously reported by Di Nola et al, (Di Nola et al,, Proteins 1994;19:174-182), The

  11. Text Mining for Protein Docking.

    Directory of Open Access Journals (Sweden)

    Varsha D Badal

    2015-12-01

    Full Text Available The rapidly growing amount of publicly available information from biomedical research is readily accessible on the Internet, providing a powerful resource for predictive biomolecular modeling. The accumulated data on experimentally determined structures transformed structure prediction of proteins and protein complexes. Instead of exploring the enormous search space, predictive tools can simply proceed to the solution based on similarity to the existing, previously determined structures. A similar major paradigm shift is emerging due to the rapidly expanding amount of information, other than experimentally determined structures, which still can be used as constraints in biomolecular structure prediction. Automated text mining has been widely used in recreating protein interaction networks, as well as in detecting small ligand binding sites on protein structures. Combining and expanding these two well-developed areas of research, we applied the text mining to structural modeling of protein-protein complexes (protein docking. Protein docking can be significantly improved when constraints on the docking mode are available. We developed a procedure that retrieves published abstracts on a specific protein-protein interaction and extracts information relevant to docking. The procedure was assessed on protein complexes from Dockground (http://dockground.compbio.ku.edu. The results show that correct information on binding residues can be extracted for about half of the complexes. The amount of irrelevant information was reduced by conceptual analysis of a subset of the retrieved abstracts, based on the bag-of-words (features approach. Support Vector Machine models were trained and validated on the subset. The remaining abstracts were filtered by the best-performing models, which decreased the irrelevant information for ~ 25% complexes in the dataset. The extracted constraints were incorporated in the docking protocol and tested on the Dockground unbound

  12. An Evaluation of Explicit Receptor Flexibility in Molecular Docking Using Molecular Dynamics and Torsion Angle Molecular Dynamics.

    Science.gov (United States)

    Armen, Roger S; Chen, Jianhan; Brooks, Charles L

    2009-10-13

    Incorporating receptor flexibility into molecular docking should improve results for flexible proteins. However, the incorporation of explicit all-atom flexibility with molecular dynamics for the entire protein chain may also introduce significant error and "noise" that could decrease docking accuracy and deteriorate the ability of a scoring function to rank native-like poses. We address this apparent paradox by comparing the success of several flexible receptor models in cross-docking and multiple receptor ensemble docking for p38α mitogen-activated protein (MAP) kinase. Explicit all-atom receptor flexibility has been incorporated into a CHARMM-based molecular docking method (CDOCKER) using both molecular dynamics (MD) and torsion angle molecular dynamics (TAMD) for the refinement of predicted protein-ligand binding geometries. These flexible receptor models have been evaluated, and the accuracy and efficiency of TAMD sampling is directly compared to MD sampling. Several flexible receptor models are compared, encompassing flexible side chains, flexible loops, multiple flexible backbone segments, and treatment of the entire chain as flexible. We find that although including side chain and some backbone flexibility is required for improved docking accuracy as expected, docking accuracy also diminishes as additional and unnecessary receptor flexibility is included into the conformational search space. Ensemble docking results demonstrate that including protein flexibility leads to to improved agreement with binding data for 227 active compounds. This comparison also demonstrates that a flexible receptor model enriches high affinity compound identification without significantly increasing the number of false positives from low affinity compounds.

  13. Protein docking prediction using predicted protein-protein interface

    Directory of Open Access Journals (Sweden)

    Li Bin

    2012-01-01

    Full Text Available Abstract Background Many important cellular processes are carried out by protein complexes. To provide physical pictures of interacting proteins, many computational protein-protein prediction methods have been developed in the past. However, it is still difficult to identify the correct docking complex structure within top ranks among alternative conformations. Results We present a novel protein docking algorithm that utilizes imperfect protein-protein binding interface prediction for guiding protein docking. Since the accuracy of protein binding site prediction varies depending on cases, the challenge is to develop a method which does not deteriorate but improves docking results by using a binding site prediction which may not be 100% accurate. The algorithm, named PI-LZerD (using Predicted Interface with Local 3D Zernike descriptor-based Docking algorithm, is based on a pair wise protein docking prediction algorithm, LZerD, which we have developed earlier. PI-LZerD starts from performing docking prediction using the provided protein-protein binding interface prediction as constraints, which is followed by the second round of docking with updated docking interface information to further improve docking conformation. Benchmark results on bound and unbound cases show that PI-LZerD consistently improves the docking prediction accuracy as compared with docking without using binding site prediction or using the binding site prediction as post-filtering. Conclusion We have developed PI-LZerD, a pairwise docking algorithm, which uses imperfect protein-protein binding interface prediction to improve docking accuracy. PI-LZerD consistently showed better prediction accuracy over alternative methods in the series of benchmark experiments including docking using actual docking interface site predictions as well as unbound docking cases.

  14. Protein docking prediction using predicted protein-protein interface.

    Science.gov (United States)

    Li, Bin; Kihara, Daisuke

    2012-01-10

    Many important cellular processes are carried out by protein complexes. To provide physical pictures of interacting proteins, many computational protein-protein prediction methods have been developed in the past. However, it is still difficult to identify the correct docking complex structure within top ranks among alternative conformations. We present a novel protein docking algorithm that utilizes imperfect protein-protein binding interface prediction for guiding protein docking. Since the accuracy of protein binding site prediction varies depending on cases, the challenge is to develop a method which does not deteriorate but improves docking results by using a binding site prediction which may not be 100% accurate. The algorithm, named PI-LZerD (using Predicted Interface with Local 3D Zernike descriptor-based Docking algorithm), is based on a pair wise protein docking prediction algorithm, LZerD, which we have developed earlier. PI-LZerD starts from performing docking prediction using the provided protein-protein binding interface prediction as constraints, which is followed by the second round of docking with updated docking interface information to further improve docking conformation. Benchmark results on bound and unbound cases show that PI-LZerD consistently improves the docking prediction accuracy as compared with docking without using binding site prediction or using the binding site prediction as post-filtering. We have developed PI-LZerD, a pairwise docking algorithm, which uses imperfect protein-protein binding interface prediction to improve docking accuracy. PI-LZerD consistently showed better prediction accuracy over alternative methods in the series of benchmark experiments including docking using actual docking interface site predictions as well as unbound docking cases.

  15. Protein-protein docking with dynamic residue protonation states.

    Directory of Open Access Journals (Sweden)

    Krishna Praneeth Kilambi

    2014-12-01

    Full Text Available Protein-protein interactions depend on a host of environmental factors. Local pH conditions influence the interactions through the protonation states of the ionizable residues that can change upon binding. In this work, we present a pH-sensitive docking approach, pHDock, that can sample side-chain protonation states of five ionizable residues (Asp, Glu, His, Tyr, Lys on-the-fly during the docking simulation. pHDock produces successful local docking funnels in approximately half (79/161 the protein complexes, including 19 cases where standard RosettaDock fails. pHDock also performs better than the two control cases comprising docking at pH 7.0 or using fixed, predetermined protonation states. On average, the top-ranked pHDock structures have lower interface RMSDs and recover more native interface residue-residue contacts and hydrogen bonds compared to RosettaDock. Addition of backbone flexibility using a computationally-generated conformational ensemble further improves native contact and hydrogen bond recovery in the top-ranked structures. Although pHDock is designed to improve docking, it also successfully predicts a large pH-dependent binding affinity change in the Fc-FcRn complex, suggesting that it can be exploited to improve affinity predictions. The approaches in the study contribute to the goal of structural simulations of whole-cell protein-protein interactions including all the environmental factors, and they can be further expanded for pH-sensitive protein design.

  16. A New Approach for Flexible Molecular Docking Based on Swarm Intelligence

    Directory of Open Access Journals (Sweden)

    Yi Fu

    2015-01-01

    Full Text Available Molecular docking methods play an important role in the field of computer-aided drug design. In the work, on the basis of the molecular docking program AutoDock, we present QLDock as a tool for flexible molecular docking. For the energy evaluation, the algorithm uses the binding free energy function that is provided by the AutoDock 4.2 tool. The new search algorithm combines the features of a quantum-behaved particle swarm optimization (QPSO algorithm and local search method of Solis and Wets for solving the highly flexible protein-ligand docking problem. We compute the interaction of 23 protein-ligand complexes and compare the results with those of the QDock and AutoDock programs. The experimental results show that our approach leads to substantially lower docking energy and higher docking precision in comparison to Lamarckian genetic algorithm and QPSO algorithm alone. QPSO-ls algorithm was able to identify the correct binding mode of 74% of the complexes. In comparison, the accuracy of QPSO and LGA is 52% and 61%, respectively. This difference in performance rises with increasing complexity of the ligand. Thus, the novel algorithm QPSO-ls may be used to dock ligand with many rotatable bonds with high accuracy.

  17. Fast and accurate grid representations for atom-based docking with partner flexibility.

    Science.gov (United States)

    de Vries, Sjoerd J; Zacharias, Martin

    2017-06-30

    Macromolecular docking methods can broadly be divided into geometric and atom-based methods. Geometric methods use fast algorithms that operate on simplified, grid-like molecular representations, while atom-based methods are more realistic and flexible, but far less efficient. Here, a hybrid approach of grid-based and atom-based docking is presented, combining precalculated grid potentials with neighbor lists for fast and accurate calculation of atom-based intermolecular energies and forces. The grid representation is compatible with simultaneous multibody docking and can tolerate considerable protein flexibility. When implemented in our docking method ATTRACT, grid-based docking was found to be ∼35x faster. With the OPLSX forcefield instead of the ATTRACT coarse-grained forcefield, the average speed improvement was >100x. Grid-based representations may allow atom-based docking methods to explore large conformational spaces with many degrees of freedom, such as multiple macromolecules including flexibility. This increases the domain of biological problems to which docking methods can be applied. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  18. PaFlexPepDock: parallel ab-initio docking of peptides onto their receptors with full flexibility based on Rosetta.

    Science.gov (United States)

    Li, Haiou; Lu, Liyao; Chen, Rong; Quan, Lijun; Xia, Xiaoyan; Lü, Qiang

    2014-01-01

    Structural information related to protein-peptide complexes can be very useful for novel drug discovery and design. The computational docking of protein and peptide can supplement the structural information available on protein-peptide interactions explored by experimental ways. Protein-peptide docking of this paper can be described as three processes that occur in parallel: ab-initio peptide folding, peptide docking with its receptor, and refinement of some flexible areas of the receptor as the peptide is approaching. Several existing methods have been used to sample the degrees of freedom in the three processes, which are usually triggered in an organized sequential scheme. In this paper, we proposed a parallel approach that combines all the three processes during the docking of a folding peptide with a flexible receptor. This approach mimics the actual protein-peptide docking process in parallel way, and is expected to deliver better performance than sequential approaches. We used 22 unbound protein-peptide docking examples to evaluate our method. Our analysis of the results showed that the explicit refinement of the flexible areas of the receptor facilitated more accurate modeling of the interfaces of the complexes, while combining all of the moves in parallel helped the constructing of energy funnels for predictions.

  19. PaFlexPepDock: parallel ab-initio docking of peptides onto their receptors with full flexibility based on Rosetta.

    Directory of Open Access Journals (Sweden)

    Haiou Li

    Full Text Available Structural information related to protein-peptide complexes can be very useful for novel drug discovery and design. The computational docking of protein and peptide can supplement the structural information available on protein-peptide interactions explored by experimental ways. Protein-peptide docking of this paper can be described as three processes that occur in parallel: ab-initio peptide folding, peptide docking with its receptor, and refinement of some flexible areas of the receptor as the peptide is approaching. Several existing methods have been used to sample the degrees of freedom in the three processes, which are usually triggered in an organized sequential scheme. In this paper, we proposed a parallel approach that combines all the three processes during the docking of a folding peptide with a flexible receptor. This approach mimics the actual protein-peptide docking process in parallel way, and is expected to deliver better performance than sequential approaches. We used 22 unbound protein-peptide docking examples to evaluate our method. Our analysis of the results showed that the explicit refinement of the flexible areas of the receptor facilitated more accurate modeling of the interfaces of the complexes, while combining all of the moves in parallel helped the constructing of energy funnels for predictions.

  20. "Flexible Ligand Docking Studies of Matrix Metalloproteinase Inhibitors Using Lamarckian Genetic Algorithm "

    Directory of Open Access Journals (Sweden)

    lOrkideh Ghorban Dadrass

    2004-06-01

    Full Text Available As important therapeutic drug targets, matrix metalloproteinases (MMPs have recently attracted great interest in the search for potent and selective inhibitors using computer-aided molecular modelling and docking techniques. Availability of more than 60 X-ray crystal structures or NMR solution structures related to MMPs in Protein Data Bank (PDB of which more than half of them are in complex with various MMP inhibitors (MMPIs, provides a great opportunity for docking studies. In this study AutoDock 3.0.5 along with its LGA algorithm were used for automated flexible ligand docking of 32 MMPI-MMP complexes and docking accuracy and reliability of the estimated inhibition constants were evaluated. Twenty-six out of 32 docks had RMSD less than 3.0 Å which is considered as well-docked, however, for the most of the cases (15 out of 27, predicted pKi values were considerably overestimated in comparison to experimental values. To improve pKi prediction regarding MMPI-MMP complexes, inclusion of at least one such a complex in calibration of empirical free energy function in the next release of AutoDock is highly recommended.

  1. Solvated protein-DNA docking using HADDOCK

    Energy Technology Data Exchange (ETDEWEB)

    Dijk, Marc van; Visscher, Koen M.; Kastritis, Panagiotis L.; Bonvin, Alexandre M. J. J., E-mail: a.m.j.j.bonvin@uu.nl [Utrecht University, Bijvoet Center for Biomolecular Research, Faculty of Science-Chemistry (Netherlands)

    2013-05-15

    Interfacial water molecules play an important role in many aspects of protein-DNA specificity and recognition. Yet they have been mostly neglected in the computational modeling of these complexes. We present here a solvated docking protocol that allows explicit inclusion of water molecules in the docking of protein-DNA complexes and demonstrate its feasibility on a benchmark of 30 high-resolution protein-DNA complexes containing crystallographically-determined water molecules at their interfaces. Our protocol is capable of reproducing the solvation pattern at the interface and recovers hydrogen-bonded water-mediated contacts in many of the benchmark cases. Solvated docking leads to an overall improvement in the quality of the generated protein-DNA models for cases with limited conformational change of the partners upon complex formation. The applicability of this approach is demonstrated on real cases by docking a representative set of 6 complexes using unbound protein coordinates, model-built DNA and knowledge-based restraints. As HADDOCK supports the inclusion of a variety of NMR restraints, solvated docking is also applicable for NMR-based structure calculations of protein-DNA complexes.

  2. Protein-Protein Docking in Drug Design and Discovery.

    Science.gov (United States)

    Kaczor, Agnieszka A; Bartuzi, Damian; Stępniewski, Tomasz Maciej; Matosiuk, Dariusz; Selent, Jana

    2018-01-01

    Protein-protein interactions (PPIs) are responsible for a number of key physiological processes in the living cells and underlie the pathomechanism of many diseases. Nowadays, along with the concept of so-called "hot spots" in protein-protein interactions, which are well-defined interface regions responsible for most of the binding energy, these interfaces can be targeted with modulators. In order to apply structure-based design techniques to design PPIs modulators, a three-dimensional structure of protein complex has to be available. In this context in silico approaches, in particular protein-protein docking, are a valuable complement to experimental methods for elucidating 3D structure of protein complexes. Protein-protein docking is easy to use and does not require significant computer resources and time (in contrast to molecular dynamics) and it results in 3D structure of a protein complex (in contrast to sequence-based methods of predicting binding interfaces). However, protein-protein docking cannot address all the aspects of protein dynamics, in particular the global conformational changes during protein complex formation. In spite of this fact, protein-protein docking is widely used to model complexes of water-soluble proteins and less commonly to predict structures of transmembrane protein assemblies, including dimers and oligomers of G protein-coupled receptors (GPCRs). In this chapter we review the principles of protein-protein docking, available algorithms and software and discuss the recent examples, benefits, and drawbacks of protein-protein docking application to water-soluble proteins, membrane anchoring and transmembrane proteins, including GPCRs.

  3. DockQ: A Quality Measure for Protein-Protein Docking Models.

    Directory of Open Access Journals (Sweden)

    Sankar Basu

    Full Text Available The state-of-the-art to assess the structural quality of docking models is currently based on three related yet independent quality measures: Fnat, LRMS, and iRMS as proposed and standardized by CAPRI. These quality measures quantify different aspects of the quality of a particular docking model and need to be viewed together to reveal the true quality, e.g. a model with relatively poor LRMS (>10Å might still qualify as 'acceptable' with a descent Fnat (>0.50 and iRMS (<3.0Å. This is also the reason why the so called CAPRI criteria for assessing the quality of docking models is defined by applying various ad-hoc cutoffs on these measures to classify a docking model into the four classes: Incorrect, Acceptable, Medium, or High quality. This classification has been useful in CAPRI, but since models are grouped in only four bins it is also rather limiting, making it difficult to rank models, correlate with scoring functions or use it as target function in machine learning algorithms. Here, we present DockQ, a continuous protein-protein docking model quality measure derived by combining Fnat, LRMS, and iRMS to a single score in the range [0, 1] that can be used to assess the quality of protein docking models. By using DockQ on CAPRI models it is possible to almost completely reproduce the original CAPRI classification into Incorrect, Acceptable, Medium and High quality. An average PPV of 94% at 90% Recall demonstrating that there is no need to apply predefined ad-hoc cutoffs to classify docking models. Since DockQ recapitulates the CAPRI classification almost perfectly, it can be viewed as a higher resolution version of the CAPRI classification, making it possible to estimate model quality in a more quantitative way using Z-scores or sum of top ranked models, which has been so valuable for the CASP community. The possibility to directly correlate a quality measure to a scoring function has been crucial for the development of scoring functions for

  4. Solvated protein-DNA docking using HADDOCK

    NARCIS (Netherlands)

    van Dijk, Marc; Visscher, Koen M; Bonvin, Alexandre M.J.J; Kastritis, Panagiotis L.

    2013-01-01

    Interfacial water molecules play an important role in many aspects of protein-DNA specificity and recognition. Yet they have been mostly neglected in the computational modeling of these complexes. We present here a solvated docking protocol that allows explicit inclusion of water molecules in the

  5. DockQ: A Quality Measure for Protein-Protein Docking Models

    Science.gov (United States)

    Basu, Sankar

    2016-01-01

    The state-of-the-art to assess the structural quality of docking models is currently based on three related yet independent quality measures: Fnat, LRMS, and iRMS as proposed and standardized by CAPRI. These quality measures quantify different aspects of the quality of a particular docking model and need to be viewed together to reveal the true quality, e.g. a model with relatively poor LRMS (>10Å) might still qualify as 'acceptable' with a descent Fnat (>0.50) and iRMS (iRMS to a single score in the range [0, 1] that can be used to assess the quality of protein docking models. By using DockQ on CAPRI models it is possible to almost completely reproduce the original CAPRI classification into Incorrect, Acceptable, Medium and High quality. An average PPV of 94% at 90% Recall demonstrating that there is no need to apply predefined ad-hoc cutoffs to classify docking models. Since DockQ recapitulates the CAPRI classification almost perfectly, it can be viewed as a higher resolution version of the CAPRI classification, making it possible to estimate model quality in a more quantitative way using Z-scores or sum of top ranked models, which has been so valuable for the CASP community. The possibility to directly correlate a quality measure to a scoring function has been crucial for the development of scoring functions for protein structure prediction, and DockQ should be useful in a similar development in the protein docking field. DockQ is available at http://github.com/bjornwallner/DockQ/ PMID:27560519

  6. GalaxyDock BP2 score: a hybrid scoring function for accurate protein-ligand docking

    Science.gov (United States)

    Baek, Minkyung; Shin, Woong-Hee; Chung, Hwan Won; Seok, Chaok

    2017-07-01

    Protein-ligand docking is a useful tool for providing atomic-level understanding of protein functions in nature and design principles for artificial ligands or proteins with desired properties. The ability to identify the true binding pose of a ligand to a target protein among numerous possible candidate poses is an essential requirement for successful protein-ligand docking. Many previously developed docking scoring functions were trained to reproduce experimental binding affinities and were also used for scoring binding poses. However, in this study, we developed a new docking scoring function, called GalaxyDock BP2 Score, by directly training the scoring power of binding poses. This function is a hybrid of physics-based, empirical, and knowledge-based score terms that are balanced to strengthen the advantages of each component. The performance of the new scoring function exhibits significant improvement over existing scoring functions in decoy pose discrimination tests. In addition, when the score is used with the GalaxyDock2 protein-ligand docking program, it outperformed other state-of-the-art docking programs in docking tests on the Astex diverse set, the Cross2009 benchmark set, and the Astex non-native set. GalaxyDock BP2 Score and GalaxyDock2 with this score are freely available at http://galaxy.seoklab.org/softwares/galaxydock.html.

  7. Protein-protein docking with F(2Dock 2.0 and GB-rerank.

    Directory of Open Access Journals (Sweden)

    Rezaul Chowdhury

    Full Text Available Computational simulation of protein-protein docking can expedite the process of molecular modeling and drug discovery. This paper reports on our new F(2 Dock protocol which improves the state of the art in initial stage rigid body exhaustive docking search, scoring and ranking by introducing improvements in the shape-complementarity and electrostatics affinity functions, a new knowledge-based interface propensity term with FFT formulation, a set of novel knowledge-based filters and finally a solvation energy (GBSA based reranking technique. Our algorithms are based on highly efficient data structures including the dynamic packing grids and octrees which significantly speed up the computations and also provide guaranteed bounds on approximation error.The improved affinity functions show superior performance compared to their traditional counterparts in finding correct docking poses at higher ranks. We found that the new filters and the GBSA based reranking individually and in combination significantly improve the accuracy of docking predictions with only minor increase in computation time. We compared F(2 Dock 2.0 with ZDock 3.0.2 and found improvements over it, specifically among 176 complexes in ZLab Benchmark 4.0, F(2 Dock 2.0 finds a near-native solution as the top prediction for 22 complexes; where ZDock 3.0.2 does so for 13 complexes. F(2 Dock 2.0 finds a near-native solution within the top 1000 predictions for 106 complexes as opposed to 104 complexes for ZDock 3.0.2. However, there are 17 and 15 complexes where F(2 Dock 2.0 finds a solution but ZDock 3.0.2 does not and vice versa; which indicates that the two docking protocols can also complement each other.The docking protocol has been implemented as a server with a graphical client (TexMol which allows the user to manage multiple docking jobs, and visualize the docked poses and interfaces. Both the server and client are available for download. Server: http

  8. Protein-Protein Docking with F2Dock 2.0 and GB-Rerank

    Science.gov (United States)

    Chowdhury, Rezaul; Rasheed, Muhibur; Keidel, Donald; Moussalem, Maysam; Olson, Arthur; Sanner, Michel; Bajaj, Chandrajit

    2013-01-01

    Motivation Computational simulation of protein-protein docking can expedite the process of molecular modeling and drug discovery. This paper reports on our new F2 Dock protocol which improves the state of the art in initial stage rigid body exhaustive docking search, scoring and ranking by introducing improvements in the shape-complementarity and electrostatics affinity functions, a new knowledge-based interface propensity term with FFT formulation, a set of novel knowledge-based filters and finally a solvation energy (GBSA) based reranking technique. Our algorithms are based on highly efficient data structures including the dynamic packing grids and octrees which significantly speed up the computations and also provide guaranteed bounds on approximation error. Results The improved affinity functions show superior performance compared to their traditional counterparts in finding correct docking poses at higher ranks. We found that the new filters and the GBSA based reranking individually and in combination significantly improve the accuracy of docking predictions with only minor increase in computation time. We compared F2 Dock 2.0 with ZDock 3.0.2 and found improvements over it, specifically among 176 complexes in ZLab Benchmark 4.0, F2 Dock 2.0 finds a near-native solution as the top prediction for 22 complexes; where ZDock 3.0.2 does so for 13 complexes. F2 Dock 2.0 finds a near-native solution within the top 1000 predictions for 106 complexes as opposed to 104 complexes for ZDock 3.0.2. However, there are 17 and 15 complexes where F2 Dock 2.0 finds a solution but ZDock 3.0.2 does not and vice versa; which indicates that the two docking protocols can also complement each other. Availability The docking protocol has been implemented as a server with a graphical client (TexMol) which allows the user to manage multiple docking jobs, and visualize the docked poses and interfaces. Both the server and client are available for download. Server: http

  9. Structure and Sequence Search on Aptamer-Protein Docking

    Science.gov (United States)

    Xiao, Jiajie; Bonin, Keith; Guthold, Martin; Salsbury, Freddie

    2015-03-01

    Interactions between proteins and deoxyribonucleic acid (DNA) play a significant role in the living systems, especially through gene regulation. However, short nucleic acids sequences (aptamers) with specific binding affinity to specific proteins exhibit clinical potential as therapeutics. Our capillary and gel electrophoresis selection experiments show that specific sequences of aptamers can be selected that bind specific proteins. Computationally, given the experimentally-determined structure and sequence of a thrombin-binding aptamer, we can successfully dock the aptamer onto thrombin in agreement with experimental structures of the complex. In order to further study the conformational flexibility of this thrombin-binding aptamer and to potentially develop a predictive computational model of aptamer-binding, we use GPU-enabled molecular dynamics simulations to both examine the conformational flexibility of the aptamer in the absence of binding to thrombin, and to determine our ability to fold an aptamer. This study should help further de-novo predictions of aptamer sequences by enabling the study of structural and sequence-dependent effects on aptamer-protein docking specificity.

  10. A unified conformational selection and induced fit approach to protein-peptide docking.

    Directory of Open Access Journals (Sweden)

    Mikael Trellet

    Full Text Available Protein-peptide interactions are vital for the cell. They mediate, inhibit or serve as structural components in nearly 40% of all macromolecular interactions, and are often associated with diseases, making them interesting leads for protein drug design. In recent years, large-scale technologies have enabled exhaustive studies on the peptide recognition preferences for a number of peptide-binding domain families. Yet, the paucity of data regarding their molecular binding mechanisms together with their inherent flexibility makes the structural prediction of protein-peptide interactions very challenging. This leaves flexible docking as one of the few amenable computational techniques to model these complexes. We present here an ensemble, flexible protein-peptide docking protocol that combines conformational selection and induced fit mechanisms. Starting from an ensemble of three peptide conformations (extended, a-helix, polyproline-II, flexible docking with HADDOCK generates 79.4% of high quality models for bound/unbound and 69.4% for unbound/unbound docking when tested against the largest protein-peptide complexes benchmark dataset available to date. Conformational selection at the rigid-body docking stage successfully recovers the most relevant conformation for a given protein-peptide complex and the subsequent flexible refinement further improves the interface by up to 4.5 Å interface RMSD. Cluster-based scoring of the models results in a selection of near-native solutions in the top three for ∼75% of the successfully predicted cases. This unified conformational selection and induced fit approach to protein-peptide docking should open the route to the modeling of challenging systems such as disorder-order transitions taking place upon binding, significantly expanding the applicability limit of biomolecular interaction modeling by docking.

  11. Accounting for Intraligand Interactions in Flexible Ligand Docking with a PMF-Based Scoring Function.

    Science.gov (United States)

    Lizunov, A Y; Gonchar, A L; Zaitseva, N I; Zosimov, V V

    2015-10-26

    We analyzed the frequency with which intraligand contacts occurred in a set of 1300 protein-ligand complexes [ Plewczynski et al. J. Comput. Chem. 2011 , 32 , 742 - 755 .]. Our analysis showed that flexible ligands often form intraligand hydrophobic contacts, while intraligand hydrogen bonds are rare. The test set was also thoroughly investigated and classified. We suggest a universal method for enhancement of a scoring function based on a potential of mean force (PMF-based score) by adding a term accounting for intraligand interactions. The method was implemented via in-house developed program, utilizing an Algo_score scoring function [ Ramensky et al. Proteins: Struct., Funct., Genet. 2007 , 69 , 349 - 357 .] based on the Tarasov-Muryshev PMF [ Muryshev et al. J. Comput.-Aided Mol. Des. 2003 , 17 , 597 - 605 .]. The enhancement of the scoring function was shown to significantly improve the docking and scoring quality for flexible ligands in the test set of 1300 protein-ligand complexes [ Plewczynski et al. J. Comput. Chem. 2011 , 32 , 742 - 755 .]. We then investigated the correlation of the docking results with two parameters of intraligand interactions estimation. These parameters are the weight of intraligand interactions and the minimum number of bonds between the ligand atoms required to take their interaction into account.

  12. Functional aspects of protein flexibility

    DEFF Research Database (Denmark)

    Teilum, Kaare; Olsen, Johan G; Kragelund, Birthe B

    2009-01-01

    this into an intuitive perception of protein function is challenging. Flexibility is of overwhelming importance for protein function, and the changes in protein structure during interactions with binding partners can be dramatic. The present review addresses protein flexibility, focusing on protein-ligand interactions...

  13. Sequence alignment reveals possible MAPK docking motifs on HIV proteins.

    Directory of Open Access Journals (Sweden)

    Perry Evans

    Full Text Available Over the course of HIV infection, virus replication is facilitated by the phosphorylation of HIV proteins by human ERK1 and ERK2 mitogen-activated protein kinases (MAPKs. MAPKs are known to phosphorylate their substrates by first binding with them at a docking site. Docking site interactions could be viable drug targets because the sequences guiding them are more specific than phosphorylation consensus sites. In this study we use multiple bioinformatics tools to discover candidate MAPK docking site motifs on HIV proteins known to be phosphorylated by MAPKs, and we discuss the possibility of targeting docking sites with drugs. Using sequence alignments of HIV proteins of different subtypes, we show that MAPK docking patterns previously described for human proteins appear on the HIV matrix, Tat, and Vif proteins in a strain dependent manner, but are absent from HIV Rev and appear on all HIV Nef strains. We revise the regular expressions of previously annotated MAPK docking patterns in order to provide a subtype independent motif that annotates all HIV proteins. One revision is based on a documented human variant of one of the substrate docking motifs, and the other reduces the number of required basic amino acids in the standard docking motifs from two to one. The proposed patterns are shown to be consistent with in silico docking between ERK1 and the HIV matrix protein. The motif usage on HIV proteins is sufficiently different from human proteins in amino acid sequence similarity to allow for HIV specific targeting using small-molecule drugs.

  14. Combination of scoring schemes for protein docking

    Directory of Open Access Journals (Sweden)

    Schomburg Dietmar

    2007-08-01

    Full Text Available Abstract Background Docking algorithms are developed to predict in which orientation two proteins are likely to bind under natural conditions. The currently used methods usually consist of a sampling step followed by a scoring step. We developed a weighted geometric correlation based on optimised atom specific weighting factors and combined them with our previously published amino acid specific scoring and with a comprehensive SVM-based scoring function. Results The scoring with the atom specific weighting factors yields better results than the amino acid specific scoring. In combination with SVM-based scoring functions the percentage of complexes for which a near native structure can be predicted within the top 100 ranks increased from 14% with the geometric scoring to 54% with the combination of all scoring functions. Especially for the enzyme-inhibitor complexes the results of the ranking are excellent. For half of these complexes a near-native structure can be predicted within the first 10 proposed structures and for more than 86% of all enzyme-inhibitor complexes within the first 50 predicted structures. Conclusion We were able to develop a combination of different scoring schemes which considers a series of previously described and some new scoring criteria yielding a remarkable improvement of prediction quality.

  15. HPEPDOCK: a web server for blind peptide-protein docking based on a hierarchical algorithm.

    Science.gov (United States)

    Zhou, Pei; Jin, Bowen; Li, Hao; Huang, Sheng-You

    2018-05-09

    Protein-peptide interactions are crucial in many cellular functions. Therefore, determining the structure of protein-peptide complexes is important for understanding the molecular mechanism of related biological processes and developing peptide drugs. HPEPDOCK is a novel web server for blind protein-peptide docking through a hierarchical algorithm. Instead of running lengthy simulations to refine peptide conformations, HPEPDOCK considers the peptide flexibility through an ensemble of peptide conformations generated by our MODPEP program. For blind global peptide docking, HPEPDOCK obtained a success rate of 33.3% in binding mode prediction on a benchmark of 57 unbound cases when the top 10 models were considered, compared to 21.1% for pepATTRACT server. HPEPDOCK also performed well in docking against homology models and obtained a success rate of 29.8% within top 10 predictions. For local peptide docking, HPEPDOCK achieved a high success rate of 72.6% on a benchmark of 62 unbound cases within top 10 predictions, compared to 45.2% for HADDOCK peptide protocol. Our HPEPDOCK server is computationally efficient and consumed an average of 29.8 mins for a global peptide docking job and 14.2 mins for a local peptide docking job. The HPEPDOCK web server is available at http://huanglab.phys.hust.edu.cn/hpepdock/.

  16. Arbitrary protein−protein docking targets biologically relevant interfaces

    Directory of Open Access Journals (Sweden)

    Martin Juliette

    2012-05-01

    Full Text Available Abstract Background Protein-protein recognition is of fundamental importance in the vast majority of biological processes. However, it has already been demonstrated that it is very hard to distinguish true complexes from false complexes in so-called cross-docking experiments, where binary protein complexes are separated and the isolated proteins are all docked against each other and scored. Does this result, at least in part, reflect a physical reality? False complexes could reflect possible nonspecific or weak associations. Results In this paper, we investigate the twilight zone of protein-protein interactions, building on an interesting outcome of cross-docking experiments: false complexes seem to favor residues from the true interaction site, suggesting that randomly chosen partners dock in a non-random fashion on protein surfaces. Here, we carry out arbitrary docking of a non-redundant data set of 198 proteins, with more than 300 randomly chosen "probe" proteins. We investigate the tendency of arbitrary partners to aggregate at localized regions of the protein surfaces, the shape and compositional bias of the generated interfaces, and the potential of this property to predict biologically relevant binding sites. We show that the non-random localization of arbitrary partners after protein-protein docking is a generic feature of protein structures. The interfaces generated in this way are not systematically planar or curved, but tend to be closer than average to the center of the proteins. These results can be used to predict biological interfaces with an AUC value up to 0.69 alone, and 0.72 when used in combination with evolutionary information. An appropriate choice of random partners and number of docking models make this method computationally practical. It is also noted that nonspecific interfaces can point to alternate interaction sites in the case of proteins with multiple interfaces. We illustrate the usefulness of arbitrary docking

  17. Arbitrary protein−protein docking targets biologically relevant interfaces

    International Nuclear Information System (INIS)

    Martin, Juliette; Lavery, Richard

    2012-01-01

    Protein-protein recognition is of fundamental importance in the vast majority of biological processes. However, it has already been demonstrated that it is very hard to distinguish true complexes from false complexes in so-called cross-docking experiments, where binary protein complexes are separated and the isolated proteins are all docked against each other and scored. Does this result, at least in part, reflect a physical reality? False complexes could reflect possible nonspecific or weak associations. In this paper, we investigate the twilight zone of protein-protein interactions, building on an interesting outcome of cross-docking experiments: false complexes seem to favor residues from the true interaction site, suggesting that randomly chosen partners dock in a non-random fashion on protein surfaces. Here, we carry out arbitrary docking of a non-redundant data set of 198 proteins, with more than 300 randomly chosen "probe" proteins. We investigate the tendency of arbitrary partners to aggregate at localized regions of the protein surfaces, the shape and compositional bias of the generated interfaces, and the potential of this property to predict biologically relevant binding sites. We show that the non-random localization of arbitrary partners after protein-protein docking is a generic feature of protein structures. The interfaces generated in this way are not systematically planar or curved, but tend to be closer than average to the center of the proteins. These results can be used to predict biological interfaces with an AUC value up to 0.69 alone, and 0.72 when used in combination with evolutionary information. An appropriate choice of random partners and number of docking models make this method computationally practical. It is also noted that nonspecific interfaces can point to alternate interaction sites in the case of proteins with multiple interfaces. We illustrate the usefulness of arbitrary docking using PEBP (Phosphatidylethanolamine binding

  18. Plasticity of the Binding Site of Renin: Optimized Selection of Protein Structures for Ensemble Docking.

    Science.gov (United States)

    Strecker, Claas; Meyer, Bernd

    2018-05-02

    Protein flexibility poses a major challenge to docking of potential ligands in that the binding site can adopt different shapes. Docking algorithms usually keep the protein rigid and only allow the ligand to be treated as flexible. However, a wrong assessment of the shape of the binding pocket can prevent a ligand from adapting a correct pose. Ensemble docking is a simple yet promising method to solve this problem: Ligands are docked into multiple structures, and the results are subsequently merged. Selection of protein structures is a significant factor for this approach. In this work we perform a comprehensive and comparative study evaluating the impact of structure selection on ensemble docking. We perform ensemble docking with several crystal structures and with structures derived from molecular dynamics simulations of renin, an attractive target for antihypertensive drugs. Here, 500 ns of MD simulations revealed binding site shapes not found in any available crystal structure. We evaluate the importance of structure selection for ensemble docking by comparing binding pose prediction, ability to rank actives above nonactives (screening utility), and scoring accuracy. As a result, for ensemble definition k-means clustering appears to be better suited than hierarchical clustering with average linkage. The best performing ensemble consists of four crystal structures and is able to reproduce the native ligand poses better than any individual crystal structure. Moreover this ensemble outperforms 88% of all individual crystal structures in terms of screening utility as well as scoring accuracy. Similarly, ensembles of MD-derived structures perform on average better than 75% of any individual crystal structure in terms of scoring accuracy at all inspected ensembles sizes.

  19. Complete cDNA sequence coding for human docking protein

    Energy Technology Data Exchange (ETDEWEB)

    Hortsch, M; Labeit, S; Meyer, D I

    1988-01-11

    Docking protein (DP, or SRP receptor) is a rough endoplasmic reticulum (ER)-associated protein essential for the targeting and translocation of nascent polypeptides across this membrane. It specifically interacts with a cytoplasmic ribonucleoprotein complex, the signal recognition particle (SRP). The nucleotide sequence of cDNA encoding the entire human DP and its deduced amino acid sequence are given.

  20. New Computational Approaches for NMR-based Drug Design: A Protocol for Ligand Docking to Flexible Target Sites

    International Nuclear Information System (INIS)

    Gracia, Luis; Speidel, Joshua A.; Weinstein, Harel

    2006-01-01

    NMR-based drug design has met with some success in the last decade, as illustrated in numerous instances by Fesik's ''ligand screening by NMR'' approach. Ongoing efforts to generalize this success have led us to the development of a new paradigm in which quantitative computational approaches are being integrated with NMR derived data and biological assays. The key component of this work is the inclusion of the intrinsic dynamic quality of NMR structures in theoretical models and its use in docking. A new computational protocol is introduced here, designed to dock small molecule ligands to flexible proteins derived from NMR structures. The algorithm makes use of a combination of simulated annealing monte carlo simulations (SA/MC) and a mean field potential informed by the NMR data. The new protocol is illustrated in the context of an ongoing project aimed at developing new selective inhibitors for the PCAF bromodomains that interact with HIV Tat

  1. Automatic design of decision-tree induction algorithms tailored to flexible-receptor docking data.

    Science.gov (United States)

    Barros, Rodrigo C; Winck, Ana T; Machado, Karina S; Basgalupp, Márcio P; de Carvalho, André C P L F; Ruiz, Duncan D; de Souza, Osmar Norberto

    2012-11-21

    This paper addresses the prediction of the free energy of binding of a drug candidate with enzyme InhA associated with Mycobacterium tuberculosis. This problem is found within rational drug design, where interactions between drug candidates and target proteins are verified through molecular docking simulations. In this application, it is important not only to correctly predict the free energy of binding, but also to provide a comprehensible model that could be validated by a domain specialist. Decision-tree induction algorithms have been successfully used in drug-design related applications, specially considering that decision trees are simple to understand, interpret, and validate. There are several decision-tree induction algorithms available for general-use, but each one has a bias that makes it more suitable for a particular data distribution. In this article, we propose and investigate the automatic design of decision-tree induction algorithms tailored to particular drug-enzyme binding data sets. We investigate the performance of our new method for evaluating binding conformations of different drug candidates to InhA, and we analyze our findings with respect to decision tree accuracy, comprehensibility, and biological relevance. The empirical analysis indicates that our method is capable of automatically generating decision-tree induction algorithms that significantly outperform the traditional C4.5 algorithm with respect to both accuracy and comprehensibility. In addition, we provide the biological interpretation of the rules generated by our approach, reinforcing the importance of comprehensible predictive models in this particular bioinformatics application. We conclude that automatically designing a decision-tree algorithm tailored to molecular docking data is a promising alternative for the prediction of the free energy from the binding of a drug candidate with a flexible-receptor.

  2. Parallel Evolutionary Optimization Algorithms for Peptide-Protein Docking

    Science.gov (United States)

    Poluyan, Sergey; Ershov, Nikolay

    2018-02-01

    In this study we examine the possibility of using evolutionary optimization algorithms in protein-peptide docking. We present the main assumptions that reduce the docking problem to a continuous global optimization problem and provide a way of using evolutionary optimization algorithms. The Rosetta all-atom force field was used for structural representation and energy scoring. We describe the parallelization scheme and MPI/OpenMP realization of the considered algorithms. We demonstrate the efficiency and the performance for some algorithms which were applied to a set of benchmark tests.

  3. Gab Docking Proteins in Cardiovascular Disease, Cancer, and Inflammation

    Directory of Open Access Journals (Sweden)

    Yoshikazu Nakaoka

    2013-01-01

    Full Text Available The docking proteins of the Grb2-associated binder (Gab family have emerged as crucial signaling compartments in metazoans. In mammals, the Gab proteins, consisting of Gab1, Gab2, and Gab3, are involved in the amplification and integration of signal transduction evoked by a variety of extracellular stimuli, including growth factors, cytokines, antigens, and other molecules. Gab proteins lack the enzymatic activity themselves; however, when phosphorylated on tyrosine residues, they provide binding sites for multiple Src homology-2 (SH2 domain-containing proteins, such as SH2-containing protein tyrosine phosphatase 2 (SHP2, phosphatidylinositol 3-kinase regulatory subunit p85, phospholipase Cγ, Crk, and GC-GAP. Through these interactions, the Gab proteins transduce signals from activated receptors into pathways with distinct biological functions, thereby contributing to signal diversification. They are known to play crucial roles in numerous physiological processes through their associations with SHP2 and p85. In addition, abnormal Gab protein signaling has been linked to human diseases including cancer, cardiovascular disease, and inflammatory disorders. In this paper, we provide an overview of the structure, effector functions, and regulation of the Gab docking proteins, with a special focus on their associations with cardiovascular disease, cancer, and inflammation.

  4. Protein-protein docking using region-based 3D Zernike descriptors

    Directory of Open Access Journals (Sweden)

    Sael Lee

    2009-12-01

    Full Text Available Abstract Background Protein-protein interactions are a pivotal component of many biological processes and mediate a variety of functions. Knowing the tertiary structure of a protein complex is therefore essential for understanding the interaction mechanism. However, experimental techniques to solve the structure of the complex are often found to be difficult. To this end, computational protein-protein docking approaches can provide a useful alternative to address this issue. Prediction of docking conformations relies on methods that effectively capture shape features of the participating proteins while giving due consideration to conformational changes that may occur. Results We present a novel protein docking algorithm based on the use of 3D Zernike descriptors as regional features of molecular shape. The key motivation of using these descriptors is their invariance to transformation, in addition to a compact representation of local surface shape characteristics. Docking decoys are generated using geometric hashing, which are then ranked by a scoring function that incorporates a buried surface area and a novel geometric complementarity term based on normals associated with the 3D Zernike shape description. Our docking algorithm was tested on both bound and unbound cases in the ZDOCK benchmark 2.0 dataset. In 74% of the bound docking predictions, our method was able to find a near-native solution (interface C-αRMSD ≤ 2.5 Å within the top 1000 ranks. For unbound docking, among the 60 complexes for which our algorithm returned at least one hit, 60% of the cases were ranked within the top 2000. Comparison with existing shape-based docking algorithms shows that our method has a better performance than the others in unbound docking while remaining competitive for bound docking cases. Conclusion We show for the first time that the 3D Zernike descriptors are adept in capturing shape complementarity at the protein-protein interface and useful for

  5. Protein-protein docking using region-based 3D Zernike descriptors.

    Science.gov (United States)

    Venkatraman, Vishwesh; Yang, Yifeng D; Sael, Lee; Kihara, Daisuke

    2009-12-09

    Protein-protein interactions are a pivotal component of many biological processes and mediate a variety of functions. Knowing the tertiary structure of a protein complex is therefore essential for understanding the interaction mechanism. However, experimental techniques to solve the structure of the complex are often found to be difficult. To this end, computational protein-protein docking approaches can provide a useful alternative to address this issue. Prediction of docking conformations relies on methods that effectively capture shape features of the participating proteins while giving due consideration to conformational changes that may occur. We present a novel protein docking algorithm based on the use of 3D Zernike descriptors as regional features of molecular shape. The key motivation of using these descriptors is their invariance to transformation, in addition to a compact representation of local surface shape characteristics. Docking decoys are generated using geometric hashing, which are then ranked by a scoring function that incorporates a buried surface area and a novel geometric complementarity term based on normals associated with the 3D Zernike shape description. Our docking algorithm was tested on both bound and unbound cases in the ZDOCK benchmark 2.0 dataset. In 74% of the bound docking predictions, our method was able to find a near-native solution (interface C-alphaRMSD 3D Zernike descriptors are adept in capturing shape complementarity at the protein-protein interface and useful for protein docking prediction. Rigorous benchmark studies show that our docking approach has a superior performance compared to existing methods.

  6. Multiscale weighted colored graphs for protein flexibility and rigidity analysis

    Science.gov (United States)

    Bramer, David; Wei, Guo-Wei

    2018-02-01

    Protein structural fluctuation, measured by Debye-Waller factors or B-factors, is known to correlate to protein flexibility and function. A variety of methods has been developed for protein Debye-Waller factor prediction and related applications to domain separation, docking pose ranking, entropy calculation, hinge detection, stability analysis, etc. Nevertheless, none of the current methodologies are able to deliver an accuracy of 0.7 in terms of the Pearson correlation coefficients averaged over a large set of proteins. In this work, we introduce a paradigm-shifting geometric graph model, multiscale weighted colored graph (MWCG), to provide a new generation of computational algorithms to significantly change the current status of protein structural fluctuation analysis. Our MWCG model divides a protein graph into multiple subgraphs based on interaction types between graph nodes and represents the protein rigidity by generalized centralities of subgraphs. MWCGs not only predict the B-factors of protein residues but also accurately analyze the flexibility of all atoms in a protein. The MWCG model is validated over a number of protein test sets and compared with many standard methods. An extensive numerical study indicates that the proposed MWCG offers an accuracy of over 0.8 and thus provides perhaps the first reliable method for estimating protein flexibility and B-factors. It also simultaneously predicts all-atom flexibility in a molecule.

  7. Assessment and Challenges of Ligand Docking into Comparative Models of G-Protein Coupled Receptors

    DEFF Research Database (Denmark)

    Nguyen, E.D.; Meiler, J.; Norn, C.

    2013-01-01

    screening and to design and optimize drug candidates. However, low sequence identity between receptors, conformational flexibility, and chemical diversity of ligands present an enormous challenge to molecular modeling approaches. It is our hypothesis that rapid Monte-Carlo sampling of protein backbone...... extracellular loop. Furthermore, these models are consistently correlated with low Rosetta energy score. To predict their binding modes, ligand conformers of the 14 ligands co-crystalized with the GPCRs were docked against the top ranked comparative models. In contrast to the comparative models themselves...

  8. β-lactoglobulin's conformational requirements for ligand binding at the calyx and the dimer interphase: a flexible docking study.

    Directory of Open Access Journals (Sweden)

    Lenin Domínguez-Ramírez

    Full Text Available β-lactoglobulin (BLG is an abundant milk protein relevant for industry and biotechnology, due significantly to its ability to bind a wide range of polar and apolar ligands. While hydrophobic ligand sites are known, sites for hydrophilic ligands such as the prevalent milk sugar, lactose, remain undetermined. Through the use of molecular docking we first, analyzed the known fatty acid binding sites in order to dissect their atomistic determinants and second, predicted the interaction sites for lactose with monomeric and dimeric BLG. We validated our approach against BLG structures co-crystallized with ligands and report a computational setup with a reduced number of flexible residues that is able to reproduce experimental results with high precision. Blind dockings with and without flexible side chains on BLG showed that: i 13 experimentally-determined ligands fit the calyx requiring minimal movement of up to 7 residues out of the 23 that constitute this binding site. ii Lactose does not bind the calyx despite conformational flexibility, but binds the dimer interface and an alternate Site C. iii Results point to a probable lactolation site in the BLG dimer interface, at K141, consistent with previous biochemical findings. In contrast, no accessible lysines are found near Site C. iv lactose forms hydrogen bonds with residues from both monomers stabilizing the dimer through a claw-like structure. Overall, these results improve our understanding of BLG's binding sites, importantly narrowing down the calyx residues that control ligand binding. Moreover, our results emphasize the importance of the dimer interface as an insufficiently explored, biologically relevant binding site of particular importance for hydrophilic ligands. Furthermore our analyses suggest that BLG is a robust scaffold for multiple ligand-binding, suitable for protein design, and advance our molecular understanding of its ligand sites to a point that allows manipulation to control

  9. HDOCK: a web server for protein-protein and protein-DNA/RNA docking based on a hybrid strategy.

    Science.gov (United States)

    Yan, Yumeng; Zhang, Di; Zhou, Pei; Li, Botong; Huang, Sheng-You

    2017-07-03

    Protein-protein and protein-DNA/RNA interactions play a fundamental role in a variety of biological processes. Determining the complex structures of these interactions is valuable, in which molecular docking has played an important role. To automatically make use of the binding information from the PDB in docking, here we have presented HDOCK, a novel web server of our hybrid docking algorithm of template-based modeling and free docking, in which cases with misleading templates can be rescued by the free docking protocol. The server supports protein-protein and protein-DNA/RNA docking and accepts both sequence and structure inputs for proteins. The docking process is fast and consumes about 10-20 min for a docking run. Tested on the cases with weakly homologous complexes of server. The HDOCK web server is available at http://hdock.phys.hust.edu.cn/. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

  10. Re-docking scheme for generating near-native protein complexes by assembling residue interaction fingerprints.

    Directory of Open Access Journals (Sweden)

    Nobuyuki Uchikoga

    Full Text Available Interaction profile method is a useful method for processing rigid-body docking. After the docking process, the resulting set of docking poses could be classified by calculating similarities among them using these interaction profiles to search for near-native poses. However, there are some cases where the near-native poses are not included in this set of docking poses even when the bound-state structures are used. Therefore, we have developed a method for generating near-native docking poses by introducing a re-docking process. We devised a method for calculating the profile of interaction fingerprints by assembling protein complexes after determining certain core-protein complexes. For our analysis, we used 44 bound-state protein complexes selected from the ZDOCK benchmark dataset ver. 2.0, including some protein pairs none of which generated near-native poses in the docking process. Consequently, after the re-docking process we obtained profiles of interaction fingerprints, some of which yielded near-native poses. The re-docking process involved searching for possible docking poses in a restricted area using the profile of interaction fingerprints. If the profile includes interactions identical to those in the native complex, we obtained near-native docking poses. Accordingly, near-native poses were obtained for all bound-state protein complexes examined here. Application of interaction fingerprints to the re-docking process yielded structures with more native interactions, even when a docking pose, obtained following the initial docking process, contained only a small number of native amino acid interactions. Thus, utilization of the profile of interaction fingerprints in the re-docking process yielded more near-native poses.

  11. Re-docking scheme for generating near-native protein complexes by assembling residue interaction fingerprints.

    Science.gov (United States)

    Uchikoga, Nobuyuki; Matsuzaki, Yuri; Ohue, Masahito; Hirokawa, Takatsugu; Akiyama, Yutaka

    2013-01-01

    Interaction profile method is a useful method for processing rigid-body docking. After the docking process, the resulting set of docking poses could be classified by calculating similarities among them using these interaction profiles to search for near-native poses. However, there are some cases where the near-native poses are not included in this set of docking poses even when the bound-state structures are used. Therefore, we have developed a method for generating near-native docking poses by introducing a re-docking process. We devised a method for calculating the profile of interaction fingerprints by assembling protein complexes after determining certain core-protein complexes. For our analysis, we used 44 bound-state protein complexes selected from the ZDOCK benchmark dataset ver. 2.0, including some protein pairs none of which generated near-native poses in the docking process. Consequently, after the re-docking process we obtained profiles of interaction fingerprints, some of which yielded near-native poses. The re-docking process involved searching for possible docking poses in a restricted area using the profile of interaction fingerprints. If the profile includes interactions identical to those in the native complex, we obtained near-native docking poses. Accordingly, near-native poses were obtained for all bound-state protein complexes examined here. Application of interaction fingerprints to the re-docking process yielded structures with more native interactions, even when a docking pose, obtained following the initial docking process, contained only a small number of native amino acid interactions. Thus, utilization of the profile of interaction fingerprints in the re-docking process yielded more near-native poses.

  12. A python-based docking program utilizing a receptor bound ligand shape: PythDock.

    Science.gov (United States)

    Chung, Jae Yoon; Cho, Seung Joo; Hah, Jung-Mi

    2011-09-01

    PythDock is a heuristic docking program that uses Python programming language with a simple scoring function and a population based search engine. The scoring function considers electrostatic and dispersion/repulsion terms. The search engine utilizes a particle swarm optimization algorithm. A grid potential map is generated using the shape information of a bound ligand within the active site. Therefore, the searching area is more relevant to the ligand binding. To evaluate the docking performance of PythDock, two well-known docking programs (AutoDock and DOCK) were also used with the same data. The accuracy of docked results were measured by the difference of the ligand structure between x-ray structure, and docked pose, i.e., average root mean squared deviation values of the bound ligand were compared for fourteen protein-ligand complexes. Since the number of ligands' rotational flexibility is an important factor affecting the accuracy of a docking, the data set was chosen to have various degrees of flexibility. Although PythDock has a scoring function simpler than those of other programs (AutoDock and DOCK), our results showed that PythDock predicted more accurate poses than both AutoDock4.2 and DOCK6.2. This indicates that PythDock could be a useful tool to study ligand-receptor interactions and could also be beneficial in structure based drug design.

  13. DOCLASP - Docking ligands to target proteins using spatial and electrostatic congruence extracted from a known holoenzyme and applying simple geometrical transformations.

    Science.gov (United States)

    Chakraborty, Sandeep

    2014-01-01

    The ability to accurately and effectively predict the interaction between proteins and small drug-like compounds has long intrigued researchers for pedagogic, humanitarian and economic reasons. Protein docking methods (AutoDock, GOLD, DOCK, FlexX and Glide to name a few) rank a large number of possible conformations of protein-ligand complexes using fast algorithms. Previously, it has been shown that structural congruence leading to the same enzymatic function necessitates the congruence of electrostatic properties (CLASP). The current work presents a methodology for docking a ligand into a target protein, provided that there is at least one known holoenzyme with ligand bound - DOCLASP (Docking using CLASP). The contact points of the ligand in the holoenzyme defines a motif, which is used to query the target enzyme using CLASP. If there are significant matches, the holoenzyme and the target protein are superimposed based on congruent atoms. The same linear and rotational transformations are also applied to the ligand, thus creating a unified coordinate framework having the holoenzyme, the ligand and the target enzyme. In the current work, the dipeptidyl peptidase-IV inhibitor vildagliptin was docked to the PI-PLC structure complexed with myo-inositol using DOCLASP. Also, corroboration of the docking of phenylthiourea to the modelled structure of polyphenol oxidase (JrPPO1) from walnut is provided based on the subsequently solved structure of JrPPO1 (PDBid:5CE9). Analysis of the binding of the antitrypanosomial drug suramin to nine non-homologous proteins in the PDB database shows a diverse set of binding motifs, and multiple binding sites in the phospholipase A2-likeproteins from the Bothrops genus of pitvipers. The conformational changes in the suramin molecule on binding highlights the challenges in docking flexible ligands into an already 'plastic' binding site. Thus, DOCLASP presents a method for 'soft docking' ligands to proteins with low computational

  14. PEPSI-Dock: a detailed data-driven protein–protein interaction potential accelerated by polar Fourier correlation

    OpenAIRE

    Neveu , Emilie; Ritchie , David; Popov , Petr; Grudinin , Sergei

    2016-01-01

    International audience; Motivation: Docking prediction algorithms aim to find the native conformation of a complex of proteins from knowledge of their unbound structures. They rely on a combination of sampling and scoring methods, adapted to different scales. Polynomial Expansion of Protein Structures and Interactions for Docking (PEPSI-Dock) improves the accuracy of the first stage of the docking pipeline , which will sharpen up the final predictions. Indeed, PEPSI-Dock benefits from the pre...

  15. Systematic Protein-Protein Docking and Molecular Dynamics Studies of HIV-1 gp120 and CD4: Insights for New Drug Development

    Directory of Open Access Journals (Sweden)

    M. Rizman-Idid

    2011-12-01

    Full Text Available Background and the purpose of the study: The interactions between HIV-1 gp120 and mutated CD4 proteins were investigated in order to identify a lead structure for therapy based on competitive blocking of the HIV binding receptor for human T-cells. Crystal structures of HIV gp120-CD4 complexes reveal a close interaction of the virus receptor with CD4 Phe43, which is embedded in a pocket of the virus protein.Methods: This study applies computer simulations to determine the best binding of amino acid 43 CD4 mutants to HIV gp120. Besides natural CD4, three mutants carrying alternate aromatic residues His, Trp and Tyr at position 43 were investigated. Several docking programs were applied on isolated proteins based on selected crystal structures of gp120-CD4 complexes, as well as a 5 ns molecular dynamics study on the protein complexes. The initial structures were minimized in Gromacs to avoid crystal packing effects, and then subjected to docking experiments using AutoDock4, FireDock, ClusPro and ZDock. In molecular dynamics, the Gibbs free binding energy was calculated for the gp120-CD4 complexes. The docking outputs were analyzed on energy within the respective docking software.Results and conclusion: Visualization and hydrogen bonding analysis were performed using the Swiss-PdbViewer. Strong binding to HIV gp120 can be achieved with an extended aromatic group (Trp. However, the sterical demand of the interaction affects the binding kinetics. In conclusion, a ligand for an efficient blocking of HIV gp120 should involve an extended but conformational flexible aromatic group, i.e. a biphenyl. A docking study on biphenylalanine-43 confirms this expectation

  16. Encompassing receptor flexibility in virtual screening using ensemble docking-based hybrid QSAR: discovery of novel phytochemicals for BACE1 inhibition.

    Science.gov (United States)

    Chakraborty, Sandipan; Ramachandran, Balaji; Basu, Soumalee

    2014-10-01

    Mimicking receptor flexibility during receptor-ligand binding is a challenging task in computational drug design since it is associated with a large increase in the conformational search space. In the present study, we have devised an in silico design strategy incorporating receptor flexibility in virtual screening to identify potential lead compounds as inhibitors for flexible proteins. We have considered BACE1 (β-secretase), a key target protease from a therapeutic perspective for Alzheimer's disease, as the highly flexible receptor. The protein undergoes significant conformational transitions from open to closed form upon ligand binding, which makes it a difficult target for inhibitor design. We have designed a hybrid structure-activity model containing both ligand based descriptors and energetic descriptors obtained from molecular docking based on a dataset of structurally diverse BACE1 inhibitors. An ensemble of receptor conformations have been used in the docking study, further improving the prediction ability of the model. The designed model that shows significant prediction ability judged by several statistical parameters has been used to screen an in house developed 3-D structural library of 731 phytochemicals. 24 highly potent, novel BACE1 inhibitors with predicted activity (Ki) ≤ 50 nM have been identified. Detailed analysis reveals pharmacophoric features of these novel inhibitors required to inhibit BACE1.

  17. Molecular docking.

    Science.gov (United States)

    Morris, Garrett M; Lim-Wilby, Marguerita

    2008-01-01

    Molecular docking is a key tool in structural molecular biology and computer-assisted drug design. The goal of ligand-protein docking is to predict the predominant binding mode(s) of a ligand with a protein of known three-dimensional structure. Successful docking methods search high-dimensional spaces effectively and use a scoring function that correctly ranks candidate dockings. Docking can be used to perform virtual screening on large libraries of compounds, rank the results, and propose structural hypotheses of how the ligands inhibit the target, which is invaluable in lead optimization. The setting up of the input structures for the docking is just as important as the docking itself, and analyzing the results of stochastic search methods can sometimes be unclear. This chapter discusses the background and theory of molecular docking software, and covers the usage of some of the most-cited docking software.

  18. PSOVina: The hybrid particle swarm optimization algorithm for protein-ligand docking.

    Science.gov (United States)

    Ng, Marcus C K; Fong, Simon; Siu, Shirley W I

    2015-06-01

    Protein-ligand docking is an essential step in modern drug discovery process. The challenge here is to accurately predict and efficiently optimize the position and orientation of ligands in the binding pocket of a target protein. In this paper, we present a new method called PSOVina which combined the particle swarm optimization (PSO) algorithm with the efficient Broyden-Fletcher-Goldfarb-Shannon (BFGS) local search method adopted in AutoDock Vina to tackle the conformational search problem in docking. Using a diverse data set of 201 protein-ligand complexes from the PDBbind database and a full set of ligands and decoys for four representative targets from the directory of useful decoys (DUD) virtual screening data set, we assessed the docking performance of PSOVina in comparison to the original Vina program. Our results showed that PSOVina achieves a remarkable execution time reduction of 51-60% without compromising the prediction accuracies in the docking and virtual screening experiments. This improvement in time efficiency makes PSOVina a better choice of a docking tool in large-scale protein-ligand docking applications. Our work lays the foundation for the future development of swarm-based algorithms in molecular docking programs. PSOVina is freely available to non-commercial users at http://cbbio.cis.umac.mo .

  19. DECK: Distance and environment-dependent, coarse-grained, knowledge-based potentials for protein-protein docking

    Directory of Open Access Journals (Sweden)

    Vakser Ilya A

    2011-07-01

    Full Text Available Abstract Background Computational approaches to protein-protein docking typically include scoring aimed at improving the rank of the near-native structure relative to the false-positive matches. Knowledge-based potentials improve modeling of protein complexes by taking advantage of the rapidly increasing amount of experimentally derived information on protein-protein association. An essential element of knowledge-based potentials is defining the reference state for an optimal description of the residue-residue (or atom-atom pairs in the non-interaction state. Results The study presents a new Distance- and Environment-dependent, Coarse-grained, Knowledge-based (DECK potential for scoring of protein-protein docking predictions. Training sets of protein-protein matches were generated based on bound and unbound forms of proteins taken from the DOCKGROUND resource. Each residue was represented by a pseudo-atom in the geometric center of the side chain. To capture the long-range and the multi-body interactions, residues in different secondary structure elements at protein-protein interfaces were considered as different residue types. Five reference states for the potentials were defined and tested. The optimal reference state was selected and the cutoff effect on the distance-dependent potentials investigated. The potentials were validated on the docking decoys sets, showing better performance than the existing potentials used in scoring of protein-protein docking results. Conclusions A novel residue-based statistical potential for protein-protein docking was developed and validated on docking decoy sets. The results show that the scoring function DECK can successfully identify near-native protein-protein matches and thus is useful in protein docking. In addition to the practical application of the potentials, the study provides insights into the relative utility of the reference states, the scope of the distance dependence, and the coarse-graining of

  20. Surfing the Protein-Protein Interaction Surface Using Docking Methods: Application to the Design of PPI Inhibitors

    Directory of Open Access Journals (Sweden)

    Rushikesh Sable

    2015-06-01

    Full Text Available Blocking protein-protein interactions (PPI using small molecules or peptides modulates biochemical pathways and has therapeutic significance. PPI inhibition for designing drug-like molecules is a new area that has been explored extensively during the last decade. Considering the number of available PPI inhibitor databases and the limited number of 3D structures available for proteins, docking and scoring methods play a major role in designing PPI inhibitors as well as stabilizers. Docking methods are used in the design of PPI inhibitors at several stages of finding a lead compound, including modeling the protein complex, screening for hot spots on the protein-protein interaction interface and screening small molecules or peptides that bind to the PPI interface. There are three major challenges to the use of docking on the relatively flat surfaces of PPI. In this review we will provide some examples of the use of docking in PPI inhibitor design as well as its limitations. The combination of experimental and docking methods with improved scoring function has thus far resulted in few success stories of PPI inhibitors for therapeutic purposes. Docking algorithms used for PPI are in the early stages, however, and as more data are available docking will become a highly promising area in the design of PPI inhibitors or stabilizers.

  1. Surfing the Protein-Protein Interaction Surface Using Docking Methods: Application to the Design of PPI Inhibitors.

    Science.gov (United States)

    Sable, Rushikesh; Jois, Seetharama

    2015-06-23

    Blocking protein-protein interactions (PPI) using small molecules or peptides modulates biochemical pathways and has therapeutic significance. PPI inhibition for designing drug-like molecules is a new area that has been explored extensively during the last decade. Considering the number of available PPI inhibitor databases and the limited number of 3D structures available for proteins, docking and scoring methods play a major role in designing PPI inhibitors as well as stabilizers. Docking methods are used in the design of PPI inhibitors at several stages of finding a lead compound, including modeling the protein complex, screening for hot spots on the protein-protein interaction interface and screening small molecules or peptides that bind to the PPI interface. There are three major challenges to the use of docking on the relatively flat surfaces of PPI. In this review we will provide some examples of the use of docking in PPI inhibitor design as well as its limitations. The combination of experimental and docking methods with improved scoring function has thus far resulted in few success stories of PPI inhibitors for therapeutic purposes. Docking algorithms used for PPI are in the early stages, however, and as more data are available docking will become a highly promising area in the design of PPI inhibitors or stabilizers.

  2. HDOCK: a web server for protein–protein and protein–DNA/RNA docking based on a hybrid strategy

    Science.gov (United States)

    Yan, Yumeng; Zhang, Di; Zhou, Pei; Li, Botong

    2017-01-01

    Abstract Protein–protein and protein–DNA/RNA interactions play a fundamental role in a variety of biological processes. Determining the complex structures of these interactions is valuable, in which molecular docking has played an important role. To automatically make use of the binding information from the PDB in docking, here we have presented HDOCK, a novel web server of our hybrid docking algorithm of template-based modeling and free docking, in which cases with misleading templates can be rescued by the free docking protocol. The server supports protein–protein and protein–DNA/RNA docking and accepts both sequence and structure inputs for proteins. The docking process is fast and consumes about 10–20 min for a docking run. Tested on the cases with weakly homologous complexes of server. The HDOCK web server is available at http://hdock.phys.hust.edu.cn/. PMID:28521030

  3. The focal adhesion-associated proteins DOCK5 and GIT2 comprise a rheostat in control of epithelial invasion

    DEFF Research Database (Denmark)

    Frank, Scott R; Köllmann, C P; van Lidth de Jeude, J F

    2017-01-01

    DOCK proteins are guanine nucleotide exchange factors for Rac and Cdc42 GTPases. DOCK1 is the founding member of the family and acts downstream of integrins via the canonical Crk-p130Cas complex to activate Rac GTPases in numerous contexts. In contrast, DOCK5, which possesses the greatest similar......:10.1038/onc.2016.345....

  4. Evaluation of Docking Target Functions by the Comprehensive Investigation of Protein-Ligand Energy Minima.

    Science.gov (United States)

    Oferkin, Igor V; Katkova, Ekaterina V; Sulimov, Alexey V; Kutov, Danil C; Sobolev, Sergey I; Voevodin, Vladimir V; Sulimov, Vladimir B

    2015-01-01

    The adequate choice of the docking target function impacts the accuracy of the ligand positioning as well as the accuracy of the protein-ligand binding energy calculation. To evaluate a docking target function we compared positions of its minima with the experimentally known pose of the ligand in the protein active site. We evaluated five docking target functions based on either the MMFF94 force field or the PM7 quantum-chemical method with or without implicit solvent models: PCM, COSMO, and SGB. Each function was tested on the same set of 16 protein-ligand complexes. For exhaustive low-energy minima search the novel MPI parallelized docking program FLM and large supercomputer resources were used. Protein-ligand binding energies calculated using low-energy minima were compared with experimental values. It was demonstrated that the docking target function on the base of the MMFF94 force field in vacuo can be used for discovery of native or near native ligand positions by finding the low-energy local minima spectrum of the target function. The importance of solute-solvent interaction for the correct ligand positioning is demonstrated. It is shown that docking accuracy can be improved by replacement of the MMFF94 force field by the new semiempirical quantum-chemical PM7 method.

  5. Evaluation of Docking Target Functions by the Comprehensive Investigation of Protein-Ligand Energy Minima

    Directory of Open Access Journals (Sweden)

    Igor V. Oferkin

    2015-01-01

    Full Text Available The adequate choice of the docking target function impacts the accuracy of the ligand positioning as well as the accuracy of the protein-ligand binding energy calculation. To evaluate a docking target function we compared positions of its minima with the experimentally known pose of the ligand in the protein active site. We evaluated five docking target functions based on either the MMFF94 force field or the PM7 quantum-chemical method with or without implicit solvent models: PCM, COSMO, and SGB. Each function was tested on the same set of 16 protein-ligand complexes. For exhaustive low-energy minima search the novel MPI parallelized docking program FLM and large supercomputer resources were used. Protein-ligand binding energies calculated using low-energy minima were compared with experimental values. It was demonstrated that the docking target function on the base of the MMFF94 force field in vacuo can be used for discovery of native or near native ligand positions by finding the low-energy local minima spectrum of the target function. The importance of solute-solvent interaction for the correct ligand positioning is demonstrated. It is shown that docking accuracy can be improved by replacement of the MMFF94 force field by the new semiempirical quantum-chemical PM7 method.

  6. istar: a web platform for large-scale protein-ligand docking.

    Directory of Open Access Journals (Sweden)

    Hongjian Li

    Full Text Available Protein-ligand docking is a key computational method in the design of starting points for the drug discovery process. We are motivated by the desire to automate large-scale docking using our popular docking engine idock and thus have developed a publicly-accessible web platform called istar. Without tedious software installation, users can submit jobs using our website. Our istar website supports 1 filtering ligands by desired molecular properties and previewing the number of ligands to dock, 2 monitoring job progress in real time, and 3 visualizing ligand conformations and outputting free energy and ligand efficiency predicted by idock, binding affinity predicted by RF-Score, putative hydrogen bonds, and supplier information for easy purchase, three useful features commonly lacked on other online docking platforms like DOCK Blaster or iScreen. We have collected 17,224,424 ligands from the All Clean subset of the ZINC database, and revamped our docking engine idock to version 2.0, further improving docking speed and accuracy, and integrating RF-Score as an alternative rescoring function. To compare idock 2.0 with the state-of-the-art AutoDock Vina 1.1.2, we have carried out a rescoring benchmark and a redocking benchmark on the 2,897 and 343 protein-ligand complexes of PDBbind v2012 refined set and CSAR NRC HiQ Set 24Sept2010 respectively, and an execution time benchmark on 12 diverse proteins and 3,000 ligands of different molecular weight. Results show that, under various scenarios, idock achieves comparable success rates while outperforming AutoDock Vina in terms of docking speed by at least 8.69 times and at most 37.51 times. When evaluated on the PDBbind v2012 core set, our istar platform combining with RF-Score manages to reproduce Pearson's correlation coefficient and Spearman's correlation coefficient of as high as 0.855 and 0.859 respectively between the experimental binding affinity and the predicted binding affinity of the docked

  7. istar: a web platform for large-scale protein-ligand docking.

    Science.gov (United States)

    Li, Hongjian; Leung, Kwong-Sak; Ballester, Pedro J; Wong, Man-Hon

    2014-01-01

    Protein-ligand docking is a key computational method in the design of starting points for the drug discovery process. We are motivated by the desire to automate large-scale docking using our popular docking engine idock and thus have developed a publicly-accessible web platform called istar. Without tedious software installation, users can submit jobs using our website. Our istar website supports 1) filtering ligands by desired molecular properties and previewing the number of ligands to dock, 2) monitoring job progress in real time, and 3) visualizing ligand conformations and outputting free energy and ligand efficiency predicted by idock, binding affinity predicted by RF-Score, putative hydrogen bonds, and supplier information for easy purchase, three useful features commonly lacked on other online docking platforms like DOCK Blaster or iScreen. We have collected 17,224,424 ligands from the All Clean subset of the ZINC database, and revamped our docking engine idock to version 2.0, further improving docking speed and accuracy, and integrating RF-Score as an alternative rescoring function. To compare idock 2.0 with the state-of-the-art AutoDock Vina 1.1.2, we have carried out a rescoring benchmark and a redocking benchmark on the 2,897 and 343 protein-ligand complexes of PDBbind v2012 refined set and CSAR NRC HiQ Set 24Sept2010 respectively, and an execution time benchmark on 12 diverse proteins and 3,000 ligands of different molecular weight. Results show that, under various scenarios, idock achieves comparable success rates while outperforming AutoDock Vina in terms of docking speed by at least 8.69 times and at most 37.51 times. When evaluated on the PDBbind v2012 core set, our istar platform combining with RF-Score manages to reproduce Pearson's correlation coefficient and Spearman's correlation coefficient of as high as 0.855 and 0.859 respectively between the experimental binding affinity and the predicted binding affinity of the docked conformation. istar

  8. CPdock: the complementarity plot for docking of proteins: implementing multi-dielectric continuum electrostatics.

    Science.gov (United States)

    Basu, Sankar

    2017-12-07

    The complementarity plot (CP) is an established validation tool for protein structures, applicable to both globular proteins (folding) as well as protein-protein complexes (binding). It computes the shape and electrostatic complementarities (S m , E m ) for amino acid side-chains buried within the protein interior or interface and plots them in a two-dimensional plot having knowledge-based probabilistic quality estimates for the residues as well as for the whole structure. The current report essentially presents an upgraded version of the plot with the implementation of the advanced multi-dielectric functionality (as in Delphi version 6.2 or higher) in the computation of electrostatic complementarity to make the validation tool physico-chemically more realistic. The two methods (single- and multi-dielectric) agree decently in their resultant E m values, and hence, provisions for both methods have been kept in the software suite. So to speak, the global electrostatic balance within a well-folded protein and/or a well-packed interface seems only marginally perturbed by the choice of different internal dielectric values. However, both from theoretical as well as practical grounds, the more advanced multi-dielectric version of the plot is certainly recommended for potentially producing more reliable results. The report also presents a new methodology and a variant plot, namely CP dock , based on the same principles of complementarity specifically designed to be used in the docking of proteins. The efficacy of the method to discriminate between good and bad docked protein complexes has been tested on a recent state-of-the-art docking benchmark. The results unambiguously indicate that CP dock can indeed be effective in the initial screening phase of a docking scoring pipeline before going into more sophisticated and computationally expensive scoring functions. CP dock has been made available at https://github.com/nemo8130/CPdock . Graphical Abstract An example showing

  9. GPCR-Bench: A Benchmarking Set and Practitioners' Guide for G Protein-Coupled Receptor Docking.

    Science.gov (United States)

    Weiss, Dahlia R; Bortolato, Andrea; Tehan, Benjamin; Mason, Jonathan S

    2016-04-25

    Virtual screening is routinely used to discover new ligands and in particular new ligand chemotypes for G protein-coupled receptors (GPCRs). To prepare for a virtual screen, we often tailor a docking protocol that will enable us to select the best candidates for further screening. To aid this, we created GPCR-Bench, a publically available docking benchmarking set in the spirit of the DUD and DUD-E reference data sets for validation studies, containing 25 nonredundant high-resolution GPCR costructures with an accompanying set of diverse ligands and computational decoy molecules for each target. Benchmarking sets are often used to compare docking protocols; however, it is important to evaluate docking methods not by "retrospective" hit rates but by the actual likelihood that they will produce novel prospective hits. Therefore, docking protocols must not only rank active molecules highly but also produce good poses that a chemist will select for purchase and screening. Currently, no simple objective machine-scriptable function exists that can do this; instead, docking hit lists must be subjectively examined in a consistent way to compare between docking methods. We present here a case study highlighting considerations we feel are of importance when evaluating a method, intended to be useful as a practitioners' guide.

  10. MM-ISMSA: An Ultrafast and Accurate Scoring Function for Protein-Protein Docking.

    Science.gov (United States)

    Klett, Javier; Núñez-Salgado, Alfonso; Dos Santos, Helena G; Cortés-Cabrera, Álvaro; Perona, Almudena; Gil-Redondo, Rubén; Abia, David; Gago, Federico; Morreale, Antonio

    2012-09-11

    An ultrafast and accurate scoring function for protein-protein docking is presented. It includes (1) a molecular mechanics (MM) part based on a 12-6 Lennard-Jones potential; (2) an electrostatic component based on an implicit solvent model (ISM) with individual desolvation penalties for each partner in the protein-protein complex plus a hydrogen bonding term; and (3) a surface area (SA) contribution to account for the loss of water contacts upon protein-protein complex formation. The accuracy and performance of the scoring function, termed MM-ISMSA, have been assessed by (1) comparing the total binding energies, the electrostatic term, and its components (charge-charge and individual desolvation energies), as well as the per residue contributions, to results obtained with well-established methods such as APBSA or MM-PB(GB)SA for a set of 1242 decoy protein-protein complexes and (2) testing its ability to recognize the docking solution closest to the experimental structure as that providing the most favorable total binding energy. For this purpose, a test set consisting of 15 protein-protein complexes with known 3D structure mixed with 10 decoys for each complex was used. The correlation between the values afforded by MM-ISMSA and those from the other methods is quite remarkable (r(2) ∼ 0.9), and only 0.2-5.0 s (depending on the number of residues) are spent on a single calculation including an all vs all pairwise energy decomposition. On the other hand, MM-ISMSA correctly identifies the best docking solution as that closest to the experimental structure in 80% of the cases. Finally, MM-ISMSA can process molecular dynamics trajectories and reports the results as averaged values with their standard deviations. MM-ISMSA has been implemented as a plugin to the widely used molecular graphics program PyMOL, although it can also be executed in command-line mode. MM-ISMSA is distributed free of charge to nonprofit organizations.

  11. Designing coarse grained-and atom based-potentials for protein-protein docking

    Directory of Open Access Journals (Sweden)

    Tobi Dror

    2010-11-01

    Full Text Available Abstract Background Protein-protein docking is a challenging computational problem in functional genomics, particularly when one or both proteins undergo conformational change(s upon binding. The major challenge is to define a scoring function soft enough to tolerate these changes and specific enough to distinguish between near-native and "misdocked" conformations. Results Using a linear programming (LP technique, we developed two types of potentials: (i Side chain-based and (ii Heavy atom-based. To achieve this we considered a set of 161 transient complexes and generated a large set of putative docked structures (decoys, based on a shape complementarity criterion, for each complex. The demand on the potentials was to yield, for the native (correctly docked structure, a potential energy lower than those of any of the non-native (misdocked structures. We show that the heavy atom-based potentials were able to comply with this requirement but not the side chain-based one. Thus, despite the smaller number of parameters, the capability of heavy atom-based potentials to discriminate between native and "misdocked" conformations is improved relative to those of the side chain-based potentials. The performance of the atom-based potentials was evaluated by a jackknife test on a set of 50 complexes taken from the Zdock2.3 decoys set. Conclusions Our results show that, using the LP approach, we were able to train our potentials using a dataset of transient complexes only the newly developed potentials outperform three other known potentials in this test.

  12. Analysis and Ranking of Protein-Protein Docking Models Using Inter-Residue Contacts and Inter-Molecular Contact Maps

    KAUST Repository

    Oliva, Romina; Chermak, Edrisse; Cavallo, Luigi

    2015-01-01

    In view of the increasing interest both in inhibitors of protein-protein interactions and in protein drugs themselves, analysis of the three-dimensional structure of protein-protein complexes is assuming greater relevance in drug design. In the many cases where an experimental structure is not available, protein-protein docking becomes the method of choice for predicting the arrangement of the complex. However, reliably scoring protein-protein docking poses is still an unsolved problem. As a consequence, the screening of many docking models is usually required in the analysis step, to possibly single out the correct ones. Here, making use of exemplary cases, we review our recently introduced methods for the analysis of protein complex structures and for the scoring of protein docking poses, based on the use of inter-residue contacts and their visualization in inter-molecular contact maps. We also show that the ensemble of tools we developed can be used in the context of rational drug design targeting protein-protein interactions.

  13. Analysis and Ranking of Protein-Protein Docking Models Using Inter-Residue Contacts and Inter-Molecular Contact Maps

    KAUST Repository

    Oliva, Romina

    2015-07-01

    In view of the increasing interest both in inhibitors of protein-protein interactions and in protein drugs themselves, analysis of the three-dimensional structure of protein-protein complexes is assuming greater relevance in drug design. In the many cases where an experimental structure is not available, protein-protein docking becomes the method of choice for predicting the arrangement of the complex. However, reliably scoring protein-protein docking poses is still an unsolved problem. As a consequence, the screening of many docking models is usually required in the analysis step, to possibly single out the correct ones. Here, making use of exemplary cases, we review our recently introduced methods for the analysis of protein complex structures and for the scoring of protein docking poses, based on the use of inter-residue contacts and their visualization in inter-molecular contact maps. We also show that the ensemble of tools we developed can be used in the context of rational drug design targeting protein-protein interactions.

  14. Improving binding mode and binding affinity predictions of docking by ligand-based search of protein conformations: evaluation in D3R grand challenge 2015

    Science.gov (United States)

    Xu, Xianjin; Yan, Chengfei; Zou, Xiaoqin

    2017-08-01

    The growing number of protein-ligand complex structures, particularly the structures of proteins co-bound with different ligands, in the Protein Data Bank helps us tackle two major challenges in molecular docking studies: the protein flexibility and the scoring function. Here, we introduced a systematic strategy by using the information embedded in the known protein-ligand complex structures to improve both binding mode and binding affinity predictions. Specifically, a ligand similarity calculation method was employed to search a receptor structure with a bound ligand sharing high similarity with the query ligand for the docking use. The strategy was applied to the two datasets (HSP90 and MAP4K4) in recent D3R Grand Challenge 2015. In addition, for the HSP90 dataset, a system-specific scoring function (ITScore2_hsp90) was generated by recalibrating our statistical potential-based scoring function (ITScore2) using the known protein-ligand complex structures and the statistical mechanics-based iterative method. For the HSP90 dataset, better performances were achieved for both binding mode and binding affinity predictions comparing with the original ITScore2 and with ensemble docking. For the MAP4K4 dataset, although there were only eight known protein-ligand complex structures, our docking strategy achieved a comparable performance with ensemble docking. Our method for receptor conformational selection and iterative method for the development of system-specific statistical potential-based scoring functions can be easily applied to other protein targets that have a number of protein-ligand complex structures available to improve predictions on binding.

  15. Evaluation of multiple protein docking structures using correctly predicted pairwise subunits

    Directory of Open Access Journals (Sweden)

    Esquivel-Rodríguez Juan

    2012-03-01

    Full Text Available Abstract Background Many functionally important proteins in a cell form complexes with multiple chains. Therefore, computational prediction of multiple protein complexes is an important task in bioinformatics. In the development of multiple protein docking methods, it is important to establish a metric for evaluating prediction results in a reasonable and practical fashion. However, since there are only few works done in developing methods for multiple protein docking, there is no study that investigates how accurate structural models of multiple protein complexes should be to allow scientists to gain biological insights. Methods We generated a series of predicted models (decoys of various accuracies by our multiple protein docking pipeline, Multi-LZerD, for three multi-chain complexes with 3, 4, and 6 chains. We analyzed the decoys in terms of the number of correctly predicted pair conformations in the decoys. Results and conclusion We found that pairs of chains with the correct mutual orientation exist even in the decoys with a large overall root mean square deviation (RMSD to the native. Therefore, in addition to a global structure similarity measure, such as the global RMSD, the quality of models for multiple chain complexes can be better evaluated by using the local measurement, the number of chain pairs with correct mutual orientation. We termed the fraction of correctly predicted pairs (RMSD at the interface of less than 4.0Å as fpair and propose to use it for evaluation of the accuracy of multiple protein docking.

  16. Binding free energy analysis of protein-protein docking model structures by evERdock.

    Science.gov (United States)

    Takemura, Kazuhiro; Matubayasi, Nobuyuki; Kitao, Akio

    2018-03-14

    To aid the evaluation of protein-protein complex model structures generated by protein docking prediction (decoys), we previously developed a method to calculate the binding free energies for complexes. The method combines a short (2 ns) all-atom molecular dynamics simulation with explicit solvent and solution theory in the energy representation (ER). We showed that this method successfully selected structures similar to the native complex structure (near-native decoys) as the lowest binding free energy structures. In our current work, we applied this method (evERdock) to 100 or 300 model structures of four protein-protein complexes. The crystal structures and the near-native decoys showed the lowest binding free energy of all the examined structures, indicating that evERdock can successfully evaluate decoys. Several decoys that show low interface root-mean-square distance but relatively high binding free energy were also identified. Analysis of the fraction of native contacts, hydrogen bonds, and salt bridges at the protein-protein interface indicated that these decoys were insufficiently optimized at the interface. After optimizing the interactions around the interface by including interfacial water molecules, the binding free energies of these decoys were improved. We also investigated the effect of solute entropy on binding free energy and found that consideration of the entropy term does not necessarily improve the evaluations of decoys using the normal model analysis for entropy calculation.

  17. Solvated protein-protein docking using Kyte-Doolittle-based water preferences

    NARCIS (Netherlands)

    Kastritis, P.; Visscher, K.M.; van Dijk, A.D.J.; Bonvin, A.M.J.J.

    2013-01-01

    HADDOCK is one of the few docking programs that can explicitly account for water molecules in the docking process. Its solvated docking protocol starts from hydrated molecules and a fraction of the resulting interfacial waters is subsequently removed in a biased Monte Carlo procedure based on

  18. Solvated protein-protein docking using Kyte-Doolittle-based water preferences

    NARCIS (Netherlands)

    Kastritis, Panagiotis L.; Visscher, Koen M.; van Dijk, Aalt D.J.; Bonvin, Alexandre M.J.J.

    HADDOCK is one of the few docking programs that can explicitly account for water molecules in the docking process. Its solvated docking protocol starts from hydrated molecules and a fraction of the resulting interfacial waters is subsequently removed in a biased Monte Carlo procedure based on

  19. Analysis of protein-protein docking decoys using interaction fingerprints: application to the reconstruction of CaM-ligand complexes

    Directory of Open Access Journals (Sweden)

    Uchikoga Nobuyuki

    2010-05-01

    Full Text Available Abstract Background Protein-protein docking for proteins with large conformational changes was analyzed by using interaction fingerprints, one of the scales for measuring similarities among complex structures, utilized especially for searching near-native protein-ligand or protein-protein complex structures. Here, we have proposed a combined method for analyzing protein-protein docking by taking large conformational changes into consideration. This combined method consists of ensemble soft docking with multiple protein structures, refinement of complexes, and cluster analysis using interaction fingerprints and energy profiles. Results To test for the applicability of this combined method, various CaM-ligand complexes were reconstructed from the NMR structures of unbound CaM. For the purpose of reconstruction, we used three known CaM-ligands, namely, the CaM-binding peptides of cyclic nucleotide gateway (CNG, CaM kinase kinase (CaMKK and the plasma membrane Ca2+ ATPase pump (PMCA, and thirty-one structurally diverse CaM conformations. For each ligand, 62000 CaM-ligand complexes were generated in the docking step and the relationship between their energy profiles and structural similarities to the native complex were analyzed using interaction fingerprint and RMSD. Near-native clusters were obtained in the case of CNG and CaMKK. Conclusions The interaction fingerprint method discriminated near-native structures better than the RMSD method in cluster analysis. We showed that a combined method that includes the interaction fingerprint is very useful for protein-protein docking analysis of certain cases.

  20. DARC 2.0: Improved Docking and Virtual Screening at Protein Interaction Sites.

    Directory of Open Access Journals (Sweden)

    Ragul Gowthaman

    Full Text Available Over the past decade, protein-protein interactions have emerged as attractive but challenging targets for therapeutic intervention using small molecules. Due to the relatively flat surfaces that typify protein interaction sites, modern virtual screening tools developed for optimal performance against "traditional" protein targets perform less well when applied instead at protein interaction sites. Previously, we described a docking method specifically catered to the shallow binding modes characteristic of small-molecule inhibitors of protein interaction sites. This method, called DARC (Docking Approach using Ray Casting, operates by comparing the topography of the protein surface when "viewed" from a vantage point inside the protein against the topography of a bound ligand when "viewed" from the same vantage point. Here, we present five key enhancements to DARC. First, we use multiple vantage points to more accurately determine protein-ligand surface complementarity. Second, we describe a new scheme for rapidly determining optimal weights in the DARC scoring function. Third, we incorporate sampling of ligand conformers "on-the-fly" during docking. Fourth, we move beyond simple shape complementarity and introduce a term in the scoring function to capture electrostatic complementarity. Finally, we adjust the control flow in our GPU implementation of DARC to achieve greater speedup of these calculations. At each step of this study, we evaluate the performance of DARC in a "pose recapitulation" experiment: predicting the binding mode of 25 inhibitors each solved in complex with its distinct target protein (a protein interaction site. Whereas the previous version of DARC docked only one of these inhibitors to within 2 Å RMSD of its position in the crystal structure, the newer version achieves this level of accuracy for 12 of the 25 complexes, corresponding to a statistically significant performance improvement (p < 0.001. Collectively then, we find

  1. Defining the limits of homology modeling in information-driven protein docking

    NARCIS (Netherlands)

    Garcia Lopes Maia Rodrigues, João; Melquiond, A S J; Karaca, E; Trellet, M; van Dijk, M; van Zundert, G C P; Schmitz, C; de Vries, S J; Bordogna, A; Bonati, L; Kastritis, P L; Bonvin, Alexandre M J J; Garcia Lopes Maia Rodrigues, João

    2013-01-01

    Information-driven docking is currently one of the most successful approaches to obtain structural models of protein interactions as demonstrated in the latest round of CAPRI. While various experimental and computational techniques can be used to retrieve information about the binding mode, the

  2. The Drosophila DOCK family protein Sponge is required for development of the air sac primordium

    Energy Technology Data Exchange (ETDEWEB)

    Morishita, Kazushge; Anh Suong, Dang Ngoc; Yoshida, Hideki; Yamaguchi, Masamitsu, E-mail: myamaguc@kit.ac.jp

    2017-05-15

    Dedicator of cytokinesis (DOCK) family genes are known as DOCK1-DOCK11 in mammals. DOCK family proteins mainly regulate actin filament polymerization and/or depolymerization and are GEF proteins, which contribute to cellular signaling events by activating small G proteins. Sponge (Spg) is a Drosophila counterpart to mammalian DOCK3/DOCK4, and plays a role in embryonic central nervous system development, R7 photoreceptor cell differentiation, and adult thorax development. In order to conduct further functional analyses on Spg in vivo, we examined its localization in third instar larval wing imaginal discs. Immunostaining with purified anti-Spg IgG revealed that Spg mainly localized in the air sac primordium (ASP) in wing imaginal discs. Spg is therefore predicted to play an important role in the ASP. The specific knockdown of Spg by the breathless-GAL4 driver in tracheal cells induced lethality accompanied with a defect in ASP development and the induction of apoptosis. The monitoring of ERK signaling activity in wing imaginal discs by immunostaining with anti-diphospho-ERK IgG revealed reductions in the ERK signal cascade in Spg knockdown clones. Furthermore, the overexpression of D-raf suppressed defects in survival and the proliferation of cells in the ASP induced by the knockdown of Spg. Collectively, these results indicate that Spg plays a critical role in ASP development and tracheal cell viability that is mediated by the ERK signaling pathway. - Highlights: • Spg mainly localizes in the air sac primordium in wing imaginal discs. • Spg plays a critical role in air sac primordium development. • Spg positively regulates the ERK signal cascade.

  3. PEPSI-Dock: a detailed data-driven protein-protein interaction potential accelerated by polar Fourier correlation.

    Science.gov (United States)

    Neveu, Emilie; Ritchie, David W; Popov, Petr; Grudinin, Sergei

    2016-09-01

    Docking prediction algorithms aim to find the native conformation of a complex of proteins from knowledge of their unbound structures. They rely on a combination of sampling and scoring methods, adapted to different scales. Polynomial Expansion of Protein Structures and Interactions for Docking (PEPSI-Dock) improves the accuracy of the first stage of the docking pipeline, which will sharpen up the final predictions. Indeed, PEPSI-Dock benefits from the precision of a very detailed data-driven model of the binding free energy used with a global and exhaustive rigid-body search space. As well as being accurate, our computations are among the fastest by virtue of the sparse representation of the pre-computed potentials and FFT-accelerated sampling techniques. Overall, this is the first demonstration of a FFT-accelerated docking method coupled with an arbitrary-shaped distance-dependent interaction potential. First, we present a novel learning process to compute data-driven distant-dependent pairwise potentials, adapted from our previous method used for rescoring of putative protein-protein binding poses. The potential coefficients are learned by combining machine-learning techniques with physically interpretable descriptors. Then, we describe the integration of the deduced potentials into a FFT-accelerated spherical sampling provided by the Hex library. Overall, on a training set of 163 heterodimers, PEPSI-Dock achieves a success rate of 91% mid-quality predictions in the top-10 solutions. On a subset of the protein docking benchmark v5, it achieves 44.4% mid-quality predictions in the top-10 solutions when starting from bound structures and 20.5% when starting from unbound structures. The method runs in 5-15 min on a modern laptop and can easily be extended to other types of interactions. https://team.inria.fr/nano-d/software/PEPSI-Dock sergei.grudinin@inria.fr. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e

  4. Domain requirements for the Dock adapter protein in growth- cone signaling.

    Science.gov (United States)

    Rao, Y; Zipursky, S L

    1998-03-03

    Tyrosine phosphorylation has been implicated in growth-cone guidance through genetic, biochemical, and pharmacological studies. Adapter proteins containing src homology 2 (SH2) domains and src homology 3 (SH3) domains provide a means of linking guidance signaling through phosphotyrosine to downstream effectors regulating growth-cone motility. The Drosophila adapter, Dreadlocks (Dock), the homolog of mammalian Nck containing three N-terminal SH3 domains and a single SH2 domain, is highly specialized for growth-cone guidance. In this paper, we demonstrate that Dock can couple signals in either an SH2-dependent or an SH2-independent fashion in photoreceptor (R cell) growth cones, and that Dock displays different domain requirements in different neurons.

  5. The pepATTRACT web server for blind, large-scale peptide-protein docking.

    Science.gov (United States)

    de Vries, Sjoerd J; Rey, Julien; Schindler, Christina E M; Zacharias, Martin; Tuffery, Pierre

    2017-07-03

    Peptide-protein interactions are ubiquitous in the cell and form an important part of the interactome. Computational docking methods can complement experimental characterization of these complexes, but current protocols are not applicable on the proteome scale. pepATTRACT is a novel docking protocol that is fully blind, i.e. it does not require any information about the binding site. In various stages of its development, pepATTRACT has participated in CAPRI, making successful predictions for five out of seven protein-peptide targets. Its performance is similar or better than state-of-the-art local docking protocols that do require binding site information. Here we present a novel web server that carries out the rigid-body stage of pepATTRACT. On the peptiDB benchmark, the web server generates a correct model in the top 50 in 34% of the cases. Compared to the full pepATTRACT protocol, this leads to some loss of performance, but the computation time is reduced from ∼18 h to ∼10 min. Combined with the fact that it is fully blind, this makes the web server well-suited for large-scale in silico protein-peptide docking experiments. The rigid-body pepATTRACT server is freely available at http://bioserv.rpbs.univ-paris-diderot.fr/services/pepATTRACT. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

  6. On the analysis of protein-protein interactions via knowledge-based potentials for the prediction of protein-protein docking

    DEFF Research Database (Denmark)

    Feliu, Elisenda; Aloy, Patrick; Oliva, Baldo

    2011-01-01

    Development of effective methods to screen binary interactions obtained by rigid-body protein-protein docking is key for structure prediction of complexes and for elucidating physicochemical principles of protein-protein binding. We have derived empirical knowledge-based potential functions for s...... and with independence of the partner. This information is encoded at the residue level and could be easily incorporated in the initial grid scoring for Fast Fourier Transform rigid-body docking methods.......Development of effective methods to screen binary interactions obtained by rigid-body protein-protein docking is key for structure prediction of complexes and for elucidating physicochemical principles of protein-protein binding. We have derived empirical knowledge-based potential functions...... for selecting rigid-body docking poses. These potentials include the energetic component that provides the residues with a particular secondary structure and surface accessibility. These scoring functions have been tested on a state-of-art benchmark dataset and on a decoy dataset of permanent interactions. Our...

  7. QSAR Study on Caffeine Derivatives Docked on Poly(ARNA Polymerase Protein Cid1

    Directory of Open Access Journals (Sweden)

    Teodora E. Harsa

    2016-06-01

    Full Text Available Caffeine is the most commonly ingested alkylxantine and is recognized as a psycho-stimulant. It improves some aspects of cognitive performance, however it reduces the cerebral blood flow both in animals and humans. In this paper a QSAR study on caffeine derivatives, docked on the Poly(ARNA polymerase protein cid1, is reported. A set of forty caffeine derivatives, downloaded from PubChem, was modeled, within the hypermolecule strategy; the predicted activity was LD50 and prediction was done on similarity clusters with the leaders chosen as the best docked ligands on the Poly(ARNA polymerase protein cid1. It was concluded that LD50 of the studied caffeines is not influenced by their binding to the target protein. This work is licensed under a Creative Commons Attribution 4.0 International License.

  8. A Signal Processing Method to Explore Similarity in Protein Flexibility

    Directory of Open Access Journals (Sweden)

    Simina Vasilache

    2010-01-01

    Full Text Available Understanding mechanisms of protein flexibility is of great importance to structural biology. The ability to detect similarities between proteins and their patterns is vital in discovering new information about unknown protein functions. A Distance Constraint Model (DCM provides a means to generate a variety of flexibility measures based on a given protein structure. Although information about mechanical properties of flexibility is critical for understanding protein function for a given protein, the question of whether certain characteristics are shared across homologous proteins is difficult to assess. For a proper assessment, a quantified measure of similarity is necessary. This paper begins to explore image processing techniques to quantify similarities in signals and images that characterize protein flexibility. The dataset considered here consists of three different families of proteins, with three proteins in each family. The similarities and differences found within flexibility measures across homologous proteins do not align with sequence-based evolutionary methods.

  9. Domain requirements for the Dock adapter protein in growth- cone signaling

    OpenAIRE

    Rao, Yong; Zipursky, S. Lawrence

    1998-01-01

    Tyrosine phosphorylation has been implicated in growth-cone guidance through genetic, biochemical, and pharmacological studies. Adapter proteins containing src homology 2 (SH2) domains and src homology 3 (SH3) domains provide a means of linking guidance signaling through phosphotyrosine to downstream effectors regulating growth-cone motility. The Drosophila adapter, Dreadlocks (Dock), the homolog of mammalian Nck containing three N-terminal SH3 domains and a single SH2 domain, is highly speci...

  10. A collaborative filtering approach for protein-protein docking scoring functions.

    Science.gov (United States)

    Bourquard, Thomas; Bernauer, Julie; Azé, Jérôme; Poupon, Anne

    2011-04-22

    A protein-protein docking procedure traditionally consists in two successive tasks: a search algorithm generates a large number of candidate conformations mimicking the complex existing in vivo between two proteins, and a scoring function is used to rank them in order to extract a native-like one. We have already shown that using Voronoi constructions and a well chosen set of parameters, an accurate scoring function could be designed and optimized. However to be able to perform large-scale in silico exploration of the interactome, a near-native solution has to be found in the ten best-ranked solutions. This cannot yet be guaranteed by any of the existing scoring functions. In this work, we introduce a new procedure for conformation ranking. We previously developed a set of scoring functions where learning was performed using a genetic algorithm. These functions were used to assign a rank to each possible conformation. We now have a refined rank using different classifiers (decision trees, rules and support vector machines) in a collaborative filtering scheme. The scoring function newly obtained is evaluated using 10 fold cross-validation, and compared to the functions obtained using either genetic algorithms or collaborative filtering taken separately. This new approach was successfully applied to the CAPRI scoring ensembles. We show that for 10 targets out of 12, we are able to find a near-native conformation in the 10 best ranked solutions. Moreover, for 6 of them, the near-native conformation selected is of high accuracy. Finally, we show that this function dramatically enriches the 100 best-ranking conformations in near-native structures.

  11. Computational multiscale modeling in protein--ligand docking.

    Science.gov (United States)

    Taufer, Michela; Armen, Roger; Chen, Jianhan; Teller, Patricia; Brooks, Charles

    2009-01-01

    In biological systems, the binding of small molecule ligands to proteins is a crucial process for almost every aspect of biochemistry and molecular biology. Enzymes are proteins that function by catalyzing specific biochemical reactions that convert reactants into products. Complex organisms are typically composed of cells in which thousands of enzymes participate in complex and interconnected biochemical pathways. Some enzymes serve as sequential steps in specific pathways (such as energy metabolism), while others function to regulate entire pathways and cellular functions [1]. Small molecule ligands can be designed to bind to a specific enzyme and inhibit the biochemical reaction. Inhibiting the activity of key enzymes may result in the entire biochemical pathways being turned on or off [2], [3]. Many small molecule drugs marketed today function in this generic way as enzyme inhibitors. If research identifies a specific enzyme as being crucial to the progress of disease, then this enzyme may be targeted with an inhibitor, which may slow down or reverse the progress of disease. In this way, enzymes are targeted from specific pathogens (e.g., virus, bacteria, fungi) for infectious diseases [4], [5], and human enzymes are targeted for noninfectious diseases such as cardiovascular disease, cancer, diabetes, and neurodegenerative diseases [6].

  12. On the computation of molecular surface correlations for protein docking using fourier techniques.

    Science.gov (United States)

    Sakk, Eric

    2007-08-01

    The computation of surface correlations using a variety of molecular models has been applied to the unbound protein docking problem. Because of the computational complexity involved in examining all possible molecular orientations, the fast Fourier transform (FFT) (a fast numerical implementation of the discrete Fourier transform (DFT)) is generally applied to minimize the number of calculations. This approach is rooted in the convolution theorem which allows one to inverse transform the product of two DFTs in order to perform the correlation calculation. However, such a DFT calculation results in a cyclic or "circular" correlation which, in general, does not lead to the same result as the linear correlation desired for the docking problem. In this work, we provide computational bounds for constructing molecular models used in the molecular surface correlation problem. The derived bounds are then shown to be consistent with various intuitive guidelines previously reported in the protein docking literature. Finally, these bounds are applied to different molecular models in order to investigate their effect on the correlation calculation.

  13. MEGADOCK 4.0: an ultra-high-performance protein-protein docking software for heterogeneous supercomputers.

    Science.gov (United States)

    Ohue, Masahito; Shimoda, Takehiro; Suzuki, Shuji; Matsuzaki, Yuri; Ishida, Takashi; Akiyama, Yutaka

    2014-11-15

    The application of protein-protein docking in large-scale interactome analysis is a major challenge in structural bioinformatics and requires huge computing resources. In this work, we present MEGADOCK 4.0, an FFT-based docking software that makes extensive use of recent heterogeneous supercomputers and shows powerful, scalable performance of >97% strong scaling. MEGADOCK 4.0 is written in C++ with OpenMPI and NVIDIA CUDA 5.0 (or later) and is freely available to all academic and non-profit users at: http://www.bi.cs.titech.ac.jp/megadock. akiyama@cs.titech.ac.jp Supplementary data are available at Bioinformatics online. © The Author 2014. Published by Oxford University Press.

  14. Prediction of homoprotein and heteroprotein complexes by protein docking and template-based modeling : A CASP-CAPRI experiment

    NARCIS (Netherlands)

    Lensink, Marc F.; Velankar, Sameer; Kryshtafovych, Andriy; Huang, Shen You; Schneidman-Duhovny, Dina; Sali, Andrej; Segura, Joan; Fernandez-Fuentes, Narcis; Viswanath, Shruthi; Elber, Ron; Grudinin, Sergei; Popov, Petr; Neveu, Emilie; Lee, Hasup; Baek, Minkyung; Park, Sangwoo; Heo, Lim; Rie Lee, Gyu; Seok, Chaok; Qin, Sanbo; Zhou, Huan Xiang; Ritchie, David W.; Maigret, Bernard; Devignes, Marie Dominique; Ghoorah, Anisah; Torchala, Mieczyslaw; Chaleil, Raphaël A G; Bates, Paul A.; Ben-Zeev, Efrat; Eisenstein, Miriam; Negi, Surendra S.; Weng, Zhiping; Vreven, Thom; Pierce, Brian G.; Borrman, Tyler M.; Yu, Jinchao; Ochsenbein, Françoise; Guerois, Raphaël; Vangone, Anna; Garcia Lopes Maia Rodrigues, João; van Zundert, Gydo; Nellen, Mehdi; Xue, Li; Karaca, Ezgi; Melquiond, Adrien S J; Visscher, Koen; Kastritis, Panagiotis L.; Bonvin, Alexandre M J J; Xu, Xianjin; Qiu, Liming; Yan, Chengfei; Li, Jilong; Ma, Zhiwei; Cheng, Jianlin; Zou, Xiaoqin; Shen, Yang; Peterson, Lenna X.; Kim, Hyung Rae; Roy, Amit; Han, Xusi; Esquivel-Rodriguez, Juan; Kihara, Daisuke; Yu, Xiaofeng; Bruce, Neil J.; Fuller, Jonathan C.; Wade, Rebecca C.; Anishchenko, Ivan; Kundrotas, Petras J.; Vakser, Ilya A.; Imai, Kenichiro; Yamada, Kazunori; Oda, Toshiyuki; Nakamura, Tsukasa; Tomii, Kentaro; Pallara, Chiara; Romero-Durana, Miguel; Jiménez-García, Brian; Moal, Iain H.; Férnandez-Recio, Juan; Joung, Jong Young; Kim, Jong Yun; Joo, Keehyoung; Lee, Jooyoung; Kozakov, Dima; Vajda, Sandor; Mottarella, Scott; Hall, David R.; Beglov, Dmitri; Mamonov, Artem; Xia, Bing; Bohnuud, Tanggis; Del Carpio, Carlos A.; Ichiishi, Eichiro; Marze, Nicholas; Kuroda, Daisuke; Roy Burman, Shourya S.; Gray, Jeffrey J.; Chermak, Edrisse; Cavallo, Luigi; Oliva, Romina; Tovchigrechko, Andrey; Wodak, Shoshana J.

    2016-01-01

    We present the results for CAPRI Round 30, the first joint CASP-CAPRI experiment, which brought together experts from the protein structure prediction and protein-protein docking communities. The Round comprised 25 targets from amongst those submitted for the CASP11 prediction experiment of 2014.

  15. Prediction of homoprotein and heteroprotein complexes by protein docking and template-based modeling: A CASP-CAPRI experiment

    NARCIS (Netherlands)

    Lensink, Marc F.; Velankar, Sameer; Kryshtafovych, Andriy; Huang, Shen You; Schneidman-Duhovny, Dina; Sali, Andrej; Segura, Joan; Fernandez-Fuentes, Narcis; Viswanath, Shruthi; Elber, Ron; Grudinin, Sergei; Popov, Petr; Neveu, Emilie; Lee, Hasup; Baek, Minkyung; Park, Sangwoo; Heo, Lim; Lee, Gyu Rie; Seok, Chaok; Qin, Sanbo; Zhou, Huan Xiang; Ritchie, David W.; Maigret, Bernard; Devignes, Marie Dominique; Ghoorah, Anisah; Torchala, Mieczyslaw; Chaleil, Raphaël A.G.; Bates, Paul A.; Ben-Zeev, Efrat; Eisenstein, Miriam; Negi, Surendra S.; Weng, Zhiping; Vreven, Thom; Pierce, Brian G.; Borrman, Tyler M.; Yu, Jinchao; Ochsenbein, Françoise; Guerois, Raphaël; Vangone, Anna; Rodrigues, João P.G.L.M.; Van Zundert, Gydo; Nellen, Mehdi; Xue, Li; Karaca, Ezgi; Melquiond, Adrien S.J.; Visscher, Koen; Kastritis, Panagiotis L.; Bonvin, Alexandre M.J.J.; Xu, Xianjin; Qiu, Liming; Yan, Chengfei; Li, Jilong; Ma, Zhiwei; Cheng, Jianlin; Zou, Xiaoqin; Shen, Yang; Peterson, Lenna X.; Kim, Hyung Rae; Roy, Amit; Han, Xusi; Esquivel-Rodriguez, Juan; Kihara, Daisuke; Yu, Xiaofeng; Bruce, Neil J.; Fuller, Jonathan C.; Wade, Rebecca C.; Anishchenko, Ivan; Kundrotas, Petras J.; Vakser, Ilya A.; Imai, Kenichiro; Yamada, Kazunori; Oda, Toshiyuki; Nakamura, Tsukasa; Tomii, Kentaro; Pallara, Chiara; Romero-Durana, Miguel; Jiménez-García, Brian; Moal, Iain H.; Férnandez-Recio, Juan; Joung, Jong Young; Kim, Jong Yun; Joo, Keehyoung; Lee, Jooyoung; Kozakov, Dima; Vajda, Sandor; Mottarella, Scott; Hall, David R.; Beglov, Dmitri; Mamonov, Artem; Xia, Bing; Bohnuud, Tanggis; Del Carpio, Carlos A.; Ichiishi, Eichiro; Marze, Nicholas; Kuroda, Daisuke; Roy Burman, Shourya S.; Gray, Jeffrey J.; Chermak, Edrisse; Cavallo, Luigi; Oliva, Romina; Tovchigrechko, Andrey; Wodak, Shoshana J.

    2016-01-01

    We present the results for CAPRI Round 30, the first joint CASP-CAPRI experiment, which brought together experts from the protein structure prediction and protein-protein docking communities. The Round comprised 25 targets from amongst those submitted for the CASP11 prediction experiment of 2014.

  16. Docking-based modeling of protein-protein interfaces for extensive structural and functional characterization of missense mutations.

    Science.gov (United States)

    Barradas-Bautista, Didier; Fernández-Recio, Juan

    2017-01-01

    Next-generation sequencing (NGS) technologies are providing genomic information for an increasing number of healthy individuals and patient populations. In the context of the large amount of generated genomic data that is being generated, understanding the effect of disease-related mutations at molecular level can contribute to close the gap between genotype and phenotype and thus improve prevention, diagnosis or treatment of a pathological condition. In order to fully characterize the effect of a pathological mutation and have useful information for prediction purposes, it is important first to identify whether the mutation is located at a protein-binding interface, and second to understand the effect on the binding affinity of the affected interaction/s. Computational methods, such as protein docking are currently used to complement experimental efforts and could help to build the human structural interactome. Here we have extended the original pyDockNIP method to predict the location of disease-associated nsSNPs at protein-protein interfaces, when there is no available structure for the protein-protein complex. We have applied this approach to the pathological interaction networks of six diseases with low structural data on PPIs. This approach can almost double the number of nsSNPs that can be characterized and identify edgetic effects in many nsSNPs that were previously unknown. This can help to annotate and interpret genomic data from large-scale population studies, and to achieve a better understanding of disease at molecular level.

  17. Docking-based modeling of protein-protein interfaces for extensive structural and functional characterization of missense mutations.

    Directory of Open Access Journals (Sweden)

    Didier Barradas-Bautista

    Full Text Available Next-generation sequencing (NGS technologies are providing genomic information for an increasing number of healthy individuals and patient populations. In the context of the large amount of generated genomic data that is being generated, understanding the effect of disease-related mutations at molecular level can contribute to close the gap between genotype and phenotype and thus improve prevention, diagnosis or treatment of a pathological condition. In order to fully characterize the effect of a pathological mutation and have useful information for prediction purposes, it is important first to identify whether the mutation is located at a protein-binding interface, and second to understand the effect on the binding affinity of the affected interaction/s. Computational methods, such as protein docking are currently used to complement experimental efforts and could help to build the human structural interactome. Here we have extended the original pyDockNIP method to predict the location of disease-associated nsSNPs at protein-protein interfaces, when there is no available structure for the protein-protein complex. We have applied this approach to the pathological interaction networks of six diseases with low structural data on PPIs. This approach can almost double the number of nsSNPs that can be characterized and identify edgetic effects in many nsSNPs that were previously unknown. This can help to annotate and interpret genomic data from large-scale population studies, and to achieve a better understanding of disease at molecular level.

  18. Organization of functional domains in the docking protein p130Cas

    International Nuclear Information System (INIS)

    Nasertorabi, Fariborz; Garcia-Guzman, Miguel; Briknarova, Klara; Larsen, Elise; Havert, Marnie L.; Vuori, Kristiina; Ely, Kathryn R.

    2004-01-01

    The docking protein p130Cas becomes phosphorylated upon cell adhesion to extracellular matrix proteins, and is thought to play an essential role in cell transformation. Cas transmits signals through interactions with the Src-homology 3 (SH3) and Src-homology 2 domains of FAK or v-Crk signaling molecules, or with 14-3-3 protein, as well as phosphatases PTP1B and PTP-PEST. The large (130 kDa), multi-domain Cas molecule contains an SH3 domain, a Src-binding domain, a serine-rich protein interaction region, and a C-terminal region that participates in protein interactions implicated in antiestrogen resistance in breast cancer. In this study, as part of a long-term goal to examine the protein interactions of Cas by X-ray crystallography and nuclear magnetic resonance spectroscopy, molecular constructs were designed to express two adjacent domains, the serine-rich domain and the Src-binding domain, that each participate in intermolecular contacts dependent on protein phosphorylation. The protein products are soluble, homogeneous, monodisperse, and highly suitable for structural studies to define the role of Cas in integrin-mediated cell signaling

  19. Interaction of the minocycline with extracelluar protein and intracellular protein by multi-spectral techniques and molecular docking

    Science.gov (United States)

    Fang, Qing; Wang, Yirun; Hu, Taoying; Liu, Ying

    2017-02-01

    The interaction of minocyeline (MNC) with extracelluar protein (lysozyme, LYSO) or intracellular protein (bovine hemoglobin, BHb) was investigated using multi-spectral techniques and molecular docking in vitro. Fluorescence studies suggested that MNC quenched LYSO/BHb fluorescence in a static mode with binding constants of 2.01 and 0.26 × 104 L•mol-1 at 298 K, respectively. The LYZO-MNC system was more easily influenced by temperature (298 and 310 K) than the BHb-MNC system. The thermodynamic parameters demonstrated that hydrogen bonds and van der Waals forces played the major role in the binding process. Based on the Förster theory of nonradiative energy transfer, the binding distances between MNC and the inner tryptophan residues of LYSO and BHb were calculated to be 4.34 and 3.49 nm, respectively. Furthermore, circular dichroism spectra (CD), Fourier transforms infrared (FTIR), UV-vis, and three-dimensional fluorescence spectra results indicated the secondary structures of LYSO and BHb were partially destroyed by MNC with the α-helix percentage of LYZO-MNC increased (17.8-28.6%) while that of BHb-MNC was decreased (41.6-39.6%). UV-vis spectral results showed these binding interactions could cause conformational and some micro-environmental changes of LYSO and BHb. In accordance with the results of molecular docking, In LYZO-MNC system, MNC was mainly bound in the active site hinge region where Trp-62 and Trp-63 are located, and in MNC-BHb system, MNC was close to the subunit α 1 of BHb, molecular docking analysis supported the thermodynamic results well. The work contributes to clarify the mechanism of MNC with two proteins at molecular level.

  20. Empirical scoring functions for advanced protein-ligand docking with PLANTS.

    Science.gov (United States)

    Korb, Oliver; Stützle, Thomas; Exner, Thomas E

    2009-01-01

    In this paper we present two empirical scoring functions, PLANTS(CHEMPLP) and PLANTS(PLP), designed for our docking algorithm PLANTS (Protein-Ligand ANT System), which is based on ant colony optimization (ACO). They are related, regarding their functional form, to parts of already published scoring functions and force fields. The parametrization procedure described here was able to identify several parameter settings showing an excellent performance for the task of pose prediction on two test sets comprising 298 complexes in total. Up to 87% of the complexes of the Astex diverse set and 77% of the CCDC/Astex clean listnc (noncovalently bound complexes of the clean list) could be reproduced with root-mean-square deviations of less than 2 A with respect to the experimentally determined structures. A comparison with the state-of-the-art docking tool GOLD clearly shows that this is, especially for the druglike Astex diverse set, an improvement in pose prediction performance. Additionally, optimized parameter settings for the search algorithm were identified, which can be used to balance pose prediction reliability and search speed.

  1. Na(+),K (+)-ATPase as a docking station: protein-protein complexes of the Na(+),K (+)-ATPase.

    Science.gov (United States)

    Reinhard, Linda; Tidow, Henning; Clausen, Michael J; Nissen, Poul

    2013-01-01

    The Na(+),K(+)-ATPase, or sodium pump, is well known for its role in ion transport across the plasma membrane of animal cells. It carries out the transport of Na(+) ions out of the cell and of K(+) ions into the cell and thus maintains electrolyte and fluid balance. In addition to the fundamental ion-pumping function of the Na(+),K(+)-ATPase, recent work has suggested additional roles for Na(+),K(+)-ATPase in signal transduction and biomembrane structure. Several signaling pathways have been found to involve Na(+),K(+)-ATPase, which serves as a docking station for a fast-growing number of protein interaction partners. In this review, we focus on Na(+),K(+)-ATPase as a signal transducer, but also briefly discuss other Na(+),K(+)-ATPase protein-protein interactions, providing a comprehensive overview of the diverse signaling functions ascribed to this well-known enzyme.

  2. A simple and reliable approach to docking protein-protein complexes from very sparse NOE-derived intermolecular distance restraints

    International Nuclear Information System (INIS)

    Tang, Chun; Clore, G. Marius

    2006-01-01

    A simple and reliable approach for docking protein-protein complexes from very sparse NOE-derived intermolecular distance restraints (as few as three from a single point) in combination with a novel representation for an attractive potential between mapped interaction surfaces is described. Unambiguous assignments of very sparse intermolecular NOEs are obtained using a reverse labeling strategy in which one the components is fully deuterated with the exception of selective protonation of the δ-methyl groups of isoleucine, while the other component is uniformly 13 C-labeled. This labeling strategy can be readily extended to selective protonation of Ala, Leu, Val or Met. The attractive potential is described by a 'reduced' radius of gyration potential applied specifically to a subset of interfacial residues (those with an accessible surface area ≥ 50% in the free proteins) that have been delineated by chemical shift perturbation. Docking is achieved by rigid body minimization on the basis of a target function comprising the sparse NOE distance restraints, a van der Waals repulsion potential and the 'reduced' radius of gyration potential. The method is demonstrated for two protein-protein complexes (EIN-HPr and IIA Glc -HPr) from the bacterial phosphotransferase system. In both cases, starting from 100 different random orientations of the X-ray structures of the free proteins, 100% convergence is achieved to a single cluster (with near identical atomic positions) with an overall backbone accuracy of ∼2 A. The approach described is not limited to NMR, since interfaces can also be mapped by alanine scanning mutagenesis, and sparse intermolecular distance restraints can be derived from double cycle mutagenesis, cross-linking combined with mass spectrometry, or fluorescence energy transfer

  3. A simple and reliable approach to docking protein-protein complexes from very sparse NOE-derived intermolecular distance restraints

    Energy Technology Data Exchange (ETDEWEB)

    Tang, Chun; Clore, G. Marius [National Institutes of Health, Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases (United States)], E-mail: mariusc@intra.niddk.nih.gov

    2006-09-15

    A simple and reliable approach for docking protein-protein complexes from very sparse NOE-derived intermolecular distance restraints (as few as three from a single point) in combination with a novel representation for an attractive potential between mapped interaction surfaces is described. Unambiguous assignments of very sparse intermolecular NOEs are obtained using a reverse labeling strategy in which one the components is fully deuterated with the exception of selective protonation of the {delta}-methyl groups of isoleucine, while the other component is uniformly {sup 13}C-labeled. This labeling strategy can be readily extended to selective protonation of Ala, Leu, Val or Met. The attractive potential is described by a 'reduced' radius of gyration potential applied specifically to a subset of interfacial residues (those with an accessible surface area {>=} 50% in the free proteins) that have been delineated by chemical shift perturbation. Docking is achieved by rigid body minimization on the basis of a target function comprising the sparse NOE distance restraints, a van der Waals repulsion potential and the 'reduced' radius of gyration potential. The method is demonstrated for two protein-protein complexes (EIN-HPr and IIA{sup Glc}-HPr) from the bacterial phosphotransferase system. In both cases, starting from 100 different random orientations of the X-ray structures of the free proteins, 100% convergence is achieved to a single cluster (with near identical atomic positions) with an overall backbone accuracy of {approx}2 A. The approach described is not limited to NMR, since interfaces can also be mapped by alanine scanning mutagenesis, and sparse intermolecular distance restraints can be derived from double cycle mutagenesis, cross-linking combined with mass spectrometry, or fluorescence energy transfer.

  4. Fast and anisotropic flexibility-rigidity index for protein flexibility and fluctuation analysis

    Energy Technology Data Exchange (ETDEWEB)

    Opron, Kristopher [Department of Biochemistry and Molecular Biology, Michigan State University, Michigan 48824 (United States); Xia, Kelin [Department of Mathematics, Michigan State University, Michigan 48824 (United States); Wei, Guo-Wei, E-mail: wei@math.msu.edu [Department of Biochemistry and Molecular Biology, Michigan State University, Michigan 48824 (United States); Department of Mathematics, Michigan State University, Michigan 48824 (United States); Department of Electrical and Computer Engineering, Michigan State University, Michigan 48824 (United States)

    2014-06-21

    Protein structural fluctuation, typically measured by Debye-Waller factors, or B-factors, is a manifestation of protein flexibility, which strongly correlates to protein function. The flexibility-rigidity index (FRI) is a newly proposed method for the construction of atomic rigidity functions required in the theory of continuum elasticity with atomic rigidity, which is a new multiscale formalism for describing excessively large biomolecular systems. The FRI method analyzes protein rigidity and flexibility and is capable of predicting protein B-factors without resorting to matrix diagonalization. A fundamental assumption used in the FRI is that protein structures are uniquely determined by various internal and external interactions, while the protein functions, such as stability and flexibility, are solely determined by the structure. As such, one can predict protein flexibility without resorting to the protein interaction Hamiltonian. Consequently, bypassing the matrix diagonalization, the original FRI has a computational complexity of O(N{sup 2}). This work introduces a fast FRI (fFRI) algorithm for the flexibility analysis of large macromolecules. The proposed fFRI further reduces the computational complexity to O(N). Additionally, we propose anisotropic FRI (aFRI) algorithms for the analysis of protein collective dynamics. The aFRI algorithms permit adaptive Hessian matrices, from a completely global 3N × 3N matrix to completely local 3 × 3 matrices. These 3 × 3 matrices, despite being calculated locally, also contain non-local correlation information. Eigenvectors obtained from the proposed aFRI algorithms are able to demonstrate collective motions. Moreover, we investigate the performance of FRI by employing four families of radial basis correlation functions. Both parameter optimized and parameter-free FRI methods are explored. Furthermore, we compare the accuracy and efficiency of FRI with some established approaches to flexibility analysis, namely

  5. MOLECULAR DOCKING AND DYNAMICS STUDIES ON THE PROTEIN-PROTEIN INTERACTIONS OF ELECTRICALLY ACTIVE PILIN NANOWIRES OF GEOBACTER SULFURREDUCENS.

    Directory of Open Access Journals (Sweden)

    D. Jeya Sundara Sharmila1 *

    2017-06-01

    Full Text Available Molecular interactions are key aspects in biological recognitions applicable in nano/micro systems. Bacterial nanowires are pilus filament based structures that can conduct electrons. The transport of electron is proposed to be facilitated by filamentous fibers made up of polymeric assemblies of proteins called pilin. Geobacter sulfurreducens is capable of delivering electrons through extracellular electron transport (EET by employing conductive nanowires, which are pilin proteins composed of type IV subunit PilA. Protein-protein interactions play an important role in the stabilization of the pilin nanowire assembly complex and it contains transmembrane (TM domain. In current study, protein-protein docking and multiple molecular dynamic (MD simulations were performed to understand the binding mode of pilin nanowires. The MD result explains the conformational behavior and folding of pilin nanowires in water environment in different time scale duration 20, 5, 5, 10 and 20ns (total of 60ns. Direct hydrogen bonds and water mediated hydrogen bonds that play a crucial role during the simulation were investigated. The conformational state, folding, end-toend distance profile and hydrogen bonding behavior had indicated that the Geobacter sulfurreducens pilin nanowires have electrical conductivity properties.

  6. Post processing of protein-compound docking for fragment-based drug discovery (FBDD): in-silico structure-based drug screening and ligand-binding pose prediction.

    Science.gov (United States)

    Fukunishi, Yoshifumi

    2010-01-01

    For fragment-based drug development, both hit (active) compound prediction and docking-pose (protein-ligand complex structure) prediction of the hit compound are important, since chemical modification (fragment linking, fragment evolution) subsequent to the hit discovery must be performed based on the protein-ligand complex structure. However, the naïve protein-compound docking calculation shows poor accuracy in terms of docking-pose prediction. Thus, post-processing of the protein-compound docking is necessary. Recently, several methods for the post-processing of protein-compound docking have been proposed. In FBDD, the compounds are smaller than those for conventional drug screening. This makes it difficult to perform the protein-compound docking calculation. A method to avoid this problem has been reported. Protein-ligand binding free energy estimation is useful to reduce the procedures involved in the chemical modification of the hit fragment. Several prediction methods have been proposed for high-accuracy estimation of protein-ligand binding free energy. This paper summarizes the various computational methods proposed for docking-pose prediction and their usefulness in FBDD.

  7. Application of the random coil index to studying protein flexibility

    Energy Technology Data Exchange (ETDEWEB)

    Berjanskii, Mark V.; Wishart, David S. [University of Alberta, Department of Computing Science (Canada)], E-mail: david.wishart@ualberta.ca

    2008-01-15

    Protein flexibility lies at the heart of many protein-ligand binding events and enzymatic activities. However, the experimental measurement of protein motions is often difficult, tedious and error-prone. As a result, there is a considerable interest in developing simpler and faster ways of quantifying protein flexibility. Recently, we described a method, called Random Coil Index (RCI), which appears to be able to quantitatively estimate model-free order parameters and flexibility in protein structural ensembles using only backbone chemical shifts. Because of its potential utility, we have undertaken a more detailed investigation of the RCI method in an attempt to ascertain its underlying principles, its general utility, its sensitivity to chemical shift errors, its sensitivity to data completeness, its applicability to other proteins, and its general strengths and weaknesses. Overall, we find that the RCI method is very robust and that it represents a useful addition to traditional methods of studying protein flexibility. We have implemented many of the findings and refinements reported here into a web server that allows facile, automated predictions of model-free order parameters, MD RMSF and NMR RMSD values directly from backbone {sup 1}H, {sup 13}C and {sup 15}N chemical shift assignments. The server is available at http: //wishart.biology.ualberta.ca/rcihttp://wishart.biology.ualberta.ca/rci.

  8. Prediction of homoprotein and heteroprotein complexes by protein docking and template-based modeling: A CASP-CAPRI experiment

    KAUST Repository

    Lensink, Marc F.

    2016-04-28

    We present the results for CAPRI Round 30, the first joint CASP-CAPRI experiment, which brought together experts from the protein structure prediction and protein-protein docking communities. The Round comprised 25 targets from amongst those submitted for the CASP11 prediction experiment of 2014. The targets included mostly homodimers, a few homotetramers, and two heterodimers, and comprised protein chains that could readily be modeled using templates from the Protein Data Bank. On average 24 CAPRI groups and 7 CASP groups submitted docking predictions for each target, and 12 CAPRI groups per target participated in the CAPRI scoring experiment. In total more than 9500 models were assessed against the 3D structures of the corresponding target complexes. Results show that the prediction of homodimer assemblies by homology modeling techniques and docking calculations is quite successful for targets featuring large enough subunit interfaces to represent stable associations. Targets with ambiguous or inaccurate oligomeric state assignments, often featuring crystal contact-sized interfaces, represented a confounding factor. For those, a much poorer prediction performance was achieved, while nonetheless often providing helpful clues on the correct oligomeric state of the protein. The prediction performance was very poor for genuine tetrameric targets, where the inaccuracy of the homology-built subunit models and the smaller pair-wise interfaces severely limited the ability to derive the correct assembly mode. Our analysis also shows that docking procedures tend to perform better than standard homology modeling techniques and that highly accurate models of the protein components are not always required to identify their association modes with acceptable accuracy. © 2016 Wiley Periodicals, Inc.

  9. Prediction of homoprotein and heteroprotein complexes by protein docking and template-based modeling: A CASP-CAPRI experiment

    KAUST Repository

    Lensink, Marc F.; Velankar, Sameer; Kryshtafovych, Andriy; Huang, Shen-You; Schneidman-Duhovny, Dina; Sali, Andrej; Segura, Joan; Fernandez-Fuentes, Narcis; Viswanath, Shruthi; Elber, Ron; Grudinin, Sergei; Popov, Petr; Neveu, Emilie; Lee, Hasup; Baek, Minkyung; Park, Sangwoo; Heo, Lim; Rie Lee, Gyu; Seok, Chaok; Qin, Sanbo; Zhou, Huan-Xiang; Ritchie, David W.; Maigret, Bernard; Devignes, Marie-Dominique; Ghoorah, Anisah; Torchala, Mieczyslaw; Chaleil, Raphaë l A.G.; Bates, Paul A.; Ben-Zeev, Efrat; Eisenstein, Miriam; Negi, Surendra S.; Weng, Zhiping; Vreven, Thom; Pierce, Brian G.; Borrman, Tyler M.; Yu, Jinchao; Ochsenbein, Franç oise; Guerois, Raphaë l; Vangone, Anna; Rodrigues, Joã o P.G.L.M.; van Zundert, Gydo; Nellen, Mehdi; Xue, Li; Karaca, Ezgi; Melquiond, Adrien S.J.; Visscher, Koen; Kastritis, Panagiotis L.; Bonvin, Alexandre M.J.J.; Xu, Xianjin; Qiu, Liming; Yan, Chengfei; Li, Jilong; Ma, Zhiwei; Cheng, Jianlin; Zou, Xiaoqin; Shen, Yang; Peterson, Lenna X.; Kim, Hyung-Rae; Roy, Amit; Han, Xusi; Esquivel-Rodriguez, Juan; Kihara, Daisuke; Yu, Xiaofeng; Bruce, Neil J.; Fuller, Jonathan C.; Wade, Rebecca C.; Anishchenko, Ivan; Kundrotas, Petras J.; Vakser, Ilya A.; Imai, Kenichiro; Yamada, Kazunori; Oda, Toshiyuki; Nakamura, Tsukasa; Tomii, Kentaro; Pallara, Chiara; Romero-Durana, Miguel; Jimé nez-Garcí a, Brian; Moal, Iain H.; Fé rnandez-Recio, Juan; Joung, Jong Young; Kim, Jong Yun; Joo, Keehyoung; Lee, Jooyoung; Kozakov, Dima; Vajda, Sandor; Mottarella, Scott; Hall, David R.; Beglov, Dmitri; Mamonov, Artem; Xia, Bing; Bohnuud, Tanggis; Del Carpio, Carlos A.; Ichiishi, Eichiro; Marze, Nicholas; Kuroda, Daisuke; Roy Burman, Shourya S.; Gray, Jeffrey J.; Chermak, Edrisse; Cavallo, Luigi; Oliva, Romina; Tovchigrechko, Andrey; Wodak, Shoshana J.

    2016-01-01

    We present the results for CAPRI Round 30, the first joint CASP-CAPRI experiment, which brought together experts from the protein structure prediction and protein-protein docking communities. The Round comprised 25 targets from amongst those submitted for the CASP11 prediction experiment of 2014. The targets included mostly homodimers, a few homotetramers, and two heterodimers, and comprised protein chains that could readily be modeled using templates from the Protein Data Bank. On average 24 CAPRI groups and 7 CASP groups submitted docking predictions for each target, and 12 CAPRI groups per target participated in the CAPRI scoring experiment. In total more than 9500 models were assessed against the 3D structures of the corresponding target complexes. Results show that the prediction of homodimer assemblies by homology modeling techniques and docking calculations is quite successful for targets featuring large enough subunit interfaces to represent stable associations. Targets with ambiguous or inaccurate oligomeric state assignments, often featuring crystal contact-sized interfaces, represented a confounding factor. For those, a much poorer prediction performance was achieved, while nonetheless often providing helpful clues on the correct oligomeric state of the protein. The prediction performance was very poor for genuine tetrameric targets, where the inaccuracy of the homology-built subunit models and the smaller pair-wise interfaces severely limited the ability to derive the correct assembly mode. Our analysis also shows that docking procedures tend to perform better than standard homology modeling techniques and that highly accurate models of the protein components are not always required to identify their association modes with acceptable accuracy. © 2016 Wiley Periodicals, Inc.

  10. Target specific proteochemometric model development for BACE1 - protein flexibility and structural water are critical in virtual screening.

    Science.gov (United States)

    Manoharan, Prabu; Chennoju, Kiranmai; Ghoshal, Nanda

    2015-07-01

    BACE1 is an attractive target in Alzheimer's disease (AD) treatment. A rational drug design effort for the inhibition of BACE1 is actively pursued by researchers in both academic and pharmaceutical industries. This continued effort led to the steady accumulation of BACE1 crystal structures, co-complexed with different classes of inhibitors. This wealth of information is used in this study to develop target specific proteochemometric models and these models are exploited for predicting the prospective BACE1 inhibitors. The models developed in this study have performed excellently in predicting the computationally generated poses, separately obtained from single and ensemble docking approaches. The simple protein-ligand contact (SPLC) model outperforms other sophisticated high end models, in virtual screening performance, developed during this study. In an attempt to account for BACE1 protein active site flexibility information in predictive models, we included the change in the area of solvent accessible surface and the change in the volume of solvent accessible surface in our models. The ensemble and single receptor docking results obtained from this study indicate that the structural water mediated interactions improve the virtual screening results. Also, these waters are essential for recapitulating bioactive conformation during docking study. The proteochemometric models developed in this study can be used for the prediction of BACE1 inhibitors, during the early stage of AD drug discovery.

  11. How does symmetry impact the flexibility of proteins?

    Science.gov (United States)

    Schulze, Bernd; Sljoka, Adnan; Whiteley, Walter

    2014-02-13

    It is well known that (i) the flexibility and rigidity of proteins are central to their function, (ii) a number of oligomers with several copies of individual protein chains assemble with symmetry in the native state and (iii) added symmetry sometimes leads to added flexibility in structures. We observe that the most common symmetry classes of protein oligomers are also the symmetry classes that lead to increased flexibility in certain three-dimensional structures-and investigate the possible significance of this coincidence. This builds on the well-developed theory of generic rigidity of body-bar frameworks, which permits an analysis of the rigidity and flexibility of molecular structures such as proteins via fast combinatorial algorithms. In particular, we outline some very simple counting rules and possible algorithmic extensions that allow us to predict continuous symmetry-preserving motions in body-bar frameworks that possess non-trivial point-group symmetry. For simplicity, we focus on dimers, which typically assemble with twofold rotational axes, and often have allosteric function that requires motions to link distant sites on the two protein chains.

  12. Template-based protein-protein docking exploiting pairwise interfacial residue restraints

    NARCIS (Netherlands)

    Xue, Li C; Garcia Lopes Maia Rodrigues, João; Dobbs, Drena; Honavar, Vasant; Bonvin, Alexandre M J J

    2016-01-01

    Although many advanced and sophisticatedab initioapproaches for modeling protein-protein complexes have been proposed in past decades, template-based modeling (TBM) remains the most accurate and widely used approach, given a reliable template is available. However, there are many different ways to

  13. Structural insights into transient receptor potential vanilloid type 1 (TRPV1) from homology modeling, flexible docking, and mutational studies.

    Science.gov (United States)

    Lee, Jin Hee; Lee, Yoonji; Ryu, HyungChul; Kang, Dong Wook; Lee, Jeewoo; Lazar, Jozsef; Pearce, Larry V; Pavlyukovets, Vladimir A; Blumberg, Peter M; Choi, Sun

    2011-04-01

    The transient receptor potential vanilloid subtype 1 (TRPV1) is a non-selective cation channel composed of four monomers with six transmembrane helices (TM1-TM6). TRPV1 is found in the central and peripheral nervous system, and it is an important therapeutic target for pain relief. We describe here the construction of a tetrameric homology model of rat TRPV1 (rTRPV1). We experimentally evaluated by mutational analysis the contribution of residues of rTRPV1 contributing to ligand binding by the prototypical TRPV1 agonists, capsaicin and resiniferatoxin (RTX). We then performed docking analysis using our homology model. The docking results with capsaicin and RTX showed that our homology model was reliable, affording good agreement with our mutation data. Additionally, the binding mode of a simplified RTX (sRTX) ligand as predicted by the modeling agreed well with those of capsaicin and RTX, accounting for the high binding affinity of the sRTX ligand for TRPV1. Through the homology modeling, docking and mutational studies, we obtained important insights into the ligand-receptor interactions at the molecular level which should prove of value in the design of novel TRPV1 ligands.

  14. Joining RDC data from flexible protein domains

    International Nuclear Information System (INIS)

    Sgheri, Luca

    2010-01-01

    We study the inverse problem of determining the conformational freedom of two protein domains from residual dipolar coupling (RDC) measurements. For each paramagnetic ion attached to one of the domains we obtain a magnetic susceptibility tensor χ from the RDC of couples of atoms of that domain, and a mean paramagnetic susceptibility tensor χ-bar from the RDC of couples of atoms of the other domain. The latter is an integral average of rotations of χ which depends on the conformational freedom of the two domains. In this paper we consider the case when we have data from paramagnetic ions attached separately to each of the domains. We prove that in this case not all the elements of χ and χ-bar are independent. We derive the mathematical equations for the compatibility of the measurements and show how these relations can be used in the presence of noisy data to determine a compatible set of χ and χ-bar with an unconstrained minimization. If available, information about the shape of the noise can be included in the target function. We show that in this case the compatible set obtained has a reduced error with respect to the noisy data

  15. OSPREY: protein design with ensembles, flexibility, and provable algorithms.

    Science.gov (United States)

    Gainza, Pablo; Roberts, Kyle E; Georgiev, Ivelin; Lilien, Ryan H; Keedy, Daniel A; Chen, Cheng-Yu; Reza, Faisal; Anderson, Amy C; Richardson, David C; Richardson, Jane S; Donald, Bruce R

    2013-01-01

    We have developed a suite of protein redesign algorithms that improves realistic in silico modeling of proteins. These algorithms are based on three characteristics that make them unique: (1) improved flexibility of the protein backbone, protein side-chains, and ligand to accurately capture the conformational changes that are induced by mutations to the protein sequence; (2) modeling of proteins and ligands as ensembles of low-energy structures to better approximate binding affinity; and (3) a globally optimal protein design search, guaranteeing that the computational predictions are optimal with respect to the input model. Here, we illustrate the importance of these three characteristics. We then describe OSPREY, a protein redesign suite that implements our protein design algorithms. OSPREY has been used prospectively, with experimental validation, in several biomedically relevant settings. We show in detail how OSPREY has been used to predict resistance mutations and explain why improved flexibility, ensembles, and provability are essential for this application. OSPREY is free and open source under a Lesser GPL license. The latest version is OSPREY 2.0. The program, user manual, and source code are available at www.cs.duke.edu/donaldlab/software.php. osprey@cs.duke.edu. Copyright © 2013 Elsevier Inc. All rights reserved.

  16. Homology modeling, molecular docking and DNA binding studies of nucleotide excision repair UvrC protein from M. tuberculosis.

    Science.gov (United States)

    Parulekar, Rishikesh S; Barage, Sagar H; Jalkute, Chidambar B; Dhanavade, Maruti J; Fandilolu, Prayagraj M; Sonawane, Kailas D

    2013-08-01

    Mycobacterium tuberculosis is a Gram positive, acid-fast bacteria belonging to genus Mycobacterium, is the leading causative agent of most cases of tuberculosis. The pathogenicity of the bacteria is enhanced by its developed DNA repair mechanism which consists of machineries such as nucleotide excision repair. Nucleotide excision repair consists of excinuclease protein UvrABC endonuclease, multi-enzymatic complex which carries out repair of damaged DNA in sequential manner. UvrC protein is a part of this complex and thus helps to repair the damaged DNA of M. tuberculosis. Hence, structural bioinformatics study of UvrC protein from M. tuberculosis was carried out using homology modeling and molecular docking techniques. Assessment of the reliability of the homology model was carried out by predicting its secondary structure along with its model validation. The predicted structure was docked with the ATP and the interacting amino acid residues of UvrC protein with the ATP were found to be TRP539, PHE89, GLU536, ILE402 and ARG575. The binding of UvrC protein with the DNA showed two different domains. The residues from domain I of the protein VAL526, THR524 and LEU521 interact with the DNA whereas, amino acids interacting from the domain II of the UvrC protein included ARG597, GLU595, GLY594 and GLY592 residues. This predicted model could be useful to design new inhibitors of UvrC enzyme to prevent pathogenesis of Mycobacterium and so the tuberculosis.

  17. Introducing a Clustering Step in a Consensus Approach for the Scoring of Protein-Protein Docking Models

    KAUST Repository

    Chermak, Edrisse

    2016-11-15

    Correctly scoring protein-protein docking models to single out native-like ones is an open challenge. It is also an object of assessment in CAPRI (Critical Assessment of PRedicted Interactions), the community-wide blind docking experiment. We introduced in the field the first pure consensus method, CONSRANK, which ranks models based on their ability to match the most conserved contacts in the ensemble they belong to. In CAPRI, scorers are asked to evaluate a set of available models and select the top ten ones, based on their own scoring approach. Scorers\\' performance is ranked based on the number of targets/interfaces for which they could provide at least one correct solution. In such terms, blind testing in CAPRI Round 30 (a joint prediction round with CASP11) has shown that critical cases for CONSRANK are represented by targets showing multiple interfaces or for which only a very small number of correct solutions are available. To address these challenging cases, CONSRANK has now been modified to include a contact-based clustering of the models as a preliminary step of the scoring process. We used an agglomerative hierarchical clustering based on the number of common inter-residue contacts within the models. Two criteria, with different thresholds, were explored in the cluster generation, setting either the number of common contacts or of total clusters. For each clustering approach, after selecting the top (most populated) ten clusters, CONSRANK was run on these clusters and the top-ranked model for each cluster was selected, in the limit of 10 models per target. We have applied our modified scoring approach, Clust-CONSRANK, to SCORE_SET, a set of CAPRI scoring models made recently available by CAPRI assessors, and to the subset of homodimeric targets in CAPRI Round 30 for which CONSRANK failed to include a correct solution within the ten selected models. Results show that, for the challenging cases, the clustering step typically enriches the ten top ranked

  18. Introducing a Clustering Step in a Consensus Approach for the Scoring of Protein-Protein Docking Models

    KAUST Repository

    Chermak, Edrisse; De Donato, Renato; Lensink, Marc F.; Petta, Andrea; Serra, Luigi; Scarano, Vittorio; Cavallo, Luigi; Oliva, Romina

    2016-01-01

    Correctly scoring protein-protein docking models to single out native-like ones is an open challenge. It is also an object of assessment in CAPRI (Critical Assessment of PRedicted Interactions), the community-wide blind docking experiment. We introduced in the field the first pure consensus method, CONSRANK, which ranks models based on their ability to match the most conserved contacts in the ensemble they belong to. In CAPRI, scorers are asked to evaluate a set of available models and select the top ten ones, based on their own scoring approach. Scorers' performance is ranked based on the number of targets/interfaces for which they could provide at least one correct solution. In such terms, blind testing in CAPRI Round 30 (a joint prediction round with CASP11) has shown that critical cases for CONSRANK are represented by targets showing multiple interfaces or for which only a very small number of correct solutions are available. To address these challenging cases, CONSRANK has now been modified to include a contact-based clustering of the models as a preliminary step of the scoring process. We used an agglomerative hierarchical clustering based on the number of common inter-residue contacts within the models. Two criteria, with different thresholds, were explored in the cluster generation, setting either the number of common contacts or of total clusters. For each clustering approach, after selecting the top (most populated) ten clusters, CONSRANK was run on these clusters and the top-ranked model for each cluster was selected, in the limit of 10 models per target. We have applied our modified scoring approach, Clust-CONSRANK, to SCORE_SET, a set of CAPRI scoring models made recently available by CAPRI assessors, and to the subset of homodimeric targets in CAPRI Round 30 for which CONSRANK failed to include a correct solution within the ten selected models. Results show that, for the challenging cases, the clustering step typically enriches the ten top ranked

  19. Identification of new 2,5-diketopiperazine derivatives as simultaneous effective inhibitors of αβ-tubulin and BCRP proteins: Molecular docking, Structure-Activity Relationships and virtual consensus docking studies

    Science.gov (United States)

    Fani, Najmeh; Sattarinezhad, Elham; Bordbar, Abdol-Khalegh

    2017-06-01

    In the first part of this paper, docking method was employed in order to study the binding mechanism of breast cancer resistance protein (BCRP) with a group of previously synthesized TPS-A derivatives which known as potent inhibitors of this protein to get insight into drug binding site of BCRP and to explore structure-activity relationship of these compounds. Molecular docking results showed that most of these compounds bind in the binding site of BCRP at the interface between the membrane and outer environment. In the second part, a group of designed TPS-A derivatives which showed good binding energies in the binding site of αβ-tubulin in the previous study were chosen to study their binding energies in the binding site of BCRP to investigate their simultaneous inhibitory effect on both αβ-tubulin and BCRP. The results showed that all of these compounds bind to the binding site of BCRP with relatively suitable binding energies and therefore could be potential inhibitors of both αβ-tubulin and BCRP proteins. Finally, virtual consensus docking method was utilized with the aim of design of new 2,5-diketopiperazine derivatives with significant inhibitory effect on both αβ-tubulin and BCRP proteins. For this purpose binding energies of a library of 2,5-diketopiperazine derivatives in the binding sites of αβ-tubulin and BCRP was investigated by using AutoDock and AutoDock vina tools. Molecular docking results revealed that a group of 36 compounds among them exhibit strong anti-tubulin and anti-BCRP activity.

  20. A docking study of enhanced intracellular survival protein from Mycobacterium tuberculosis with human DUSP16/MKP-7

    International Nuclear Information System (INIS)

    Yoon, Hye-Jin; Kim, Kyoung Hoon; Yang, Jin Kuk; Suh, Se Won; Kim, Hyunsik; Jang, Soonmin

    2013-01-01

    A docking study of Mtb Eis with its substrate DUSP16/MKP-7 was performed. The docking model suggests dissociation of hexameric Mtb Eis into dimers or monomers. The intracellular pathogen Mycobacterium tuberculosis (Mtb) causes tuberculosis, and one of its secreted effector proteins, called enhanced intracellular survival (Eis) protein, enhances its survival in macrophages. Mtb Eis activates JNK-specific dual-specificity protein phosphatase 16 (DUSP16)/mitogen-activated protein kinase phosphatase-7 (MKP-7) through the acetylation on Lys55, thus inactivating JNK by dephosphorylation. Based on the recently reported crystal structure of Mtb Eis, a docking model for the binding of Mtb Eis to DUSP16/MKP-7 was generated. In the docking model, the substrate helix containing Lys55 of DUSP16/MKP-7 fits nicely into the active-site cleft of Mtb Eis; the twisted β-sheet of Eis domain II embraces the substrate helix from one side. Most importantly, the side-chain of Lys55 is inserted toward acetyl-CoA and the resulting distance is 4.6 Å between the NZ atom of Lys55 and the carbonyl carbon of the acetyl group in acetyl-CoA. The binding of Mtb Eis and DUSP16/MKP-7 is maintained by strong electrostatic interactions. The active-site cleft of Mtb Eis has a negatively charged surface formed by Asp25, Glu138, Asp286, Glu395 and the terminal carboxylic group of Phe396. In contrast, DUSP16/MKP-7 contains five basic residues, Lys52, Lys55, Arg56, Arg57 and Lys62, which point toward the negatively charged surface of the active-site pocket of Mtb Eis. Thus, the current docking model suggests that the binding of DUSP16/MKP-7 to Mtb Eis should be established by charge complementarity in addition to a very favorable geometric arrangement. The suggested mode of binding requires the dissociation of the hexameric Mtb Eis into dimers or monomers. This study may be useful for future studies aiming to develop inhibitors of Mtb Eis as a new anti-tuberculosis drug candidate

  1. A docking study of enhanced intracellular survival protein from Mycobacterium tuberculosis with human DUSP16/MKP-7

    Energy Technology Data Exchange (ETDEWEB)

    Yoon, Hye-Jin, E-mail: yoonhj@snu.ac.kr; Kim, Kyoung Hoon [Seoul National University, Seoul 151-747 (Korea, Republic of); Yang, Jin Kuk [Soongsil University, Seoul 156-743 (Korea, Republic of); Suh, Se Won [Seoul National University, Seoul 151-747 (Korea, Republic of); Seoul National University, Seoul 151-747 (Korea, Republic of); Kim, Hyunsik; Jang, Soonmin, E-mail: yoonhj@snu.ac.kr [Sejong University, Seoul 143-747 (Korea, Republic of)

    2013-11-01

    A docking study of Mtb Eis with its substrate DUSP16/MKP-7 was performed. The docking model suggests dissociation of hexameric Mtb Eis into dimers or monomers. The intracellular pathogen Mycobacterium tuberculosis (Mtb) causes tuberculosis, and one of its secreted effector proteins, called enhanced intracellular survival (Eis) protein, enhances its survival in macrophages. Mtb Eis activates JNK-specific dual-specificity protein phosphatase 16 (DUSP16)/mitogen-activated protein kinase phosphatase-7 (MKP-7) through the acetylation on Lys55, thus inactivating JNK by dephosphorylation. Based on the recently reported crystal structure of Mtb Eis, a docking model for the binding of Mtb Eis to DUSP16/MKP-7 was generated. In the docking model, the substrate helix containing Lys55 of DUSP16/MKP-7 fits nicely into the active-site cleft of Mtb Eis; the twisted β-sheet of Eis domain II embraces the substrate helix from one side. Most importantly, the side-chain of Lys55 is inserted toward acetyl-CoA and the resulting distance is 4.6 Å between the NZ atom of Lys55 and the carbonyl carbon of the acetyl group in acetyl-CoA. The binding of Mtb Eis and DUSP16/MKP-7 is maintained by strong electrostatic interactions. The active-site cleft of Mtb Eis has a negatively charged surface formed by Asp25, Glu138, Asp286, Glu395 and the terminal carboxylic group of Phe396. In contrast, DUSP16/MKP-7 contains five basic residues, Lys52, Lys55, Arg56, Arg57 and Lys62, which point toward the negatively charged surface of the active-site pocket of Mtb Eis. Thus, the current docking model suggests that the binding of DUSP16/MKP-7 to Mtb Eis should be established by charge complementarity in addition to a very favorable geometric arrangement. The suggested mode of binding requires the dissociation of the hexameric Mtb Eis into dimers or monomers. This study may be useful for future studies aiming to develop inhibitors of Mtb Eis as a new anti-tuberculosis drug candidate.

  2. IFACEwat: the interfacial water-implemented re-ranking algorithm to improve the discrimination of near native structures for protein rigid docking.

    Science.gov (United States)

    Su, Chinh; Nguyen, Thuy-Diem; Zheng, Jie; Kwoh, Chee-Keong

    2014-01-01

    Protein-protein docking is an in silico method to predict the formation of protein complexes. Due to limited computational resources, the protein-protein docking approach has been developed under the assumption of rigid docking, in which one of the two protein partners remains rigid during the protein associations and water contribution is ignored or implicitly presented. Despite obtaining a number of acceptable complex predictions, it seems to-date that most initial rigid docking algorithms still find it difficult or even fail to discriminate successfully the correct predictions from the other incorrect or false positive ones. To improve the rigid docking results, re-ranking is one of the effective methods that help re-locate the correct predictions in top high ranks, discriminating them from the other incorrect ones. Our results showed that the IFACEwat increased both the numbers of the near-native structures and improved their ranks as compared to the initial rigid docking ZDOCK3.0.2. In fact, the IFACEwat achieved a success rate of 83.8% for Antigen/Antibody complexes, which is 10% better than ZDOCK3.0.2. As compared to another re-ranking technique ZRANK, the IFACEwat obtains success rates of 92.3% (8% better) and 90% (5% better) respectively for medium and difficult cases. When comparing with the latest published re-ranking method F2Dock, the IFACEwat performed equivalently well or even better for several Antigen/Antibody complexes. With the inclusion of interfacial water, the IFACEwat improves mostly results of the initial rigid docking, especially for Antigen/Antibody complexes. The improvement is achieved by explicitly taking into account the contribution of water during the protein interactions, which was ignored or not fully presented by the initial rigid docking and other re-ranking techniques. In addition, the IFACEwat maintains sufficient computational efficiency of the initial docking algorithm, yet improves the ranks as well as the number of the near

  3. Domain wise docking analyses of the modular chitin binding protein CBP50 from Bacillus thuringiensis serovar konkukian S4.

    Science.gov (United States)

    Sehar, Ujala; Mehmood, Muhammad Aamer; Hussain, Khadim; Nawaz, Salman; Nadeem, Shahid; Siddique, Muhammad Hussnain; Nadeem, Habibullah; Gull, Munazza; Ahmad, Niaz; Sohail, Iqra; Gill, Saba Shahid; Majeed, Summera

    2013-01-01

    This paper presents an in silico characterization of the chitin binding protein CBP50 from B. thuringiensis serovar konkukian S4 through homology modeling and molecular docking. The CBP50 has shown a modular structure containing an N-terminal CBM33 domain, two consecutive fibronectin-III (Fn-III) like domains and a C-terminal CBM5 domain. The protein presented a unique modular structure which could not be modeled using ordinary procedures. So, domain wise modeling using MODELLER and docking analyses using Autodock Vina were performed. The best conformation for each domain was selected using standard procedure. It was revealed that four amino acid residues Glu-71, Ser-74, Glu-76 and Gln-90 from N-terminal domain are involved in protein-substrate interaction. Similarly, amino acid residues Trp-20, Asn-21, Ser-23 and Val-30 of Fn-III like domains and Glu-15, Ala-17, Ser-18 and Leu-35 of C-terminal domain were involved in substrate binding. Site-directed mutagenesis of these proposed amino acid residues in future will elucidate the key amino acids involved in chitin binding activity of CBP50 protein.

  4. Leptospira borgpetersenii hybrid leucine-rich repeat protein: Cloning and expression, immunogenic identification and molecular docking evaluation.

    Science.gov (United States)

    Sritrakul, Tepyuda; Nitipan, Supachai; Wajjwalku, Worawidh; La-Ard, Anchalee; Suphatpahirapol, Chattip; Petkarnjanapong, Wimol; Ongphiphadhanakul, Boonsong; Prapong, Siriwan

    2017-11-01

    Leptospirosis is an important zoonotic disease, and the major outbreak of this disease in Thailand in 1999 was due largely to the Leptospira borgpetersenii serovar Sejroe. Identification of the leucine-rich repeat (LRR) LBJ_2271 protein containing immunogenic epitopes and the discovery of the LBJ_2271 ortholog in Leptospira serovar Sejroe, KU_Sej_R21_2271, led to further studies of the antigenic immune properties of KU_Sej_LRR_2271. The recombinant hybrid (rh) protein was created and expressed from a hybrid PCR fragment of KU_Sej_R21_2271 fused with DNA encoding the LBJ_2271 signal sequence for targeting protein as a membrane-anchoring protein. The fusion DNA was cloned into pET160/GW/D-TOPO® to form the pET160_hKU_R21_2271 plasmid. The plasmid was used to express the rhKU_Sej_LRR_2271 protein in Escherichia coli BL21 Star™ (DE3). The expressed protein was immunologically detected by Western blotting and immunoreactivity detection with hyperimmune sera, T cell epitope prediction by HLA allele and epitope peptide binding affinity, and potential T cell reactivity analysis. The immunogenic epitopes of the protein were evaluated and verified by HLA allele and epitope peptide complex structure molecular docking. Among fourteen best allele epitopes of this protein, binding affinity values of 12 allele epitopes remained unchanged compared to LBJ_2271. Two epitopes for alleles HLA-A0202 and -A0301 had higher IC 50 values, while T cell reactivity values of these peptides were better than values from LBJ_2271 epitopes. Eight of twelve epitope peptides had positive T-cell reactivity scores. Although the molecular docking of two epitopes, 3FPLLKEFLV11/47FPLLKEFLV55 and 50KLSTVPEGV58, into an HLA-A0202 model revealed a good fit in the docked structures, 50KLSTVPEGV58 and 94KLSTVPEEV102 are still considered as the proteins' best epitopes for allele HLA-A0202. The results of this study showed that rhKU_Sej_LRR_2271 protein contained natural immunological properties that should

  5. Variability of the Cyclin-Dependent Kinase 2 Flexibility Without Significant Change in the Initial Conformation of the Protein or Its Environment; a Computational Study.

    Science.gov (United States)

    Taghizadeh, Mohammad; Goliaei, Bahram; Madadkar-Sobhani, Armin

    2016-06-01

    Protein flexibility, which has been referred as a dynamic behavior has various roles in proteins' functions. Furthermore, for some developed tools in bioinformatics, such as protein-protein docking software, considering the protein flexibility, causes a higher degree of accuracy. Through undertaking the present work, we have accomplished the quantification plus analysis of the variations in the human Cyclin Dependent Kinase 2 (hCDK2) protein flexibility without affecting a significant change in its initial environment or the protein per se. The main goal of the present research was to calculate variations in the flexibility for each residue of the hCDK2, analysis of their flexibility variations through clustering, and to investigate the functional aspects of the residues with high flexibility variations. Using Gromacs package (version 4.5.4), three independent molecular dynamics (MD) simulations of the hCDK2 protein (PDB ID: 1HCL) was accomplished with no significant changes in their initial environments, structures, or conformations, followed by Root Mean Square Fluctuations (RMSF) calculation of these MD trajectories. The amount of variations in these three curves of RMSF was calculated using two formulas. More than 50% of the variation in the flexibility (the distance between the maximum and the minimum amount of the RMSF) was found at the region of Val-154. As well, there are other major flexibility fluctuations in other residues. These residues were mostly positioned in the vicinity of the functional residues. The subsequent works were done, as followed by clustering all hCDK2 residues into four groups considering the amount of their variability with respect to flexibility and their position in the RMSF curves. This work has introduced a new class of flexibility aspect of the proteins' residues. It could also help designing and engineering proteins, with introducing a new dynamic aspect of hCDK2, and accordingly, for the other similar globular proteins. In

  6. The development of an affinity evaluation and prediction system by using protein–protein docking simulations and parameter tuning

    Directory of Open Access Journals (Sweden)

    Koki Tsukamoto

    2009-01-01

    Full Text Available Koki Tsukamoto1, Tatsuya Yoshikawa1,2, Kiyonobu Yokota1, Yuichiro Hourai1, Kazuhiko Fukui11Computational Biology Research Center (CBRC, National Institute of Advanced Industrial Science and Technology (AIST, Koto-ku, Tokyo, Japan; 2Department of Bioinformatic Engineering, Graduate School of Information Science and Technology, Osaka University, Toyonaka, Osaka, JapanAbstract: A system was developed to evaluate and predict the interaction between protein pairs by using the widely used shape complementarity search method as the algorithm for docking simulations between the proteins. We used this system, which we call the affinity evaluation and prediction (AEP system, to evaluate the interaction between 20 protein pairs. The system first executes a “round robin” shape complementarity search of the target protein group, and evaluates the interaction between the complex structures obtained by the search. These complex structures are selected by using a statistical procedure that we developed called ‘grouping’. At a prevalence of 5.0%, our AEP system predicted protein–protein interactions with a 50.0% recall, 55.6% precision, 95.5% accuracy, and an F-measure of 0.526. By optimizing the grouping process, our AEP system successfully predicted 10 protein pairs (among 20 pairs that were biologically relevant combinations. Our ultimate goal is to construct an affinity database that will provide cell biologists and drug designers with crucial information obtained using our AEP system.Keywords: protein–protein interaction, affinity analysis, protein–protein docking, FFT, massive parallel computing

  7. Exploiting protein flexibility to predict the location of allosteric sites

    Directory of Open Access Journals (Sweden)

    Panjkovich Alejandro

    2012-10-01

    Full Text Available Abstract Background Allostery is one of the most powerful and common ways of regulation of protein activity. However, for most allosteric proteins identified to date the mechanistic details of allosteric modulation are not yet well understood. Uncovering common mechanistic patterns underlying allostery would allow not only a better academic understanding of the phenomena, but it would also streamline the design of novel therapeutic solutions. This relatively unexplored therapeutic potential and the putative advantages of allosteric drugs over classical active-site inhibitors fuel the attention allosteric-drug research is receiving at present. A first step to harness the regulatory potential and versatility of allosteric sites, in the context of drug-discovery and design, would be to detect or predict their presence and location. In this article, we describe a simple computational approach, based on the effect allosteric ligands exert on protein flexibility upon binding, to predict the existence and position of allosteric sites on a given protein structure. Results By querying the literature and a recently available database of allosteric sites, we gathered 213 allosteric proteins with structural information that we further filtered into a non-redundant set of 91 proteins. We performed normal-mode analysis and observed significant changes in protein flexibility upon allosteric-ligand binding in 70% of the cases. These results agree with the current view that allosteric mechanisms are in many cases governed by changes in protein dynamics caused by ligand binding. Furthermore, we implemented an approach that achieves 65% positive predictive value in identifying allosteric sites within the set of predicted cavities of a protein (stricter parameters set, 0.22 sensitivity, by combining the current analysis on dynamics with previous results on structural conservation of allosteric sites. We also analyzed four biological examples in detail, revealing

  8. The low molecular weight protein PsaI stabilizes the light-harvesting complex II docking site of photosystem I

    DEFF Research Database (Denmark)

    Plöchinger, Magdalena; Torabi, Salar; Rantala, Marjaana

    2016-01-01

    PsaI represents one of three low molecular weight peptides of PSI. Targeted inactivation of the plastid PsaI gene in Nicotiana tabacum has no measurable effect on photosynthetic electron transport around PSI or on accumulation of proteins involved in photosynthesis. Instead, the lack of Psa......I destabilizes the association of PsaL and PsaH to PSI, both forming the light-harvesting complex (LHC)II docking site of PSI. These alterations at the LHCII binding site surprisingly did not prevent state transition but led to an increased incidence of PSI-LHCII complexes, coinciding with an elevated...

  9. Molecular docking study of Papaver alkaloids to some alkaloid receptors

    Directory of Open Access Journals (Sweden)

    A. Nofallah

    2017-11-01

    Full Text Available Background and objectives: More than 40 different alkaloids have been obtained from opium the most important of which are morphine, codeine, papaverine, noscapine and tabaine. Opioid alkaloids produce analgesia by affecting areas of the brain that have peptides with pharmacological pseudo-opioid properties. These alkaloids show important effects on some intracellular peptides like mu, delta, and kappa receptors. Therefore, studying the effects of these alkaloids on different receptors is essential. Methods: Molecular docking is a well-known method in exploring the protein-ligand interactions. In this research, five important alkaloids were docked to crystal structure of human mu opioid receptor (4DKL, human delta opioid receptor (4EJ4 and human kappa opioid receptor (4DJH which were retrieved from protein databank. The 3D-structures of alkaloids were drawn by chembiooffice2010 and minimized with hyperchem package and submitted to molecular docking utilizing autodock-vina. Flexibility of the proteins was considered. The docking studies were performed to compare the affinity of these five alkaloids to the mentioned receptors. Results: We computationally docked each alkaloid compound onto each receptor structure and estimated their binding affinity based on dock scores. Dock score is a criteria including binding energy which utilized here for prediction and comparison of the binding affinities. Binding interactions of the docked alkaloids in receptor pockets were also visually inspected and compared. Conclusion: In this approach, using docking study as a computational method provided a valuable insight of opioid receptor pocket structures which would be essential to design more efficient drugs in pain managements and addiction treatments.

  10. Flexibility.

    Science.gov (United States)

    Humphrey, L. Dennis

    1981-01-01

    Flexibility is an important aspect of all sports and recreational activities. Flexibility can be developed and maintained by stretching exercises. Exercises designed to develop flexibility in ankle joints, knees, hips, and the lower back are presented. (JN)

  11. In Silico Generation of Peptides by Replica Exchange Monte Carlo: Docking-Based Optimization of Maltose-Binding-Protein Ligands.

    Directory of Open Access Journals (Sweden)

    Anna Russo

    Full Text Available Short peptides can be designed in silico and synthesized through automated techniques, making them advantageous and versatile protein binders. A number of docking-based algorithms allow for a computational screening of peptides as binders. Here we developed ex-novo peptides targeting the maltose site of the Maltose Binding Protein, the prototypical system for the study of protein ligand recognition. We used a Monte Carlo based protocol, to computationally evolve a set of octapeptides starting from a polialanine sequence. We screened in silico the candidate peptides and characterized their binding abilities by surface plasmon resonance, fluorescence and electrospray ionization mass spectrometry assays. These experiments showed the designed binders to recognize their target with micromolar affinity. We finally discuss the obtained results in the light of further improvement in the ex-novo optimization of peptide based binders.

  12. Using the multi-objective optimization replica exchange Monte Carlo enhanced sampling method for protein-small molecule docking.

    Science.gov (United States)

    Wang, Hongrui; Liu, Hongwei; Cai, Leixin; Wang, Caixia; Lv, Qiang

    2017-07-10

    In this study, we extended the replica exchange Monte Carlo (REMC) sampling method to protein-small molecule docking conformational prediction using RosettaLigand. In contrast to the traditional Monte Carlo (MC) and REMC sampling methods, these methods use multi-objective optimization Pareto front information to facilitate the selection of replicas for exchange. The Pareto front information generated to select lower energy conformations as representative conformation structure replicas can facilitate the convergence of the available conformational space, including available near-native structures. Furthermore, our approach directly provides min-min scenario Pareto optimal solutions, as well as a hybrid of the min-min and max-min scenario Pareto optimal solutions with lower energy conformations for use as structure templates in the REMC sampling method. These methods were validated based on a thorough analysis of a benchmark data set containing 16 benchmark test cases. An in-depth comparison between MC, REMC, multi-objective optimization-REMC (MO-REMC), and hybrid MO-REMC (HMO-REMC) sampling methods was performed to illustrate the differences between the four conformational search strategies. Our findings demonstrate that the MO-REMC and HMO-REMC conformational sampling methods are powerful approaches for obtaining protein-small molecule docking conformational predictions based on the binding energy of complexes in RosettaLigand.

  13. Dynamic Docking: A Paradigm Shift in Computational Drug Discovery

    Directory of Open Access Journals (Sweden)

    Dario Gioia

    2017-11-01

    Full Text Available Molecular docking is the methodology of choice for studying in silico protein-ligand binding and for prioritizing compounds to discover new lead candidates. Traditional docking simulations suffer from major limitations, mostly related to the static or semi-flexible treatment of ligands and targets. They also neglect solvation and entropic effects, which strongly limits their predictive power. During the last decade, methods based on full atomistic molecular dynamics (MD have emerged as a valid alternative for simulating macromolecular complexes. In principle, compared to traditional docking, MD allows the full exploration of drug-target recognition and binding from both the mechanistic and energetic points of view (dynamic docking. Binding and unbinding kinetic constants can also be determined. While dynamic docking is still too computationally expensive to be routinely used in fast-paced drug discovery programs, the advent of faster computing architectures and advanced simulation methodologies are changing this scenario. It is feasible that dynamic docking will replace static docking approaches in the near future, leading to a major paradigm shift in in silico drug discovery. Against this background, we review the key achievements that have paved the way for this progress.

  14. Multi-template homology based structure prediction and molecular docking studies of protein ‘L’ of Zaire ebolavirus (EBOV

    Directory of Open Access Journals (Sweden)

    Jayasree Ganugapati

    2017-01-01

    Full Text Available Ebola is one of the most dangerous pathogenic RNA virus that causes severe hemorrhagic fever in humans and is considered to be a threat to humanity. The RNA genome of EBOV encodes seven proteins viz., glycoprotein (GP, nucleoprotein (NP, RNA-dependent RNA polymerase (protein ‘L’, VP35, VP30, VP40 andVP24. The objective of the present study is to find a suitable inhibitor for protein ‘L’. The large structural protein ‘L’, is made up of 2212 amino acid residues. This protein works as an RNA-dependent RNA polymerase (RdRp and a methyl transferase. It is carried by the virus during the infection as the host mechanisms cannot be used to transcribe the –ss RNA genome of the virus. As the protein is crucial for the replication of the viral genome and no other host enzyme can perform the same function, this viral protein ‘L’ was considered as a potential drug target to design inhibitors. The 3D structure of protein ‘L’ is not available to date. This is a limitation in understanding the protein's function. Hence, the present work is aimed at predicting the first homology-based model of protein ‘L’ and elucidating the function by providing insight into the molecular details of the protein. As there is no drug available for the treatment of EBOV infection our findings play a crucial a role to identify an inhibitor of the protein ‘L’ of EBOV. HTS against ZINC database resulted in identification of few possible inhibitors. Molecular docking studies resulted in finding a suitable inhibitor for protein ‘L’.

  15. NPPD: A Protein-Protein Docking Scoring Function Based on Dyadic Differences in Networks of Hydrophobic and Hydrophilic Amino Acid Residues

    Directory of Open Access Journals (Sweden)

    Edward S. C. Shih

    2015-03-01

    Full Text Available Protein-protein docking (PPD predictions usually rely on the use of a scoring function to rank docking models generated by exhaustive sampling. To rank good models higher than bad ones, a large number of scoring functions have been developed and evaluated, but the methods used for the computation of PPD predictions remain largely unsatisfactory. Here, we report a network-based PPD scoring function, the NPPD, in which the network consists of two types of network nodes, one for hydrophobic and the other for hydrophilic amino acid residues, and the nodes are connected when the residues they represent are within a certain contact distance. We showed that network parameters that compute dyadic interactions and those that compute heterophilic interactions of the amino acid networks thus constructed allowed NPPD to perform well in a benchmark evaluation of 115 PPD scoring functions, most of which, unlike NPPD, are based on some sort of protein-protein interaction energy. We also showed that NPPD was highly complementary to these energy-based scoring functions, suggesting that the combined use of conventional scoring functions and NPPD might significantly improve the accuracy of current PPD predictions.

  16. Structural Bioinformatics and Protein Docking Analysis of the Molecular Chaperone-Kinase Interactions: Towards Allosteric Inhibition of Protein Kinases by Targeting the Hsp90-Cdc37 Chaperone Machinery

    Directory of Open Access Journals (Sweden)

    Gennady Verkhivker

    2013-11-01

    Full Text Available A fundamental role of the Hsp90-Cdc37 chaperone system in mediating maturation of protein kinase clients and supporting kinase functional activity is essential for the integrity and viability of signaling pathways involved in cell cycle control and organism development. Despite significant advances in understanding structure and function of molecular chaperones, the molecular mechanisms and guiding principles of kinase recruitment to the chaperone system are lacking quantitative characterization. Structural and thermodynamic characterization of Hsp90-Cdc37 binding with protein kinase clients by modern experimental techniques is highly challenging, owing to a transient nature of chaperone-mediated interactions. In this work, we used experimentally-guided protein docking to probe the allosteric nature of the Hsp90-Cdc37 binding with the cyclin-dependent kinase 4 (Cdk4 kinase clients. The results of docking simulations suggest that the kinase recognition and recruitment to the chaperone system may be primarily determined by Cdc37 targeting of the N-terminal kinase lobe. The interactions of Hsp90 with the C-terminal kinase lobe may provide additional “molecular brakes” that can lock (or unlock kinase from the system during client loading (release stages. The results of this study support a central role of the Cdc37 chaperone in recognition and recruitment of the kinase clients. Structural analysis may have useful implications in developing strategies for allosteric inhibition of protein kinases by targeting the Hsp90-Cdc37 chaperone machinery.

  17. Flexible Molybdenum Electrodes towards Designing Affinity Based Protein Biosensors.

    Science.gov (United States)

    Kamakoti, Vikramshankar; Panneer Selvam, Anjan; Radha Shanmugam, Nandhinee; Muthukumar, Sriram; Prasad, Shalini

    2016-07-18

    Molybdenum electrode based flexible biosensor on porous polyamide substrates has been fabricated and tested for its functionality as a protein affinity based biosensor. The biosensor performance was evaluated using a key cardiac biomarker; cardiac Troponin-I (cTnI). Molybdenum is a transition metal and demonstrates electrochemical behavior upon interaction with an electrolyte. We have leveraged this property of molybdenum for designing an affinity based biosensor using electrochemical impedance spectroscopy. We have evaluated the feasibility of detection of cTnI in phosphate-buffered saline (PBS) and human serum (HS) by measuring impedance changes over a frequency window from 100 mHz to 1 MHz. Increasing changes to the measured impedance was correlated to the increased dose of cTnI molecules binding to the cTnI antibody functionalized molybdenum surface. We achieved cTnI detection limit of 10 pg/mL in PBS and 1 ng/mL in HS medium. The use of flexible substrates for designing the biosensor demonstrates promise for integration with a large-scale batch manufacturing process.

  18. Evaluating the binding efficiency of pheromone binding protein with its natural ligand using molecular docking and fluorescence analysis

    Science.gov (United States)

    Ilayaraja, Renganathan; Rajkumar, Ramalingam; Rajesh, Durairaj; Muralidharan, Arumugam Ramachandran; Padmanabhan, Parasuraman; Archunan, Govindaraju

    2014-06-01

    Chemosignals play a crucial role in social and sexual communication among inter- and intra-species. Chemical cues are bound with protein that is present in the pheromones irrespective of sex are commonly called as pheromone binding protein (PBP). In rats, the pheromone compounds are bound with low molecular lipocalin protein α2u-globulin (α2u). We reported farnesol is a natural endogenous ligand (compound) present in rat preputial gland as a bound volatile compound. In the present study, an attempt has been made through computational method to evaluating the binding efficiency of α2u with the natural ligand (farnesol) and standard fluorescent molecule (2-naphthol). The docking analysis revealed that the binding energy of farnesol and 2-naphthol was almost equal and likely to share some binding pocket of protein. Further, to extrapolate the results generated through computational approach, the α2u protein was purified and subjected to fluorescence titration and binding assay. The results showed that the farnesol is replaced by 2-naphthol with high hydrophobicity of TYR120 in binding sites of α2u providing an acceptable dissociation constant indicating the binding efficiency of α2u. The obtained results are in corroboration with the data made through computational approach.

  19. DockingShop: A Tool for Interactive Molecular Docking

    Energy Technology Data Exchange (ETDEWEB)

    Lu, Ting-Cheng; Max, Nelson L.; Ding, Jinhui; Bethel, E. Wes; Crivelli, Silvia N.

    2005-04-24

    Given two independently determined molecular structures, the molecular docking problem predicts the bound association, or best fit between them, while allowing for conformational changes of the individual molecules during construction of a molecular complex. Docking Shop is an integrated environment that permits interactive molecular docking by navigating a ligand or protein to an estimated binding site of a receptor with real-time graphical feedback of scoring factors as visual guides. Our program can be used to create initial configurations for a protein docking prediction process. Its output--the structure of aprotein-ligand or protein-protein complex--may serve as an input for aprotein docking algorithm, or an optimization process. This tool provides molecular graphics interfaces for structure modeling, interactive manipulation, navigation, optimization, and dynamic visualization to aid users steer the prediction process using their biological knowledge.

  20. Flexibility damps macromolecular crowding effects on protein folding dynamics: Application to the murine prion protein (121-231)

    Science.gov (United States)

    Bergasa-Caceres, Fernando; Rabitz, Herschel A.

    2014-01-01

    A model of protein folding kinetics is applied to study the combined effects of protein flexibility and macromolecular crowding on protein folding rate and stability. It is found that the increase in stability and folding rate promoted by macromolecular crowding is damped for proteins with highly flexible native structures. The model is applied to the folding dynamics of the murine prion protein (121-231). It is found that the high flexibility of the native isoform of the murine prion protein (121-231) reduces the effects of macromolecular crowding on its folding dynamics. The relevance of these findings for the pathogenic mechanism are discussed.

  1. Insight into the intermolecular recognition mechanism between Keap1 and IKKβ combining homology modelling, protein-protein docking, molecular dynamics simulations and virtual alanine mutation.

    Directory of Open Access Journals (Sweden)

    Zheng-Yu Jiang

    Full Text Available Degradation of certain proteins through the ubiquitin-proteasome pathway is a common strategy taken by the key modulators responsible for stress responses. Kelch-like ECH-associated protein-1(Keap1, a substrate adaptor component of the Cullin3 (Cul3-based ubiquitin E3 ligase complex, mediates the ubiquitination of two key modulators, NF-E2-related factor 2 (Nrf2 and IκB kinase β (IKKβ, which are involved in the redox control of gene transcription. However, compared to the Keap1-Nrf2 protein-protein interaction (PPI, the intermolecular recognition mechanism of Keap1 and IKKβ has been poorly investigated. In order to explore the binding pattern between Keap1 and IKKβ, the PPI model of Keap1 and IKKβ was investigated. The structure of human IKKβ was constructed by means of the homology modeling method and using reported crystal structure of Xenopus laevis IKKβ as the template. A protein-protein docking method was applied to develop the Keap1-IKKβ complex model. After the refinement and visual analysis of docked proteins, the chosen pose was further optimized through molecular dynamics simulations. The resulting structure was utilized to conduct the virtual alanine mutation for the exploration of hot-spots significant for the intermolecular interaction. Overall, our results provided structural insights into the PPI model of Keap1-IKKβ and suggest that the substrate specificity of Keap1 depend on the interaction with the key tyrosines, namely Tyr525, Tyr574 and Tyr334. The study presented in the current project may be useful to design molecules that selectively modulate Keap1. The selective recognition mechanism of Keap1 with IKKβ or Nrf2 will be helpful to further know the crosstalk between NF-κB and Nrf2 signaling.

  2. Cell adhesion controlled by adhesion G protein-coupled receptor GPR124/ADGRA2 is mediated by a protein complex comprising intersectins and Elmo-Dock.

    Science.gov (United States)

    Hernández-Vásquez, Magda Nohemí; Adame-García, Sendi Rafael; Hamoud, Noumeira; Chidiac, Rony; Reyes-Cruz, Guadalupe; Gratton, Jean Philippe; Côté, Jean-François; Vázquez-Prado, José

    2017-07-21

    Developmental angiogenesis and the maintenance of the blood-brain barrier involve endothelial cell adhesion, which is linked to cytoskeletal dynamics. GPR124 (also known as TEM5/ADGRA2) is an adhesion G protein-coupled receptor family member that plays a pivotal role in brain angiogenesis and in ensuring a tight blood-brain barrier. However, the signaling properties of GPR124 remain poorly defined. Here, we show that ectopic expression of GPR124 promotes cell adhesion, additive to extracellular matrix-dependent effect, coupled with filopodia and lamellipodia formation and an enrichment of a pool of the G protein-coupled receptor at actin-rich cellular protrusions containing VASP, a filopodial marker. Accordingly, GPR124-expressing cells also displayed increased activation of both Rac and Cdc42 GTPases. Mechanistically, we uncover novel direct interactions between endogenous GPR124 and the Rho guanine nucleotide exchange factors Elmo/Dock and intersectin (ITSN). Small fragments of either Elmo or ITSN1 that bind GPR124 blocked GPR124-induced cell adhesion. In addition, Gβγ interacts with the C-terminal tail of GPR124 and promotes the formation of a GPR124-Elmo complex. Furthermore, GPR124 also promotes the activation of the Elmo-Dock complex, as measured by Elmo phosphorylation on a conserved C-terminal tyrosine residue. Interestingly, Elmo and ITSN1 also interact with each other independently of their GPR124-recognition regions. Moreover, endogenous phospho-Elmo and ITSN1 co-localize with GPR124 at lamellipodia of adhering endothelial cells, where GPR124 expression contributes to polarity acquisition during wound healing. Collectively, our results indicate that GPR124 promotes cell adhesion via Elmo-Dock and ITSN. This constitutes a previously unrecognized complex formed of atypical and conventional Rho guanine nucleotide exchange factors for Rac and Cdc42 that is putatively involved in GPR124-dependent angiogenic responses. © 2017 by The American Society for

  3. Dimerization of the docking/adaptor protein HEF1 via a carboxy-terminal helix-loop-helix domain.

    Science.gov (United States)

    Law, S F; Zhang, Y Z; Fashena, S J; Toby, G; Estojak, J; Golemis, E A

    1999-10-10

    HEF1, p130(Cas), and Efs define a family of multidomain docking proteins which plays a central coordinating role for tyrosine-kinase-based signaling related to cell adhesion. HEF1 function has been specifically implicated in signaling pathways important for cell adhesion and differentiation in lymphoid and epithelial cells. While the SH3 domains and SH2-binding site domains (substrate domains) of HEF1 family proteins are well characterized and binding partners known, to date the highly conserved carboxy-terminal domains of the three proteins have lacked functional definition. In this study, we have determined that the carboxy-terminal domain of HEF1 contains a divergent helix-loop-helix (HLH) motif. This motif mediates HEF1 homodimerization and HEF1 heterodimerization with a recognition specificity similar to that of the transcriptional regulatory HLH proteins Id2, E12, and E47. We had previously demonstrated that the HEF1 carboxy-terminus expressed as a separate domain in yeast reprograms cell division patterns, inducing constitutive pseudohyphal growth. Here we show that pseudohyphal induction by HEF1 requires an intact HLH, further supporting the idea that this motif has an effector activity for HEF1, and implying that HEF1 pseudohyphal activity derives in part from interactions with yeast helix-loop-helix proteins. These combined results provide initial insight into the mode of function of the HEF1 carboxy-terminal domain and suggest that the HEF1 protein may interact with cellular proteins which control differentiation. Copyright 1999 Academic Press.

  4. Production of antioxidant and ACE-inhibitory peptides from Kluyveromyces marxianus protein hydrolysates: Purification and molecular docking

    Directory of Open Access Journals (Sweden)

    Mahta Mirzaei

    2018-04-01

    Full Text Available Kluyveromyces marxianus protein hydrolysates were prepared by two different sonicated-enzymatic (trypsin and chymotrypsin hydrolysis treatments to obtain antioxidant and ACE-inhibitory peptides. Trypsin and chymotrypsin hydrolysates obtained by 5 h, exhibited the highest antioxidant and ACE-inhibitory activities. After fractionation using ultrafiltration and reverse phase high performance liquid chromatography (RP-HPLC techniques, two new peptides were identified. One fragment (LL-9, MW = 1180 Da with the amino acid sequence of Leu-Pro-Glu-Ser-Val-His-Leu-Asp-Lys showed significant ACE inhibitory activity (IC50 = 22.88 μM while another peptide fragment (VL-9, MW = 1118 Da with the amino acid sequence of Val-Leu-Ser-Thr-Ser-Phe-Pro-Pro-Lys showed the highest antioxidant and ACE inhibitory properties (IC50 = 15.20 μM, 5568 μM TE/mg protein. The molecular docking studies revealed that the ACE inhibitory activities of VL-9 is due to interaction with the S2 (His513, His353, Glu281 and S′1 (Glu162 pockets of ACE and LL-9 can fit perfectly into the S1 (Thr345 and S2 (Tyr520, Lys511, Gln281 pockets of ACE. Keywords: K. marxianus, Bioactive peptides, Antioxidant, ACE inhibitory, Protein hydrolysate

  5. Ranking docking poses by graph matching of protein-ligand interactions: lessons learned from the D3R Grand Challenge 2

    Science.gov (United States)

    da Silva Figueiredo Celestino Gomes, Priscila; Da Silva, Franck; Bret, Guillaume; Rognan, Didier

    2018-01-01

    A novel docking challenge has been set by the Drug Design Data Resource (D3R) in order to predict the pose and affinity ranking of a set of Farnesoid X receptor (FXR) agonists, prior to the public release of their bound X-ray structures and potencies. In a first phase, 36 agonists were docked to 26 Protein Data Bank (PDB) structures of the FXR receptor, and next rescored using the in-house developed GRIM method. GRIM aligns protein-ligand interaction patterns of docked poses to those of available PDB templates for the target protein, and rescore poses by a graph matching method. In agreement with results obtained during the previous 2015 docking challenge, we clearly show that GRIM rescoring improves the overall quality of top-ranked poses by prioritizing interaction patterns already visited in the PDB. Importantly, this challenge enables us to refine the applicability domain of the method by better defining the conditions of its success. We notably show that rescoring apolar ligands in hydrophobic pockets leads to frequent GRIM failures. In the second phase, 102 FXR agonists were ranked by decreasing affinity according to the Gibbs free energy of the corresponding GRIM-selected poses, computed by the HYDE scoring function. Interestingly, this fast and simple rescoring scheme provided the third most accurate ranking method among 57 contributions. Although the obtained ranking is still unsuitable for hit to lead optimization, the GRIM-HYDE scoring scheme is accurate and fast enough to post-process virtual screening data.

  6. A Unified Conformational Selection and Induced Fit Approach to Protein-Peptide Docking

    NARCIS (Netherlands)

    Trellet, M.; Melquiond, A.S.J.; Bonvin, A.M.J.J.

    2013-01-01

    Protein-peptide interactions are vital for the cell. They mediate, inhibit or serve as structural components in nearly 40% of all macromolecular interactions, and are often associated with diseases, making them interesting leads for protein drug design. In recent years, large-scale technologies have

  7. Stealing the spotlight: CUL4-DDB1 ubiquitin ligase docks WD40-repeat proteins to destroy

    Directory of Open Access Journals (Sweden)

    Zhang Hui

    2007-02-01

    Full Text Available Abstract Recent investigation of Cullin 4 (CUL4 has ushered this class of multiprotein ubiquitin E3 ligases to center stage as critical regulators of diverse processes including cell cycle regulation, developmental patterning, DNA replication, DNA damage and repair, and epigenetic control of gene expression. CUL4 associates with DNA Damage Binding protein 1 (DDB1 to assemble an ubiquitin E3 ligase that targets protein substrates for ubiquitin-dependent proteolysis. CUL4 ligase activity is also regulated by the covalent attachment of the ubiquitin-like protein NEDD8 to CUL4, or neddylation, and the COP9 signalosome complex (CSN that removes this important modification. Recently, multiple WD40-repeat proteins (WDR were found to interact with DDB1 and serve as the substrate-recognition subunits of the CUL4-DDB1 ubiquitin ligase. As more than 150–300 WDR proteins exist in the human genome, these findings impact a wide array of biological processes through CUL4 ligase-mediated proteolysis. Here, we review the recent progress in understanding the mechanism of CUL4 ubiquitin E3 ligase and discuss the architecture of CUL4-assembled E3 ubiquitin ligase complexes by comparison to CUL1-based E3s (SCF. Then, we will review several examples to highlight the critical roles of CUL4 ubiquitin ligase in genome stability, cell cycle regulation, and histone lysine methylation. Together, these studies provide insights into the mechanism of this novel ubiquitin ligase in the regulation of important biological processes.

  8. Modelling substrate specificity and enantioselectivity for lipases and esterases by substrate-imprinted docking

    Directory of Open Access Journals (Sweden)

    Tyagi Sadhna

    2009-06-01

    Full Text Available Abstract Background Previously, ways to adapt docking programs that were developed for modelling inhibitor-receptor interaction have been explored. Two main issues were discussed. First, when trying to model catalysis a reaction intermediate of the substrate is expected to provide more valid information than the ground state of the substrate. Second, the incorporation of protein flexibility is essential for reliable predictions. Results Here we present a predictive and robust method to model substrate specificity and enantioselectivity of lipases and esterases that uses reaction intermediates and incorporates protein flexibility. Substrate-imprinted docking starts with covalent docking of reaction intermediates, followed by geometry optimisation of the resulting enzyme-substrate complex. After a second round of docking the same substrate into the geometry-optimised structures, productive poses are identified by geometric filter criteria and ranked by their docking scores. Substrate-imprinted docking was applied in order to model (i enantioselectivity of Candida antarctica lipase B and a W104A mutant, (ii enantioselectivity and substrate specificity of Candida rugosa lipase and Burkholderia cepacia lipase, and (iii substrate specificity of an acetyl- and a butyrylcholine esterase toward the substrates acetyl- and butyrylcholine. Conclusion The experimentally observed differences in selectivity and specificity of the enzymes were reproduced with an accuracy of 81%. The method was robust toward small differences in initial structures (different crystallisation conditions or a co-crystallised ligand, although large displacements of catalytic residues often resulted in substrate poses that did not pass the geometric filter criteria.

  9. The flexible C-terminal arm of the Lassa arenavirus Z-protein mediates interactions with multiple binding partners.

    Science.gov (United States)

    May, Eric R; Armen, Roger S; Mannan, Aristotle M; Brooks, Charles L

    2010-08-01

    The arenavirus genome encodes for a Z-protein, which contains a RING domain that coordinates two zinc ions, and has been identified as having several functional roles at various stages of the virus life cycle. Z-protein binds to multiple host proteins and has been directly implicated in the promotion of viral budding, repression of mRNA translation, and apoptosis of infected cells. Using homology models of the Z-protein from Lassa strain arenavirus, replica exchange molecular dynamics (MD) was used to refine the structures, which were then subsequently clustered. Population-weighted ensembles of low-energy cluster representatives were predicted based upon optimal agreement of the chemical shifts computed with the SPARTA program with the experimental NMR chemical shifts. A member of the refined ensemble was identified to be a potential binder of budding factor Tsg101 based on its correspondence to the structure of the HIV-1 Gag late domain when bound to Tsg101. Members of these ensembles were docked against the crystal structure of human eIF4E translation initiation factor. Two plausible binding modes emerged based upon their agreement with experimental observation, favorable interaction energies and stability during MD trajectories. Mutations to Z are proposed that would either inhibit both binding mechanisms or selectively inhibit only one mode. The C-terminal domain conformation of the most populated member of the representative ensemble shielded protein-binding recognition motifs for Tsg101 and eIF4E and represents the most populated state free in solution. We propose that C-terminal flexibility is key for mediating the different functional states of the Z-protein. (c) 2010 Wiley-Liss, Inc.

  10. Discovery of Novel Inhibitors for Nek6 Protein through Homology Model Assisted Structure Based Virtual Screening and Molecular Docking Approaches

    Directory of Open Access Journals (Sweden)

    P. Srinivasan

    2014-01-01

    Full Text Available Nek6 is a member of the NIMA (never in mitosis, gene A-related serine/threonine kinase family that plays an important role in the initiation of mitotic cell cycle progression. This work is an attempt to emphasize the structural and functional relationship of Nek6 protein based on homology modeling and binding pocket analysis. The three-dimensional structure of Nek6 was constructed by molecular modeling studies and the best model was further assessed by PROCHECK, ProSA, and ERRAT plot in order to analyze the quality and consistency of generated model. The overall quality of computed model showed 87.4% amino acid residues under the favored region. A 3 ns molecular dynamics simulation confirmed that the structure was reliable and stable. Two lead compounds (Binding database ID: 15666, 18602 were retrieved through structure-based virtual screening and induced fit docking approaches as novel Nek6 inhibitors. Hence, we concluded that the potential compounds may act as new leads for Nek6 inhibitors designing.

  11. Virtual screening of natural inhibitors to the predicted HBx protein structure of Hepatitis B Virus using molecular docking for identification of potential lead molecules for liver cancer

    Science.gov (United States)

    Pathak, Rajesh Kumar; Baunthiyal, Mamta; Taj, Gohar; Kumar, Anil

    2014-01-01

    The HBx protein in Hepatitis B Virus (HBV) is a potential target for anti-liver cancer molecules. Therefore, it is of interest to screen known natural compounds against the HBx protein using molecular docking. However, the structure of HBx is not yet known. Therefore, the predicted structure of HBx using threading in LOMET was used for docking against plant derived natural compounds (curcumin, oleanolic acid, resveratrol, bilobetin, luteoline, ellagic acid, betulinic acid and rutin) by Molegro Virtual Docker. The screening identified rutin with binding energy of -161.65 Kcal/mol. Thus, twenty derivatives of rutin were further designed and screened against HBx. These in silico experiments identified compounds rutin01 (-163.16 Kcal/mol) and rutin08 (- 165.76 Kcal/mol) for further consideration and downstream validation. PMID:25187683

  12. Applications of the NRGsuite and the Molecular Docking Software FlexAID in Computational Drug Discovery and Design.

    Science.gov (United States)

    Morency, Louis-Philippe; Gaudreault, Francis; Najmanovich, Rafael

    2018-01-01

    Docking simulations help us understand molecular interactions. Here we present a hands-on tutorial to utilize FlexAID (Flexible Artificial Intelligence Docking), an open source molecular docking software between ligands such as small molecules or peptides and macromolecules such as proteins and nucleic acids. The tutorial uses the NRGsuite PyMOL plugin graphical user interface to set up and visualize docking simulations in real time as well as detect and refine target cavities. The ease of use of FlexAID and the NRGsuite combined with its superior performance relative to widely used docking software provides nonexperts with an important tool to understand molecular interactions with direct applications in structure-based drug design and virtual high-throughput screening.

  13. The Interaction Pattern between a Homology Model of 40S Ribosomal S9 Protein of Rhizoctonia solani and 1-Hydroxyphenaize by Docking Study

    Directory of Open Access Journals (Sweden)

    Seema Dharni

    2014-01-01

    Full Text Available 1-Hydroxyphenazine (1-OH-PHZ, a natural product from Pseudomonas aeruginosa strain SD12, was earlier reported to have potent antifungal activity against Rhizoctonia solani. In the present work, the antifungal activity of 1-OH-PHZ on 40S ribosomal S9 protein was validated by molecular docking approach. 1-OH-PHZ showed interaction with two polar contacts with residues, Arg69 and Phe19, which inhibits the synthesis of fungal protein. Our study reveals that 1-OH-PHZ can be a potent inhibitor of 40S ribosomal S9 protein of R. solani that may be a promising approach for the management of fungal diseases.

  14. Molecular surface representation using 3D Zernike descriptors for protein shape comparison and docking.

    Science.gov (United States)

    Kihara, Daisuke; Sael, Lee; Chikhi, Rayan; Esquivel-Rodriguez, Juan

    2011-09-01

    The tertiary structures of proteins have been solved in an increasing pace in recent years. To capitalize the enormous efforts paid for accumulating the structure data, efficient and effective computational methods need to be developed for comparing, searching, and investigating interactions of protein structures. We introduce the 3D Zernike descriptor (3DZD), an emerging technique to describe molecular surfaces. The 3DZD is a series expansion of mathematical three-dimensional function, and thus a tertiary structure is represented compactly by a vector of coefficients of terms in the series. A strong advantage of the 3DZD is that it is invariant to rotation of target object to be represented. These two characteristics of the 3DZD allow rapid comparison of surface shapes, which is sufficient for real-time structure database screening. In this article, we review various applications of the 3DZD, which have been recently proposed.

  15. Conformation guides molecular efficacy in docking screens of activated β-2 adrenergic G protein coupled receptor.

    Science.gov (United States)

    Weiss, Dahlia R; Ahn, SeungKirl; Sassano, Maria F; Kleist, Andrew; Zhu, Xiao; Strachan, Ryan; Roth, Bryan L; Lefkowitz, Robert J; Shoichet, Brian K

    2013-05-17

    A prospective, large library virtual screen against an activated β2-adrenergic receptor (β2AR) structure returned potent agonists to the exclusion of inverse-agonists, providing the first complement to the previous virtual screening campaigns against inverse-agonist-bound G protein coupled receptor (GPCR) structures, which predicted only inverse-agonists. In addition, two hits recapitulated the signaling profile of the co-crystal ligand with respect to the G protein and arrestin mediated signaling. This functional fidelity has important implications in drug design, as the ability to predict ligands with predefined signaling properties is highly desirable. However, the agonist-bound state provides an uncertain template for modeling the activated conformation of other GPCRs, as a dopamine D2 receptor (DRD2) activated model templated on the activated β2AR structure returned few hits of only marginal potency.

  16. Predicting the tolerated sequences for proteins and protein interfaces using RosettaBackrub flexible backbone design.

    Directory of Open Access Journals (Sweden)

    Colin A Smith

    Full Text Available Predicting the set of sequences that are tolerated by a protein or protein interface, while maintaining a desired function, is useful for characterizing protein interaction specificity and for computationally designing sequence libraries to engineer proteins with new functions. Here we provide a general method, a detailed set of protocols, and several benchmarks and analyses for estimating tolerated sequences using flexible backbone protein design implemented in the Rosetta molecular modeling software suite. The input to the method is at least one experimentally determined three-dimensional protein structure or high-quality model. The starting structure(s are expanded or refined into a conformational ensemble using Monte Carlo simulations consisting of backrub backbone and side chain moves in Rosetta. The method then uses a combination of simulated annealing and genetic algorithm optimization methods to enrich for low-energy sequences for the individual members of the ensemble. To emphasize certain functional requirements (e.g. forming a binding interface, interactions between and within parts of the structure (e.g. domains can be reweighted in the scoring function. Results from each backbone structure are merged together to create a single estimate for the tolerated sequence space. We provide an extensive description of the protocol and its parameters, all source code, example analysis scripts and three tests applying this method to finding sequences predicted to stabilize proteins or protein interfaces. The generality of this method makes many other applications possible, for example stabilizing interactions with small molecules, DNA, or RNA. Through the use of within-domain reweighting and/or multistate design, it may also be possible to use this method to find sequences that stabilize particular protein conformations or binding interactions over others.

  17. Molecular dynamics and docking simulation of a natural variant of Activated Protein C with impaired protease activity: implications for integrin-mediated antiseptic function.

    Science.gov (United States)

    D'Ursi, Pasqualina; Orro, Alessandro; Morra, Giulia; Moscatelli, Marco; Trombetti, Gabriele; Milanesi, Luciano; Rovida, Ermanna

    2015-01-01

    Activated Protein C (APC) is a multifunctional serine protease, primarily known for its anticoagulant function in the coagulation system. Several studies have already elucidated its role in counteracting apoptosis and inflammation in cells, while significant effort is still ongoing for defining its involvement in sepsis. Earlier literature has shown that the antiseptic function of APC is mediated by its binding to leukocyte integrins, which is due to the presence of the integrin binding motif Arg-Gly-Asp at the N-terminus of the APC catalytic chain. Many natural mutants have been identified in patients with Protein C deficiency diagnosis including a variant of specificity pocket (Gly216Asp). In this work, we present a molecular model of the complex of APC with αVβ3 integrin obtained by protein-protein docking approach. A computational analysis of this variant is hereby presented, based on molecular dynamics and docking simulations, aiming at investigating the effects of the Gly216Asp mutation on the protein conformation and inferring its functional implications. Our study shows that such mutation is likely to impair the protease activity while preserving the overall protein fold. Moreover, superposition of the integrin binding motifs in wild-type and mutant forms suggests that the interaction with integrin can still occur and thus the mutant is likely to retain its antiseptic function related to the neutrophyl integrin binding. Therapeutic applications could result in this APC mutant which retains antiseptic function without anticoagulant side effects.

  18. Multidrug resistance-associated protein 4 is a bile transporter of Clonorchis sinensis simulated by in silico docking.

    Science.gov (United States)

    Dai, Fuhong; Yoo, Won Gi; Lee, Ji-Yun; Lu, Yanyan; Pak, Jhang Ho; Sohn, Woon-Mok; Hong, Sung-Jong

    2017-11-21

    Multidrug resistance-associated protein 4 (MRP4) is a member of the C subfamily of the ABC family of ATP-binding cassette (ABC) transporters. MRP4 regulates ATP-dependent efflux of various organic anionic substrates and bile acids out of cells. Since Clonorchis sinensis lives in host's bile duct, accumulation of bile juice can be toxic to the worm's tissues and cells. Therefore, C. sinensis needs bile transporters to reduce accumulation of bile acids within its body. We cloned MRP4 (CsMRP4) from C. sinensis and obtained a cDNA encoding an open reading frame of 1469 amino acids. Phylogenetic analysis revealed that CsMRP4 belonged to the MRP/SUR/CFTR subfamily. A tertiary structure of CsMRP4 was generated by homology modeling based on multiple structures of MRP1 and P-glycoprotein. CsMRP4 had two membrane-spanning domains (MSD1 & 2) and two nucleotide-binding domains (NBD1 & 2) as common structural folds. Docking simulation with nine bile acids showed that CsMRP4 transports bile acids through the inner cavity. Moreover, it was found that CsMRP4 mRNA was more abundant in the metacercariae than in the adults. Mouse immune serum, generated against the CsMRP4-NBD1 (24.9 kDa) fragment, localized CsMRP4 mainly in mesenchymal tissues and oral and ventral suckers of the metacercariae and the adults. Our findings shed new light on MRPs and their homologs and provide a platform for further structural and functional investigations on the bile transporters and parasites' survival.

  19. Multidrug resistance-associated protein 4 is a bile transporter of Clonorchis sinensis simulated by in silico docking

    Directory of Open Access Journals (Sweden)

    Fuhong Dai

    2017-11-01

    Full Text Available Abstract Background Multidrug resistance-associated protein 4 (MRP4 is a member of the C subfamily of the ABC family of ATP-binding cassette (ABC transporters. MRP4 regulates ATP-dependent efflux of various organic anionic substrates and bile acids out of cells. Since Clonorchis sinensis lives in host’s bile duct, accumulation of bile juice can be toxic to the worm’s tissues and cells. Therefore, C. sinensis needs bile transporters to reduce accumulation of bile acids within its body. Results We cloned MRP4 (CsMRP4 from C. sinensis and obtained a cDNA encoding an open reading frame of 1469 amino acids. Phylogenetic analysis revealed that CsMRP4 belonged to the MRP/SUR/CFTR subfamily. A tertiary structure of CsMRP4 was generated by homology modeling based on multiple structures of MRP1 and P-glycoprotein. CsMRP4 had two membrane-spanning domains (MSD1 & 2 and two nucleotide-binding domains (NBD1 & 2 as common structural folds. Docking simulation with nine bile acids showed that CsMRP4 transports bile acids through the inner cavity. Moreover, it was found that CsMRP4 mRNA was more abundant in the metacercariae than in the adults. Mouse immune serum, generated against the CsMRP4-NBD1 (24.9 kDa fragment, localized CsMRP4 mainly in mesenchymal tissues and oral and ventral suckers of the metacercariae and the adults. Conclusions Our findings shed new light on MRPs and their homologs and provide a platform for further structural and functional investigations on the bile transporters and parasites’ survival.

  20. A cross docking pipeline for improving pose prediction and virtual screening performance

    Science.gov (United States)

    Kumar, Ashutosh; Zhang, Kam Y. J.

    2018-01-01

    Pose prediction and virtual screening performance of a molecular docking method depend on the choice of protein structures used for docking. Multiple structures for a target protein are often used to take into account the receptor flexibility and problems associated with a single receptor structure. However, the use of multiple receptor structures is computationally expensive when docking a large library of small molecules. Here, we propose a new cross-docking pipeline suitable to dock a large library of molecules while taking advantage of multiple target protein structures. Our method involves the selection of a suitable receptor for each ligand in a screening library utilizing ligand 3D shape similarity with crystallographic ligands. We have prospectively evaluated our method in D3R Grand Challenge 2 and demonstrated that our cross-docking pipeline can achieve similar or better performance than using either single or multiple-receptor structures. Moreover, our method displayed not only decent pose prediction performance but also better virtual screening performance over several other methods.

  1. FlexAID: Revisiting Docking on Non-Native-Complex Structures.

    Science.gov (United States)

    Gaudreault, Francis; Najmanovich, Rafael J

    2015-07-27

    Small-molecule protein docking is an essential tool in drug design and to understand molecular recognition. In the present work we introduce FlexAID, a small-molecule docking algorithm that accounts for target side-chain flexibility and utilizes a soft scoring function, i.e. one that is not highly dependent on specific geometric criteria, based on surface complementarity. The pairwise energy parameters were derived from a large dataset of true positive poses and negative decoys from the PDBbind database through an iterative process using Monte Carlo simulations. The prediction of binding poses is tested using the widely used Astex dataset as well as the HAP2 dataset, while performance in virtual screening is evaluated using a subset of the DUD dataset. We compare FlexAID to AutoDock Vina, FlexX, and rDock in an extensive number of scenarios to understand the strengths and limitations of the different programs as well as to reported results for Glide, GOLD, and DOCK6 where applicable. The most relevant among these scenarios is that of docking on flexible non-native-complex structures where as is the case in reality, the target conformation in the bound form is not known a priori. We demonstrate that FlexAID, unlike other programs, is robust against increasing structural variability. FlexAID obtains equivalent sampling success as GOLD and performs better than AutoDock Vina or FlexX in all scenarios against non-native-complex structures. FlexAID is better than rDock when there is at least one critical side-chain movement required upon ligand binding. In virtual screening, FlexAID results are lower on average than those of AutoDock Vina and rDock. The higher accuracy in flexible targets where critical movements are required, intuitive PyMOL-integrated graphical user interface and free source code as well as precompiled executables for Windows, Linux, and Mac OS make FlexAID a welcome addition to the arsenal of existing small-molecule protein docking methods.

  2. Combined Docking with Classical Force Field and Quantum Chemical Semiempirical Method PM7

    Directory of Open Access Journals (Sweden)

    A. V. Sulimov

    2017-01-01

    Full Text Available Results of the combined use of the classical force field and the recent quantum chemical PM7 method for docking are presented. Initially the gridless docking of a flexible low molecular weight ligand into the rigid target protein is performed with the energy function calculated in the MMFF94 force field with implicit water solvent in the PCM model. Among several hundred thousand local minima, which are found in the docking procedure, about eight thousand lowest energy minima are chosen and then energies of these minima are recalculated with the recent quantum chemical semiempirical PM7 method. This procedure is applied to 16 test complexes with different proteins and ligands. For almost all test complexes such energy recalculation results in the global energy minimum configuration corresponding to the ligand pose near the native ligand position in the crystalized protein-ligand complex. A significant improvement of the ligand positioning accuracy comparing with MMFF94 energy calculations is demonstrated.

  3. Combined Docking with Classical Force Field and Quantum Chemical Semiempirical Method PM7.

    Science.gov (United States)

    Sulimov, A V; Kutov, D C; Katkova, E V; Sulimov, V B

    2017-01-01

    Results of the combined use of the classical force field and the recent quantum chemical PM7 method for docking are presented. Initially the gridless docking of a flexible low molecular weight ligand into the rigid target protein is performed with the energy function calculated in the MMFF94 force field with implicit water solvent in the PCM model. Among several hundred thousand local minima, which are found in the docking procedure, about eight thousand lowest energy minima are chosen and then energies of these minima are recalculated with the recent quantum chemical semiempirical PM7 method. This procedure is applied to 16 test complexes with different proteins and ligands. For almost all test complexes such energy recalculation results in the global energy minimum configuration corresponding to the ligand pose near the native ligand position in the crystalized protein-ligand complex. A significant improvement of the ligand positioning accuracy comparing with MMFF94 energy calculations is demonstrated.

  4. Adverse drug reaction prediction using scores produced by large-scale drug-protein target docking on high-performance computing machines.

    Science.gov (United States)

    LaBute, Montiago X; Zhang, Xiaohua; Lenderman, Jason; Bennion, Brian J; Wong, Sergio E; Lightstone, Felice C

    2014-01-01

    Late-stage or post-market identification of adverse drug reactions (ADRs) is a significant public health issue and a source of major economic liability for drug development. Thus, reliable in silico screening of drug candidates for possible ADRs would be advantageous. In this work, we introduce a computational approach that predicts ADRs by combining the results of molecular docking and leverages known ADR information from DrugBank and SIDER. We employed a recently parallelized version of AutoDock Vina (VinaLC) to dock 906 small molecule drugs to a virtual panel of 409 DrugBank protein targets. L1-regularized logistic regression models were trained on the resulting docking scores of a 560 compound subset from the initial 906 compounds to predict 85 side effects, grouped into 10 ADR phenotype groups. Only 21% (87 out of 409) of the drug-protein binding features involve known targets of the drug subset, providing a significant probe of off-target effects. As a control, associations of this drug subset with the 555 annotated targets of these compounds, as reported in DrugBank, were used as features to train a separate group of models. The Vina off-target models and the DrugBank on-target models yielded comparable median area-under-the-receiver-operating-characteristic-curves (AUCs) during 10-fold cross-validation (0.60-0.69 and 0.61-0.74, respectively). Evidence was found in the PubMed literature to support several putative ADR-protein associations identified by our analysis. Among them, several associations between neoplasm-related ADRs and known tumor suppressor and tumor invasiveness marker proteins were found. A dual role for interstitial collagenase in both neoplasms and aneurysm formation was also identified. These associations all involve off-target proteins and could not have been found using available drug/on-target interaction data. This study illustrates a path forward to comprehensive ADR virtual screening that can potentially scale with increasing number

  5. Adverse drug reaction prediction using scores produced by large-scale drug-protein target docking on high-performance computing machines.

    Directory of Open Access Journals (Sweden)

    Montiago X LaBute

    Full Text Available Late-stage or post-market identification of adverse drug reactions (ADRs is a significant public health issue and a source of major economic liability for drug development. Thus, reliable in silico screening of drug candidates for possible ADRs would be advantageous. In this work, we introduce a computational approach that predicts ADRs by combining the results of molecular docking and leverages known ADR information from DrugBank and SIDER. We employed a recently parallelized version of AutoDock Vina (VinaLC to dock 906 small molecule drugs to a virtual panel of 409 DrugBank protein targets. L1-regularized logistic regression models were trained on the resulting docking scores of a 560 compound subset from the initial 906 compounds to predict 85 side effects, grouped into 10 ADR phenotype groups. Only 21% (87 out of 409 of the drug-protein binding features involve known targets of the drug subset, providing a significant probe of off-target effects. As a control, associations of this drug subset with the 555 annotated targets of these compounds, as reported in DrugBank, were used as features to train a separate group of models. The Vina off-target models and the DrugBank on-target models yielded comparable median area-under-the-receiver-operating-characteristic-curves (AUCs during 10-fold cross-validation (0.60-0.69 and 0.61-0.74, respectively. Evidence was found in the PubMed literature to support several putative ADR-protein associations identified by our analysis. Among them, several associations between neoplasm-related ADRs and known tumor suppressor and tumor invasiveness marker proteins were found. A dual role for interstitial collagenase in both neoplasms and aneurysm formation was also identified. These associations all involve off-target proteins and could not have been found using available drug/on-target interaction data. This study illustrates a path forward to comprehensive ADR virtual screening that can potentially scale with

  6. Protein flexibility in the light of structural alphabets. \

    Czech Academy of Sciences Publication Activity Database

    Craveur, P.; Joseph, A,P.; Esque, J.; Narwani, T.J.; Noël, F.; Shinada, N.; Goguet, M.; Leonard, S.; Poulain, P.; Bertrand, O.; Faure, G.; Rebehmed, J.; Ghozlane, A.; Swapna, L.S.; Bhaskara, R.M.; Barnoud, J.; Téletchéa, S.; Jallu, V.; Černý, Jiří; Schneider, Bohdan; Etchebest, C.; Srinivasan, N.; Gelly, J.-Ch.; deBrevern, A.G.

    2015-01-01

    Roč. 2, 27 May 2015 (2015) ISSN 2296-889X R&D Projects: GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:86652036 Keywords : allostery * protein complexes * protein folding Subject RIV: EB - Genetics ; Molecular Biology

  7. Modification of S-Adenosyl-l-Homocysteine as Inhibitor of Nonstructural Protein 5 Methyltransferase Dengue Virus Through Molecular Docking and Molecular Dynamics Simulation.

    Science.gov (United States)

    Tambunan, Usman Sumo Friend; Nasution, Mochammad Arfin Fardiansyah; Azhima, Fauziah; Parikesit, Arli Aditya; Toepak, Erwin Prasetya; Idrus, Syarifuddin; Kerami, Djati

    2017-01-01

    Dengue fever is still a major threat worldwide, approximately threatening two-fifths of the world's population in tropical and subtropical countries. Nonstructural protein 5 (NS5) methyltransferase enzyme plays a vital role in the process of messenger RNA capping of dengue by transferring methyl groups from S -adenosyl-l-methionine to N7 atom of the guanine bases of RNA and the RNA ribose group of 2'OH, resulting in S -adenosyl-l-homocysteine (SAH). The modification of SAH compound was screened using molecular docking and molecular dynamics simulation, along with computational ADME-Tox (absorption, distribution, metabolism, excretion, and toxicity) test. The 2 simulations were performed using Molecular Operating Environment (MOE) 2008.10 software, whereas the ADME-Tox test was performed using various software. The modification of SAH compound was done using several functional groups that possess different polarities and properties, resulting in 3460 ligands to be docked. After conducting docking simulation, we earned 3 best ligands (SAH-M331, SAH-M2696, and SAH-M1356) based on ΔG binding and molecular interactions, which show better results than the standard ligands. Moreover, the results of molecular dynamics simulation show that the best ligands are still able to maintain the active site residue interaction with the binding site until the end of the simulation. After a series of molecular docking and molecular dynamics simulation were performed, we concluded that SAH-M1356 ligand is the most potential SAH-based compound to inhibit NS5 methyltransferase enzyme for treating dengue fever.

  8. Modification of -Adenosyl--Homocysteine as Inhibitor of Nonstructural Protein 5 Methyltransferase Dengue Virus Through Molecular Docking and Molecular Dynamics Simulation

    Directory of Open Access Journals (Sweden)

    Usman Sumo Friend Tambunan

    2017-04-01

    Full Text Available Dengue fever is still a major threat worldwide, approximately threatening two-fifths of the world’s population in tropical and subtropical countries. Nonstructural protein 5 (NS5 methyltransferase enzyme plays a vital role in the process of messenger RNA capping of dengue by transferring methyl groups from S -adenosyl- l -methionine to N7 atom of the guanine bases of RNA and the RNA ribose group of 2′OH, resulting in S -adenosyl- l -homocysteine (SAH. The modification of SAH compound was screened using molecular docking and molecular dynamics simulation, along with computational ADME-Tox (absorption, distribution, metabolism, excretion, and toxicity test. The 2 simulations were performed using Molecular Operating Environment (MOE 2008.10 software, whereas the ADME-Tox test was performed using various software. The modification of SAH compound was done using several functional groups that possess different polarities and properties, resulting in 3460 ligands to be docked. After conducting docking simulation, we earned 3 best ligands (SAH-M331, SAH-M2696, and SAH-M1356 based on ΔG binding and molecular interactions, which show better results than the standard ligands. Moreover, the results of molecular dynamics simulation show that the best ligands are still able to maintain the active site residue interaction with the binding site until the end of the simulation. After a series of molecular docking and molecular dynamics simulation were performed, we concluded that SAH-M1356 ligand is the most potential SAH-based compound to inhibit NS5 methyltransferase enzyme for treating dengue fever.

  9. Protein flexibility: coordinate uncertainties and interpretation of structural differences

    Energy Technology Data Exchange (ETDEWEB)

    Rashin, Alexander A., E-mail: alexander-rashin@hotmail.com [BioChemComp Inc., 543 Sagamore Avenue, Teaneck, NJ 07666 (United States); LH Baker Center for Bioinformatics and Department of Biochemistry, Biophysics and Molecular Biology, 112 Office and Lab Building, Iowa State University, Ames, IA 50011-3020 (United States); Rashin, Abraham H. L. [BioChemComp Inc., 543 Sagamore Avenue, Teaneck, NJ 07666 (United States); Rutgers, The State University of New Jersey, 22371 BPO WAY, Piscataway, NJ 08854-8123 (United States); Jernigan, Robert L. [LH Baker Center for Bioinformatics and Department of Biochemistry, Biophysics and Molecular Biology, 112 Office and Lab Building, Iowa State University, Ames, IA 50011-3020 (United States); BioChemComp Inc., 543 Sagamore Avenue, Teaneck, NJ 07666 (United States)

    2009-11-01

    Criteria for the interpretability of coordinate differences and a new method for identifying rigid-body motions and nonrigid deformations in protein conformational changes are developed and applied to functionally induced and crystallization-induced conformational changes. Valid interpretations of conformational movements in protein structures determined by X-ray crystallography require that the movement magnitudes exceed their uncertainty threshold. Here, it is shown that such thresholds can be obtained from the distance difference matrices (DDMs) of 1014 pairs of independently determined structures of bovine ribonuclease A and sperm whale myoglobin, with no explanations provided for reportedly minor coordinate differences. The smallest magnitudes of reportedly functional motions are just above these thresholds. Uncertainty thresholds can provide objective criteria that distinguish between true conformational changes and apparent ‘noise’, showing that some previous interpretations of protein coordinate changes attributed to external conditions or mutations may be doubtful or erroneous. The use of uncertainty thresholds, DDMs, the newly introduced CDDMs (contact distance difference matrices) and a novel simple rotation algorithm allows a more meaningful classification and description of protein motions, distinguishing between various rigid-fragment motions and nonrigid conformational deformations. It is also shown that half of 75 pairs of identical molecules, each from the same asymmetric crystallographic cell, exhibit coordinate differences that range from just outside the coordinate uncertainty threshold to the full magnitude of large functional movements. Thus, crystallization might often induce protein conformational changes that are comparable to those related to or induced by the protein function.

  10. Structure refinement of flexible proteins using dipolar couplings: Application to the protein p8MTCP1

    International Nuclear Information System (INIS)

    Demene, Helene; Ducat, Thierry; Barthe, Philippe; Delsuc, Marc-Andre; Roumestand, Christian

    2002-01-01

    The present study deals with the relevance of using mobility-averaged dipolar couplings for the structure refinement of flexible proteins. The 68-residue protein p8 MTCP1 has been chosen as model for this study. Its solution state consists mainly of three α-helices. The two N-terminal helices are strapped in a well-determined α-hairpin, whereas, due to an intrinsic mobility, the position of the third helix is less well defined in the NMR structure. To further characterize the degrees of freedom of this helix, we have measured the dipolar coupling constants in the backbone of p8 MTCP1 in a bicellar medium. We show here that including D HN dip dipolar couplings in the structure calculation protocol improves the structure of the α-hairpin but not the positioning of the third helix. This is due to the motional averaging of the dipolar couplings measured in the last helix. Performing two calculations with different force constants for the dipolar restraints highlights the inconstancy of these mobility-averaged dipolar couplings. Alternatively, prior to any structure calculations, comparing the values of the dipolar couplings measured in helix III to values back-calculated from an ideal helix demonstrates that they are atypical for a helix. This can be partly attributed to mobility effects since the inclusion of the 15 N relaxation derived order parameter allows for a better fit

  11. In-silico determination of insecticidal potential of Vip3Aa-Cry1Ac fusion protein against Lepidopteran targets using molecular docking

    Directory of Open Access Journals (Sweden)

    Aftab eAhmad

    2015-12-01

    Full Text Available Study and research of Bt (Bacillus thuringiensis transgenic plants have opened new ways to combat insect pests. Over the decades, however, insect pests, especially the Lepidopteran, have developed tolerance against Bt delta-endotoxins. Such issues can be addressed through the development of novel toxins with greater toxicity and affinity against a broad range of insect receptors. In this computational study, functional domains of Bacillus thuringiensis crystal delta-endotoxin (Cry1Ac insecticidal protein and vegetative insecticidal protein (Vip3Aa have been fused to develop a broad-range Vip3Aa-Cry1Ac fusion protein. Cry1Ac and Vip3Aa are non-homologous insecticidal proteins possessing receptors against different targets within the midgut of insects. The insecticidal proteins were fused to broaden the insecticidal activity. Molecular docking analysis of the fusion protein against aminopeptidase-N (APN and cadherin receptors of five Lepidopteran insects (Agrotis ipsilon, Helicoverpa armigera, Pectinophora gossypiella, Spodoptera exigua and Spodoptera litura revealed that the Ser290, Ser293, Leu337, Thr340 and Arg437 residues of the fusion protein are involved in the interaction with insect receptors. The Helicoverpa armigera cadherin receptor, however, showed no interaction, which might be due to either loss or burial of interactive residues inside the fusion protein. These findings revealed that the Vip3Aa-Cry1Ac fusion protein has a strong affinity against Lepidopteran insect receptors and hence has a potential to be an efficient broad-range insecticidal protein.

  12. Flexible, Symmetry-Directed Approach To Assembling Protein Cages (Publisher’s Version Open Access)

    Science.gov (United States)

    2016-08-01

    construction of enzyme nanoreactors, encapsulation of protein cargos, targeted drug delivery , and polyvalent display of epitopes, where atomic-level precision...Flexible, symmetry-directed approach to assembling protein cages Aaron Sciorea, Min Sub, Philipp Koldeweyc, Joseph D. Eschweilera, Kelsey A. Diffleya...approved June 10, 2016 (received for review April 15, 2016) The assembly of individual protein subunits into large-scale symmet- rical structures is

  13. Room temperature phosphorescence study on the structural flexibility of single tryptophan containing proteins

    Science.gov (United States)

    Kowalska-Baron, Agnieszka; Gałęcki, Krystian; Wysocki, Stanisław

    2015-01-01

    In this study, we have undertaken efforts to find correlation between phosphorescence lifetimes of single tryptophan containing proteins and some structural indicators of protein flexibility/rigidity, such as the degree of tryptophan burial or its exposure to solvent, protein secondary and tertiary structure of the region of localization of tryptophan as well as B factors for tryptophan residue and its immediate surroundings. Bearing in mind that, apart from effective local viscosity of the protein/solvent matrix, the other factor that concur in determining room temperature tryptophan phosphorescence (RTTP) lifetime in proteins is the extent of intramolecular quenching by His, Cys, Tyr and Trp side chains, the crystallographic structures derived from the Brookhaven Protein Data Bank were also analyzed concentrating on the presence of potentially quenching amino acid side chains in the close proximity of the indole chromophore. The obtained results indicated that, in most cases, the phosphorescence lifetimes of tryptophan containing proteins studied tend to correlate with the above mentioned structural indicators of protein rigidity/flexibility. This correlation is expected to provide guidelines for the future development of phosphorescence lifetime-based method for the prediction of structural flexibility of proteins, which is directly linked to their biological function.

  14. Fabrication of Flexible, Fully Organic, Degradable Energy Storage Devices Using Silk Proteins.

    Science.gov (United States)

    Pal, Ramendra K; Kundu, Subhas C; Yadavalli, Vamsi K

    2018-03-21

    Flexible and thin-film devices are of great interest in epidermal and implantable bioelectronics. The integration of energy storage and delivery devices such as supercapacitors (SCs) with properties such as flexibility, miniaturization, biocompatibility, and degradability are sought for such systems. Reducing e-waste and using sustainable materials and processes are additional desirable qualities. Herein, a silk protein-based biocompatible and degradable thin-film microSC (μSC) is reported. A protein carrier with the conducting polymer poly(3,4-ethylenedioxythiophene) polystyrene sulfonate and reduced graphene oxide dopant is used as a photopatternable biocomposite ink. Active electrodes are fabricated using photolithography under benign conditions, using only water as the solvent. These electrodes are printed on flexible protein sheets to form degradable, organic devices with a benign agarose-NaCl gel electrolyte. High capacitance, power density, cycling stability over 500 cycles, and the ability to power a light-emitting diode are shown. The device is flexible, can sustain cyclic mechanical stresses over 450 cycles, and retain capacitive properties over several days in liquid. Significantly, the μSCs are cytocompatible and completely degraded over the period of ∼1 month. By precise control of the device configuration, these silk protein-based, all-polymer organic devices can be designed to be tunably transient and provide viable alternatives for powering flexible and implantable bioelectronics.

  15. Environmental constraints in the study of flexible segments of proteins

    Energy Technology Data Exchange (ETDEWEB)

    D' Ursi, Annamaria; Albrizio, Stefania; Tancredi, Teodorico; Temussi, Piero A

    1998-05-15

    The structural problem posed by ill-defined segments in protein structures is similar to those encountered in the study of most peptide hormones, with terminal tracts resembling linear peptides and loops resembling cyclic peptides. The conformational preferences of short linear peptides in solution can be influenced by the use of solvent mixtures of viscosity higher than that of pure water but comparable to that of cytoplasm. In order to check whether it is possible to use these media in the structural study of proteins, we undertook an exploratory study on BPTI in a mixture of dimethylsulfoxide and water. The complete assignment of BPTI in an 80:20 (by volume) DMSO-d{sub 6}/water cryomixture at two temperatures showed that all resonances parallel those in water, hinting at the persistence of the correct protein architecture, which is also confirmed by NOESY experiments. In addition to the NOEs present in the aqueous solution it was possible to detect numerous new cross peaks, in particular from residues belonging to the less-defined regions. The new cross peaks do not originate from spin diffusion and are consistent with the best NMR structure and with the X-ray structures of BPTI.

  16. Prediction of flexible/rigid regions from protein sequences using k-spaced amino acid pairs

    Directory of Open Access Journals (Sweden)

    Ruan Jishou

    2007-04-01

    Full Text Available Abstract Background Traditionally, it is believed that the native structure of a protein corresponds to a global minimum of its free energy. However, with the growing number of known tertiary (3D protein structures, researchers have discovered that some proteins can alter their structures in response to a change in their surroundings or with the help of other proteins or ligands. Such structural shifts play a crucial role with respect to the protein function. To this end, we propose a machine learning method for the prediction of the flexible/rigid regions of proteins (referred to as FlexRP; the method is based on a novel sequence representation and feature selection. Knowledge of the flexible/rigid regions may provide insights into the protein folding process and the 3D structure prediction. Results The flexible/rigid regions were defined based on a dataset, which includes protein sequences that have multiple experimental structures, and which was previously used to study the structural conservation of proteins. Sequences drawn from this dataset were represented based on feature sets that were proposed in prior research, such as PSI-BLAST profiles, composition vector and binary sequence encoding, and a newly proposed representation based on frequencies of k-spaced amino acid pairs. These representations were processed by feature selection to reduce the dimensionality. Several machine learning methods for the prediction of flexible/rigid regions and two recently proposed methods for the prediction of conformational changes and unstructured regions were compared with the proposed method. The FlexRP method, which applies Logistic Regression and collocation-based representation with 95 features, obtained 79.5% accuracy. The two runner-up methods, which apply the same sequence representation and Support Vector Machines (SVM and Naïve Bayes classifiers, obtained 79.2% and 78.4% accuracy, respectively. The remaining considered methods are

  17. Combinatorial multispectral, thermodynamics, docking and site-directed mutagenesis reveal the cognitive characteristics of honey bee chemosensory protein to plant semiochemical.

    Science.gov (United States)

    Tan, Jing; Song, Xinmi; Fu, Xiaobin; Wu, Fan; Hu, Fuliang; Li, Hongliang

    2018-05-09

    In the chemoreceptive system of insects, there are always some soluble binding proteins, such as some antennal-specific chemosensory proteins (CSPs), which are abundantly distributed in the chemosensory sensillar lymph. The antennal-specific CSPs usually have strong capability to bind diverse semiochemicals, while the detailed interaction between CSPs and the semiochemicals remain unclear. Here, by means of the combinatorial multispectral, thermodynamics, docking and site-directed mutagenesis, we detailedly interpreted a binding interaction between a plant semiochemical β-ionone and antennal-specific CSP1 from the worker honey bee. Thermodynamic parameters (ΔH  0) indicate that the interaction is mainly driven by hydrophobic forces and electrostatic interactions. Docking prediction results showed that there are two key amino acids, Phe44 and Gln63, may be involved in the interacting process of CSP1 to β-ionone. In order to confirm the two key amino acids, site-directed mutagenesis were performed and the binding constant (K A ) for two CSP1 mutant proteins was reduced by 60.82% and 46.80% compared to wild-type CSP1. The thermodynamic analysis of mutant proteins furtherly verified that Phe44 maintained an electrostatic interaction and Gln63 contributes hydrophobic and electrostatic forces. Our investigation initially elucidates the physicochemical mechanism of the interaction between antennal-special CSPs in insects including bees to plant semiochemicals, as well as the development of twice thermodynamic analysis (wild type and mutant proteins) combined with multispectral and site-directed mutagenesis methods. Copyright © 2018. Published by Elsevier B.V.

  18. Protein Hydration Thermodynamics: The Influence of Flexibility and Salt on Hydrophobin II Hydration.

    Science.gov (United States)

    Remsing, Richard C; Xi, Erte; Patel, Amish J

    2018-04-05

    The solubility of proteins and other macromolecular solutes plays an important role in numerous biological, chemical, and medicinal processes. An important determinant of protein solubility is the solvation free energy of the protein, which quantifies the overall strength of the interactions between the protein and the aqueous solution that surrounds it. Here we present an all-atom explicit-solvent computational framework for the rapid estimation of protein solvation free energies. Using this framework, we estimate the hydration free energy of hydrophobin II, an amphiphilic fungal protein, in a computationally efficient manner. We further explore how the protein hydration free energy is influenced by enhancing flexibility and by the addition of sodium chloride, and find that it increases in both cases, making protein hydration less favorable.

  19. WEBnm@ v2.0: Web server and services for comparing protein flexibility.

    Science.gov (United States)

    Tiwari, Sandhya P; Fuglebakk, Edvin; Hollup, Siv M; Skjærven, Lars; Cragnolini, Tristan; Grindhaug, Svenn H; Tekle, Kidane M; Reuter, Nathalie

    2014-12-30

    Normal mode analysis (NMA) using elastic network models is a reliable and cost-effective computational method to characterise protein flexibility and by extension, their dynamics. Further insight into the dynamics-function relationship can be gained by comparing protein motions between protein homologs and functional classifications. This can be achieved by comparing normal modes obtained from sets of evolutionary related proteins. We have developed an automated tool for comparative NMA of a set of pre-aligned protein structures. The user can submit a sequence alignment in the FASTA format and the corresponding coordinate files in the Protein Data Bank (PDB) format. The computed normalised squared atomic fluctuations and atomic deformation energies of the submitted structures can be easily compared on graphs provided by the web user interface. The web server provides pairwise comparison of the dynamics of all proteins included in the submitted set using two measures: the Root Mean Squared Inner Product and the Bhattacharyya Coefficient. The Comparative Analysis has been implemented on our web server for NMA, WEBnm@, which also provides recently upgraded functionality for NMA of single protein structures. This includes new visualisations of protein motion, visualisation of inter-residue correlations and the analysis of conformational change using the overlap analysis. In addition, programmatic access to WEBnm@ is now available through a SOAP-based web service. Webnm@ is available at http://apps.cbu.uib.no/webnma . WEBnm@ v2.0 is an online tool offering unique capability for comparative NMA on multiple protein structures. Along with a convenient web interface, powerful computing resources, and several methods for mode analyses, WEBnm@ facilitates the assessment of protein flexibility within protein families and superfamilies. These analyses can give a good view of how the structures move and how the flexibility is conserved over the different structures.

  20. Virtual screening for HIV protease inhibitors: a comparison of AutoDock 4 and Vina.

    Directory of Open Access Journals (Sweden)

    Max W Chang

    Full Text Available BACKGROUND: The AutoDock family of software has been widely used in protein-ligand docking research. This study compares AutoDock 4 and AutoDock Vina in the context of virtual screening by using these programs to select compounds active against HIV protease. METHODOLOGY/PRINCIPAL FINDINGS: Both programs were used to rank the members of two chemical libraries, each containing experimentally verified binders to HIV protease. In the case of the NCI Diversity Set II, both AutoDock 4 and Vina were able to select active compounds significantly better than random (AUC = 0.69 and 0.68, respectively; p<0.001. The binding energy predictions were highly correlated in this case, with r = 0.63 and iota = 0.82. For a set of larger, more flexible compounds from the Directory of Universal Decoys, the binding energy predictions were not correlated, and only Vina was able to rank compounds significantly better than random. CONCLUSIONS/SIGNIFICANCE: In ranking smaller molecules with few rotatable bonds, AutoDock 4 and Vina were equally capable, though both exhibited a size-related bias in scoring. However, as Vina executes more quickly and is able to more accurately rank larger molecules, researchers should look to it first when undertaking a virtual screen.

  1. A general approach for developing system-specific functions to score protein-ligand docked complexes using support vector inductive logic programming.

    Science.gov (United States)

    Amini, Ata; Shrimpton, Paul J; Muggleton, Stephen H; Sternberg, Michael J E

    2007-12-01

    Despite the increased recent use of protein-ligand and protein-protein docking in the drug discovery process due to the increases in computational power, the difficulty of accurately ranking the binding affinities of a series of ligands or a series of proteins docked to a protein receptor remains largely unsolved. This problem is of major concern in lead optimization procedures and has lead to the development of scoring functions tailored to rank the binding affinities of a series of ligands to a specific system. However, such methods can take a long time to develop and their transferability to other systems remains open to question. Here we demonstrate that given a suitable amount of background information a new approach using support vector inductive logic programming (SVILP) can be used to produce system-specific scoring functions. Inductive logic programming (ILP) learns logic-based rules for a given dataset that can be used to describe properties of each member of the set in a qualitative manner. By combining ILP with support vector machine regression, a quantitative set of rules can be obtained. SVILP has previously been used in a biological context to examine datasets containing a series of singular molecular structures and properties. Here we describe the use of SVILP to produce binding affinity predictions of a series of ligands to a particular protein. We also for the first time examine the applicability of SVILP techniques to datasets consisting of protein-ligand complexes. Our results show that SVILP performs comparably with other state-of-the-art methods on five protein-ligand systems as judged by similar cross-validated squares of their correlation coefficients. A McNemar test comparing SVILP to CoMFA and CoMSIA across the five systems indicates our method to be significantly better on one occasion. The ability to graphically display and understand the SVILP-produced rules is demonstrated and this feature of ILP can be used to derive hypothesis for

  2. Towards ligand docking including explicit interface water molecules.

    Directory of Open Access Journals (Sweden)

    Gordon Lemmon

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

  3. Binding affinity toward human prion protein of some anti-prion compounds - Assessment based on QSAR modeling, molecular docking and non-parametric ranking.

    Science.gov (United States)

    Kovačević, Strahinja; Karadžić, Milica; Podunavac-Kuzmanović, Sanja; Jevrić, Lidija

    2018-01-01

    The present study is based on the quantitative structure-activity relationship (QSAR) analysis of binding affinity toward human prion protein (huPrP C ) of quinacrine, pyridine dicarbonitrile, diphenylthiazole and diphenyloxazole analogs applying different linear and non-linear chemometric regression techniques, including univariate linear regression, multiple linear regression, partial least squares regression and artificial neural networks. The QSAR analysis distinguished molecular lipophilicity as an important factor that contributes to the binding affinity. Principal component analysis was used in order to reveal similarities or dissimilarities among the studied compounds. The analysis of in silico absorption, distribution, metabolism, excretion and toxicity (ADMET) parameters was conducted. The ranking of the studied analogs on the basis of their ADMET parameters was done applying the sum of ranking differences, as a relatively new chemometric method. The main aim of the study was to reveal the most important molecular features whose changes lead to the changes in the binding affinities of the studied compounds. Another point of view on the binding affinity of the most promising analogs was established by application of molecular docking analysis. The results of the molecular docking were proven to be in agreement with the experimental outcome. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Intrinsic disorder in pathogen effectors: protein flexibility as an evolutionary hallmark in a molecular arms race.

    Science.gov (United States)

    Marín, Macarena; Uversky, Vladimir N; Ott, Thomas

    2013-09-01

    Effector proteins represent a refined mechanism of bacterial pathogens to overcome plants' innate immune systems. These modular proteins often manipulate host physiology by directly interfering with immune signaling of plant cells. Even if host cells have developed efficient strategies to perceive the presence of pathogenic microbes and to recognize intracellular effector activity, it remains an open question why only few effectors are recognized directly by plant resistance proteins. Based on in-silico genome-wide surveys and a reevaluation of published structural data, we estimated that bacterial effectors of phytopathogens are highly enriched in long-disordered regions (>50 residues). These structurally flexible segments have no secondary structure under physiological conditions but can fold in a stimulus-dependent manner (e.g., during protein-protein interactions). The high abundance of intrinsic disorder in effectors strongly suggests positive evolutionary selection of this structural feature and highlights the dynamic nature of these proteins. We postulate that such structural flexibility may be essential for (1) effector translocation, (2) evasion of the innate immune system, and (3) host function mimicry. The study of these dynamical regions will greatly complement current structural approaches to understand the molecular mechanisms of these proteins and may help in the prediction of new effectors.

  5. Optimization of memory use of fragment extension-based protein-ligand docking with an original fast minimum cost flow algorithm.

    Science.gov (United States)

    Yanagisawa, Keisuke; Komine, Shunta; Kubota, Rikuto; Ohue, Masahito; Akiyama, Yutaka

    2018-03-16

    The need to accelerate large-scale protein-ligand docking in virtual screening against a huge compound database led researchers to propose a strategy that entails memorizing the evaluation result of the partial structure of a compound and reusing it to evaluate other compounds. However, the previous method required frequent disk accesses, resulting in insufficient acceleration. Thus, more efficient memory usage can be expected to lead to further acceleration, and optimal memory usage could be achieved by solving the minimum cost flow problem. In this research, we propose a fast algorithm for the minimum cost flow problem utilizing the characteristics of the graph generated for this problem as constraints. The proposed algorithm, which optimized memory usage, was approximately seven times faster compared to existing minimum cost flow algorithms. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

  6. Monte Carlo simulations of flexible polyanions complexing with whey proteins at their isoelectric point.

    Science.gov (United States)

    de Vries, R

    2004-02-15

    Electrostatic complexation of flexible polyanions with the whey proteins alpha-lactalbumin and beta-lactoglobulin is studied using Monte Carlo simulations. The proteins are considered at their respective isoelectric points. Discrete charges on the model polyelectrolytes and proteins interact through Debye-Huckel potentials. Protein excluded volume is taken into account through a coarse-grained model of the protein shape. Consistent with experimental results, it is found that alpha-lactalbumin complexes much more strongly than beta-lactoglobulin. For alpha-lactalbumin, strong complexation is due to localized binding to a single large positive "charge patch," whereas for beta-lactoglobulin, weak complexation is due to diffuse binding to multiple smaller charge patches. Copyright 2004 American Institute of Physics

  7. Conformational Flexibility of Proteins Involved in Ribosome Biogenesis: Investigations via Small Angle X-ray Scattering (SAXS

    Directory of Open Access Journals (Sweden)

    Dritan Siliqi

    2018-02-01

    Full Text Available The dynamism of proteins is central to their function, and several proteins have been described as flexible, as consisting of multiple domains joined by flexible linkers, and even as intrinsically disordered. Several techniques exist to study protein structures, but small angle X-ray scattering (SAXS has proven to be particularly powerful for the quantitative analysis of such flexible systems. In the present report, we have used SAXS in combination with X-ray crystallography to highlight their usefulness at characterizing flexible proteins, using as examples two proteins involved in different steps of ribosome biogenesis. The yeast BRCA2 and CDKN1A-interactig protein, Bcp1, is a chaperone for Rpl23 of unknown structure. We showed that it consists of a rigid, slightly elongated protein, with a secondary structure comprising a mixture of alpha helices and beta sheets. As an example of a flexible molecule, we studied the SBDS (Shwachman-Bodian-Diamond Syndrome protein that is involved in the cytoplasmic maturation of the 60S subunit and constitutes the mutated target in the Shwachman-Diamond Syndrome. In solution, this protein coexists in an ensemble of three main conformations, with the N- and C-terminal ends adopting different orientations with respect to the central domain. The structure observed in the protein crystal corresponds to an average of those predicted by the SAXS flexibility analysis.

  8. Miniaturized protein separation using a liquid chromatography column on a flexible substrate

    International Nuclear Information System (INIS)

    Yang Yongmo; Chae, Junseok

    2008-01-01

    We report a prototype protein separator that successfully miniaturizes existing technology for potential use in biocompatible health monitoring implants. The prototype is a liquid chromatography (LC) column (LC mini-column) fabricated on an inexpensive, flexible, biocompatible polydimethylsiloxane (PDMS) enclosure. The LC mini-column separates a mixture of proteins using size exclusion chromatography (SEC) with polydivinylbenzene beads (5–20 µm in diameter with 10 nm pore size). The LC mini-column is smaller than any commercially available LC column by a factor of ∼11 000 and successfully separates denatured and native protein mixtures at ∼71 psi of the applied fluidic pressure. Separated proteins are analyzed using NuPAGE-gel electrophoresis, high-performance liquid chromatography (HPLC) and an automated electrophoresis system. Quantitative HPLC results demonstrate successful separation based on intensity change: within 12 min, the intensity between large and small protein peaks changed by a factor of ∼20. In further evaluation using the automated electrophoresis system, the plate height of the LC mini-column is between 36 µm and 100 µm. The prototype LC mini-column shows the potential for real-time health monitoring in applications that require inexpensive, flexible implant technology that can function effectively under non-laboratory conditions

  9. Molecular Docking Explains Atomic Interaction between Plant-originated Ligands and Oncogenic E7 Protein of High Risk Human Papillomavirus Type 16

    Directory of Open Access Journals (Sweden)

    Satish Kumar

    2014-12-01

    Full Text Available Cervical cancer caused by Human papillomavirus (HPV is one of the leading causes of cancer mortality in women worldwide, particularly in the developing countries. In the last few decades, various compounds from plant origin such as Curcumin, Epigallocatechin gallate (EGCG, Jaceosidin, Resveratrol etc. have been used as anti cancer therapeutic agents. Different studies have shown these plant-originated compounds are able to suppress HPV infection. The E6 and E7 oncoproteins of high-risk HPV play a key role in HPV related cancers. In this study, we explored these ligands from plants origin against E7 oncoprotein of high risk HPV 16, which is known to inactivate tumor suppressor pRb protein. A robust homology model of HPV 16 E7 was built to foresee the interaction mechanism of E7 oncoprotein with these ligands using structure-based drug designing approach. Docking studies demonstrate the interaction of these ligands with pRb binding site of E7 protein by residues Tyr52, Asn53, Val55, Phe57, Cys59, Ser63, Thr64, Thr72, Arg77, Glu80 and Asp81 and help restoration of pRb functioning. This in silico based atomic interaction between these ligands and E7 protein may assist in validating the plant-originated ligands as effective drugs against HPV.

  10. Modeling and Docking Studies on Novel Mutants (K71L and T204V of the ATPase Domain of Human Heat Shock 70 kDa Protein 1

    Directory of Open Access Journals (Sweden)

    Asita Elengoe

    2014-04-01

    Full Text Available The purpose of exploring protein interactions between human adenovirus and heat shock protein 70 is to exploit a potentially synergistic interaction to enhance anti-tumoral efficacy and decrease toxicity in cancer treatment. However, the protein interaction of Hsp70 with E1A32 kDa of human adenovirus serotype 5 remains to be elucidated. In this study, two residues of ATPase domain of human heat shock 70 kDa protein 1 (PDB: 1 HJO were mutated. 3D mutant models (K71L and T204V using PyMol software were then constructed. The structures were evaluated by PROCHECK, ProQ, ERRAT, Verify 3D and ProSA modules. All evidence suggests that all protein models are acceptable and of good quality. The E1A32 kDa motif was retrieved from UniProt (P03255, as well as subjected to docking interaction with NBD, K71L and T204V, using the Autodock 4.2 program. The best lowest binding energy value of −9.09 kcal/mol was selected for novel T204V. Moreover, the protein-ligand complex structures were validated by RMSD, RMSF, hydrogen bonds and salt bridge analysis. This revealed that the T204V-E1A32 kDa motif complex was the most stable among all three complex structures. This study provides information about the interaction between Hsp70 and the E1A32 kDa motif, which emphasizes future perspectives to design rational drugs and vaccines in cancer therapy.

  11. A Flexible Domain-Domain Hinge Promotes an Induced-fit Dominant Mechanism for the Loading of Guide-DNA into Argonaute Protein in Thermus thermophilus

    KAUST Repository

    Zhu, Lizhe

    2016-02-24

    Argonaute proteins (Ago) are core components of the RNA Induced Silencing Complex (RISC) that load and utilize small guide nucleic acids to silence mRNAs or cleave foreign DNAs. Despite the essential role of Ago in gene regulation and defense against virus, the molecular mechanism of guide-strand loading into Ago remains unclear. We explore such a mechanism in the bacterium Thermus thermophilus Ago (TtAgo), via a computational approach combining molecular dynamics, bias-exchange metadynamics, and protein-DNA docking. We show that apo TtAgo adopts multiple closed states that are unable to accommodate guide-DNA. Conformations able to accommodate the guide are beyond the reach of thermal fluctuations from the closed states. These results suggest an induced-fit dominant mechanism for guide-strand loading in TtAgo, drastically different from the two-step mechanism for human Ago 2 (hAgo2) identified in our previous study. Such a difference between TtAgo and hAgo2 is found to mainly originate from the distinct rigidity of their L1-PAZ hinge. Further comparison among known Ago structures from various species indicates that the L1-PAZ hinge may be flexible in general for prokaryotic Agos but rigid for eukaryotic Agos. © 2016 American Chemical Society.

  12. A Flexible Domain-Domain Hinge Promotes an Induced-fit Dominant Mechanism for the Loading of Guide-DNA into Argonaute Protein in Thermus thermophilus.

    Science.gov (United States)

    Zhu, Lizhe; Jiang, Hanlun; Sheong, Fu Kit; Cui, Xuefeng; Gao, Xin; Wang, Yanli; Huang, Xuhui

    2016-03-17

    Argonaute proteins (Ago) are core components of the RNA Induced Silencing Complex (RISC) that load and utilize small guide nucleic acids to silence mRNAs or cleave foreign DNAs. Despite the essential role of Ago in gene regulation and defense against virus, the molecular mechanism of guide-strand loading into Ago remains unclear. We explore such a mechanism in the bacterium Thermus thermophilus Ago (TtAgo), via a computational approach combining molecular dynamics, bias-exchange metadynamics, and protein-DNA docking. We show that apo TtAgo adopts multiple closed states that are unable to accommodate guide-DNA. Conformations able to accommodate the guide are beyond the reach of thermal fluctuations from the closed states. These results suggest an induced-fit dominant mechanism for guide-strand loading in TtAgo, drastically different from the two-step mechanism for human Ago 2 (hAgo2) identified in our previous study. Such a difference between TtAgo and hAgo2 is found to mainly originate from the distinct rigidity of their L1-PAZ hinge. Further comparison among known Ago structures from various species indicates that the L1-PAZ hinge may be flexible in general for prokaryotic Ago's but rigid for eukaryotic Ago's.

  13. Identifying the adaptive mechanism in globular proteins: Fluctuations in densely packed regions manipulate flexible parts

    Science.gov (United States)

    Yilmaz, Lutfu Safak; Atilgan, Ali Rana

    2000-09-01

    A low-resolution structural model based on the packing geometry of α-carbons is utilized to establish a connection between the flexible and rigid parts of a folded protein. The former commonly recognizes a complementing molecule for making a complex, while the latter manipulates the necessary conformational change for binding. We attempt analytically to distinguish this control architecture that intrinsically exists in globular proteins. First with two-dimensional simple models, then for a native protein, bovine pancreatic trypsin inhibitor, we explicitly demonstrate that inserting fluctuations in tertiary contacts supported by the stable core, one can regulate the displacement of residues on loop regions. The positional fluctuations of the flexible regions are annihilated by the rest of the protein in conformity with the Le Chatelier-Braun principle. The results indicate that the distortion of the principal nonbonded contacts between highly packed residues is accompanied by that of the slavery fluctuations that are widely distributed over the native structure. These positional arrangements do not appear in a reciprocal relation between a perturbation and the associated response; the effect of a movement of residue i on residue j is not equal to that of the same movement of residue j on residue i.

  14. Discovery of a new chemical series of BRD4(1) inhibitors using protein-ligand docking and structure-guided design.

    Science.gov (United States)

    Duffy, Bryan C; Liu, Shuang; Martin, Gregory S; Wang, Ruifang; Hsia, Ming Min; Zhao, He; Guo, Cheng; Ellis, Michael; Quinn, John F; Kharenko, Olesya A; Norek, Karen; Gesner, Emily M; Young, Peter R; McLure, Kevin G; Wagner, Gregory S; Lakshminarasimhan, Damodharan; White, Andre; Suto, Robert K; Hansen, Henrik C; Kitchen, Douglas B

    2015-07-15

    Bromodomains are key transcriptional regulators that are thought to be druggable epigenetic targets for cancer, inflammation, diabetes and cardiovascular therapeutics. Of particular importance is the first of two bromodomains in bromodomain containing 4 protein (BRD4(1)). Protein-ligand docking in BRD4(1) was used to purchase a small, focused screening set of compounds possessing a large variety of core structures. Within this set, a small number of weak hits each contained a dihydroquinoxalinone ring system. We purchased other analogs with this ring system and further validated the new hit series and obtained improvement in binding inhibition. Limited exploration by new analog synthesis showed that the binding inhibition in a FRET assay could be improved to the low μM level making this new core a potential hit-to-lead series. Additionally, the predicted geometries of the initial hit and an improved analog were confirmed by X-ray co-crystallography with BRD4(1). Copyright © 2015 Elsevier Ltd. All rights reserved.

  15. Three-dimensional models of Mycobacterium tuberculosis proteins Rv1555, Rv1554 and their docking analyses with sildenafil, tadalafil, vardenafil drugs, suggest interference with quinol binding likely to affect protein's function.

    Science.gov (United States)

    Dash, Pallabini; Bala Divya, M; Guruprasad, Lalitha; Guruprasad, Kunchur

    2018-04-18

    Earlier based on bioinformatics analyses, we had predicted the Mycobacterium tuberculosis (M.tb) proteins; Rv1555 and Rv1554, among the potential new tuberculosis drug targets. According to the 'TB-drugome' the Rv1555 protein is 'druggable' with sildenafil (Viagra), tadalafil (Cialis) and vardenafil (Levitra) drugs. In the present work, we intended to understand via computer modeling studies, how the above drugs are likely to inhibit the M.tb protein's function. The three-dimensional computer models for M.tb proteins; Rv1555 and Rv1554 constructed on the template of equivalent membrane anchor subunits of the homologous E.coli quinol fumarate reductase respiratory protein complex, followed by drug docking analyses, suggested that the binding of above drugs interferes with quinol binding sites. Also, we experimentally observed the in-vitro growth inhibition of E.coli bacteria containing the homologous M.tb protein sequences with sildenafil and tadalafil drugs. The predicted binding sites of the drugs is likely to affect the above M.tb proteins function as quinol binding is known to be essential for electron transfer function during anaerobic respiration in the homologous E.coli protein complex. Therefore, sildenafil and related drugs currently used in the treatment of male erectile dysfunction targeting the human phosphodiesterase 5 enzyme may be evaluated for their plausible role as repurposed drugs to treat human tuberculosis.

  16. Full automation and validation of a flexible ELISA platform for host cell protein and protein A impurity detection in biopharmaceuticals.

    Science.gov (United States)

    Rey, Guillaume; Wendeler, Markus W

    2012-11-01

    Monitoring host cell protein (HCP) and protein A impurities is important to ensure successful development of recombinant antibody drugs. Here, we report the full automation and validation of an ELISA platform on a robotic system that allows the detection of Chinese hamster ovary (CHO) HCPs and residual protein A of in-process control samples and final drug substance. The ELISA setup is designed to serve three main goals: high sample throughput, high quality of results, and sample handling flexibility. The processing of analysis requests, determination of optimal sample dilutions, and calculation of impurity content is performed automatically by a spreadsheet. Up to 48 samples in three unspiked and spiked dilutions each are processed within 24 h. The dilution of each sample is individually prepared based on the drug concentration and the expected impurity content. Adaptable dilution protocols allow the analysis of sample dilutions ranging from 1:2 to 1:2×10(7). The validity of results is assessed by automatic testing for dilutional linearity and spike recovery for each sample. This automated impurity ELISA facilitates multi-project process development, is easily adaptable to other impurity ELISA formats, and increases analytical capacity by combining flexible sample handling with high data quality. Copyright © 2012 Elsevier B.V. All rights reserved.

  17. High protein flexibility and reduced hydration water dynamics are key pressure adaptive strategies in prokaryotes

    KAUST Repository

    Martinez, N.

    2016-09-06

    Water and protein dynamics on a nanometer scale were measured by quasi-elastic neutron scattering in the piezophile archaeon Thermococcus barophilus and the closely related pressure-sensitive Thermococcus kodakarensis, at 0.1 and 40 MPa. We show that cells of the pressure sensitive organism exhibit higher intrinsic stability. Both the hydration water dynamics and the fast protein and lipid dynamics are reduced under pressure. In contrast, the proteome of T. barophilus is more pressure sensitive than that of T. kodakarensis. The diffusion coefficient of hydration water is reduced, while the fast protein and lipid dynamics are slightly enhanced with increasing pressure. These findings show that the coupling between hydration water and cellular constituents might not be simply a master-slave relationship. We propose that the high flexibility of the T. barophilus proteome associated with reduced hydration water may be the keys to the molecular adaptation of the cells to high hydrostatic pressure.

  18. High protein flexibility and reduced hydration water dynamics are key pressure adaptive strategies in prokaryotes

    KAUST Repository

    Martinez, N.; Michoud, Gregoire; Cario, A.; Ollivier, J.; Franzetti, B.; Jebbar, M.; Oger, P.; Peters, J.

    2016-01-01

    Water and protein dynamics on a nanometer scale were measured by quasi-elastic neutron scattering in the piezophile archaeon Thermococcus barophilus and the closely related pressure-sensitive Thermococcus kodakarensis, at 0.1 and 40 MPa. We show that cells of the pressure sensitive organism exhibit higher intrinsic stability. Both the hydration water dynamics and the fast protein and lipid dynamics are reduced under pressure. In contrast, the proteome of T. barophilus is more pressure sensitive than that of T. kodakarensis. The diffusion coefficient of hydration water is reduced, while the fast protein and lipid dynamics are slightly enhanced with increasing pressure. These findings show that the coupling between hydration water and cellular constituents might not be simply a master-slave relationship. We propose that the high flexibility of the T. barophilus proteome associated with reduced hydration water may be the keys to the molecular adaptation of the cells to high hydrostatic pressure.

  19. Investigation of the Flexibility of Protein Kinases Implicated in the Pathology of Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Michael P. Mazanetz

    2014-06-01

    Full Text Available The pathological characteristics of Alzheimer’s Disease (AD have been linked to the activity of three particular kinases—Glycogen Synthase Kinase 3β (GSK3β, Cyclin-Dependent Kinase 5 (CDK5 and Extracellular-signal Regulated Kinase 2 (ERK2. As a consequence, the design of selective, potent and drug-like inhibitors of these kinases is of particular interest. Structure-based design methods are well-established in the development of kinase inhibitors. However, progress in this field is limited by the difficulty in obtaining X-ray crystal structures suitable for drug design and by the inability of this method to resolve highly flexible regions of the protein that are crucial for ligand binding. To address this issue, we have undertaken a study of human protein kinases CDK5/p25, CDK5, ERK2 and GSK3β using both conventional molecular dynamics (MD and the new Active Site Pressurisation (ASP methodology, to look for kinase-specific patterns of flexibility that could be leveraged for the design of selective inhibitors. ASP was used to examine the intrinsic flexibility of the ATP-binding pocket for CDK5/p25, CDK5 and GSK3β where it is shown to be capable of inducing significant conformational changes when compared with X-ray crystal structures. The results from these experiments were used to quantify the dynamics of each protein, which supported the observations made from the conventional MD simulations. Additional information was also derived from the ASP simulations, including the shape of the ATP-binding site and the rigidity of the ATP-binding pocket. These observations may be exploited in the design of selective inhibitors of GSK3β, CDK5 and ERK2.

  20. Photobehavior and docking simulations of drug within macromolecules: binding of an antioxidative isoquinolindione to a serine protease and albumin proteins.

    Science.gov (United States)

    Dhar, Sayaree; Rana, Dipak Kumar; Pal, Arunava; Bhattacharya, Subhash Chandra

    2013-12-05

    The principal intent of the present contribution is to decipher the binding domain and structural changes of trypsin (TPS), a proteolytic globular enzyme and two serum proteins, namely, bovine serum albumin (BSA), human serum albumin (HSA) association with a newly synthesized bioactive isoquinolindione derivative (ANAP) by employing steady state, time resolved fluorescence and circular dichroism (CD) techniques. Intramolecular charge transfer emission (ICT) of ANAP is found to be responsible for the commendable sensitivity of the probe as an extrinsic fluorescent marker to the protein environments. A sharp distinctive feature of determined micropolarities in proteinous media clearly demarcates the differential extent of hydrophobicity around the encapsulated ANAP. A proficient efficiency tunable fluorescence (Förster type) resonance energy transfer (FRET) from the excited tryptophan to ANAP reveals that ANAP binds in the close vicinity of the tryptophan residue in protein. Molecular modeling simulation has been exploited for evaluating the probable interaction site of ANAP in proteinous assembly which shows subdomain IIA are earmarked to possess affinity for ANAP in serum albumins whereas S1 binding pocket in TPS has been found potential binding region for ANAP. Copyright © 2013 Elsevier B.V. All rights reserved.

  1. Molecular Dynamics Simulations of a Flexible Polyethylene: A Protein-Like Behaviour in a Water Solvent

    CERN Document Server

    Kretov, D A

    2005-01-01

    We used molecular dynamics (MD) simulations to study the density and the temperature behaviour of a flexible polyethylene (PE) subjected to various heating conditions and to investigate the PE chain conformational changes in a water solvent. First, we have considered the influence of the heating process on the final state of the polymeric system and the sensitivity of its thermodynamic characteristics (density, energy, etc.) for different heating regimes. For this purpose three different simulations were performed: fast, moderate, and slow heating. Second, we have investigated the PE chain conformational dynamics in water solvent for various simulation conditions and various configurations of the environment. From the obtained results we have got the pictures of the PE dynamical motions in water. We have observed a protein-like behaviour of the PE chain, like that of the DNA and the proteins in water, and have also estimated the rates of the conformational changes. For the MD simulations we used the optimized...

  2. The role of side chain conformational flexibility in surface recognition by Tenebrio molitor antifreeze protein

    Science.gov (United States)

    Daley, Margaret E.; Sykes, Brian D.

    2003-01-01

    Two-dimensional nuclear magnetic resonance spectroscopy was used to investigate the flexibility of the threonine side chains in the β-helical Tenebrio molitor antifreeze protein (TmAFP) at low temperatures. From measurement of the 3Jαβ 1H-1H scalar coupling constants, the χ1 angles and preferred rotamer populations can be calculated. It was determined that the threonines on the ice-binding face of the protein adopt a preferred rotameric conformation at near freezing temperatures, whereas the threonines not on the ice-binding face sample many rotameric states. This suggests that TmAFP maintains a preformed ice-binding conformation in solution, wherein the rigid array of threonines that form the AFP-ice interface matches the ice crystal lattice. A key factor in binding to the ice surface and inhibition of ice crystal growth appears to be the close surface-to-surface complementarity between the AFP and crystalline ice, and the lack of an entropic penalty associated with freezing out motions in a flexible ligand. PMID:12824479

  3. Identifying Potential Protein Targets for Toluene Using a Molecular Similarity Search, in Silico Docking and in Vitro Validation

    Science.gov (United States)

    2015-01-01

    performed under standard conditions. Ana- lysis of purified hemoglobin using SDS and native polyacryl - amide gel electrophoresis (PAGE) indicated that the...search of T3DB. They represent several families of proteins (calcium-transporting ATPases, sodium/ potassium -transporting ATPase, cytochrome P450...REPORT DOCUMENTATION PAGE Form Approved OMB No. 0704-0188 Public reporting burden for this collection of information is estimated to average 1

  4. Gold nanoparticle-embedded silk protein-ZnO nanorod hybrids for flexible bio-photonic devices

    Science.gov (United States)

    Gogurla, Narendar; Kundu, Subhas C.; Ray, Samit K.

    2017-04-01

    Silk protein has been used as a biopolymer substrate for flexible photonic devices. Here, we demonstrate ZnO nanorod array hybrid photodetectors on Au nanoparticle-embedded silk protein for flexible optoelectronics. Hybrid samples exhibit optical absorption at the band edge of ZnO as well as plasmonic energy due to Au nanoparticles, making them attractive for selective UV and visible wavelength detection. The device prepared on Au-silk protein shows a much lower dark current and a higher photo to dark-current ratio of ∼105 as compared to the control sample without Au nanoparticles. The hybrid device also exhibits a higher specific detectivity due to higher responsivity arising from the photo-generated hole trapping by Au nanoparticles. Sharp pulses in the transient photocurrent have been observed in devices prepared on glass and Au-silk protein substrates due to the light induced pyroelectric effect of ZnO, enabling the demonstration of self-powered photodetectors at zero bias. Flexible hybrid detectors have been demonstrated on Au-silk/polyethylene terephthalate substrates, exhibiting characteristics similar to those fabricated on rigid glass substrates. A study of the performance of photodetectors with different bending angles indicates very good mechanical stability of silk protein based flexible devices. This novel concept of ZnO nanorod array photodetectors on a natural silk protein platform provides an opportunity to realize integrated flexible and self-powered bio-photonic devices for medical applications in near future.

  5. Lessons learned in induced fit docking and metadynamics in the Drug Design Data Resource Grand Challenge 2

    Science.gov (United States)

    Baumgartner, Matthew P.; Evans, David A.

    2018-01-01

    Two of the major ongoing challenges in computational drug discovery are predicting the binding pose and affinity of a compound to a protein. The Drug Design Data Resource Grand Challenge 2 was developed to address these problems and to drive development of new methods. The challenge provided the 2D structures of compounds for which the organizers help blinded data in the form of 35 X-ray crystal structures and 102 binding affinity measurements and challenged participants to predict the binding pose and affinity of the compounds. We tested a number of pose prediction methods as part of the challenge; we found that docking methods that incorporate protein flexibility (Induced Fit Docking) outperformed methods that treated the protein as rigid. We also found that using binding pose metadynamics, a molecular dynamics based method, to score docked poses provided the best predictions of our methods with an average RMSD of 2.01 Å. We tested both structure-based (e.g. docking) and ligand-based methods (e.g. QSAR) in the affinity prediction portion of the competition. We found that our structure-based methods based on docking with Smina (Spearman ρ = 0.614), performed slightly better than our ligand-based methods (ρ = 0.543), and had equivalent performance with the other top methods in the competition. Despite the overall good performance of our methods in comparison to other participants in the challenge, there exists significant room for improvement especially in cases such as these where protein flexibility plays such a large role.

  6. Virtual Ligand Screening Using PL-PatchSurfer2, a Molecular Surface-Based Protein-Ligand Docking Method.

    Science.gov (United States)

    Shin, Woong-Hee; Kihara, Daisuke

    2018-01-01

    Virtual screening is a computational technique for predicting a potent binding compound for a receptor protein from a ligand library. It has been a widely used in the drug discovery field to reduce the efforts of medicinal chemists to find hit compounds by experiments.Here, we introduce our novel structure-based virtual screening program, PL-PatchSurfer, which uses molecular surface representation with the three-dimensional Zernike descriptors, which is an effective mathematical representation for identifying physicochemical complementarities between local surfaces of a target protein and a ligand. The advantage of the surface-patch description is its tolerance on a receptor and compound structure variation. PL-PatchSurfer2 achieves higher accuracy on apo form and computationally modeled receptor structures than conventional structure-based virtual screening programs. Thus, PL-PatchSurfer2 opens up an opportunity for targets that do not have their crystal structures. The program is provided as a stand-alone program at http://kiharalab.org/plps2 . We also provide files for two ligand libraries, ChEMBL and ZINC Drug-like.

  7. Molecular dynamics modeling the synthetic and biological polymers interactions pre-studied via docking

    Science.gov (United States)

    Tsvetkov, Vladimir B.; Serbin, Alexander V.

    2014-06-01

    In previous works we reported the design, synthesis and in vitro evaluations of synthetic anionic polymers modified by alicyclic pendant groups (hydrophobic anchors), as a novel class of inhibitors of the human immunodeficiency virus type 1 ( HIV-1) entry into human cells. Recently, these synthetic polymers interactions with key mediator of HIV-1 entry-fusion, the tri-helix core of the first heptad repeat regions [ HR1]3 of viral envelope protein gp41, were pre-studied via docking in terms of newly formulated algorithm for stepwise approximation from fragments of polymeric backbone and side-group models toward real polymeric chains. In the present article the docking results were verified under molecular dynamics ( MD) modeling. In contrast with limited capabilities of the docking, the MD allowed of using much more large models of the polymeric ligands, considering flexibility of both ligand and target simultaneously. Among the synthesized polymers the dinorbornen anchors containing alternating copolymers of maleic acid were selected as the most representative ligands (possessing the top anti-HIV activity in vitro in correlation with the highest binding energy in the docking). To verify the probability of binding of the polymers with the [HR1]3 in the sites defined via docking, various starting positions of polymer chains were tried. The MD simulations confirmed the main docking-predicted priority for binding sites, and possibilities for axial and belting modes of the ligands-target interactions. Some newly MD-discovered aspects of the ligand's backbone and anchor units dynamic cooperation in binding the viral target clarify mechanisms of the synthetic polymers anti-HIV activity and drug resistance prevention.

  8. Global Structural Flexibility of Metalloproteins Regulates Reactivity of Transition Metal Ion in the Protein Core: An Experimental Study Using Thiol-subtilisin as a Model Protein.

    Science.gov (United States)

    Matsuo, Takashi; Kono, Takamasa; Shobu, Isamu; Ishida, Masaya; Gonda, Katsuya; Hirota, Shun

    2018-02-21

    The functions of metal-containing proteins (metalloproteins) are determined by the reactivities of transition metal ions at their active sites. Because protein macromolecular structures have several molecular degrees of freedom, global structural flexibility may also regulate the properties of metalloproteins. However, the influence of this factor has not been fully delineated in mechanistic studies of metalloproteins. Accordingly, we have investigated the relationship between global protein flexibility and the characteristics of a transition metal ion in the protein core using thiol-subtilisin (tSTL) with a Cys-coordinated Cu 2+ ion as a model system. Although tSTL has two Ca 2+ -binding sites, the Ca 2+ -binding status hardly affects its secondary structure. Nevertheless, guanidinium-induced denaturation and amide H/D exchange indicated the increase in the structural flexibility of tSTL by the removal of bound Ca 2+ ions. Electron paramagnetic resonance and absorption spectral changes have revealed that the protein flexibility determines the characteristics of a Cu 2+ ion in tSTL. Therefore, global protein flexibility should be recognized as an important factor that regulates the properties of metalloproteins. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. A hydrazone Schiff base single crystal (E)-Methyl N"′-(3,4,5-trimethoxybenzylidene) hydrazine carboxylate: Physicochemical, in vitro investigation of antimicrobial activities and molecular docking with DNA gyrase protein

    International Nuclear Information System (INIS)

    Gomathi, G.; Gopalakrishnan, R.

    2016-01-01

    Hydrazone Schiff bases have been widely explored for their antimicrobial, anticancer, anticonvulsant properties. The aim of the present work is to investigate the spectroscopic, electrochemical, thermal properties, in vitro study of antimicrobial activity and molecular docking studies of the MBHC compound. Slow evaporation solution growth technique was used to grow the single crystal of the MBHC compound. Single crystal X-ray diffraction, FTIR and FT-Raman spectroscopic studies are performed and confirmed the grown MBHC compound. UV–Vis spectroscopy and electrochemical studies deduced the absorption region and HOMO-LUMO band gap value of the compound. Resazurin reduction assay method was utilized to perform antibacterial and antifungal studies which resulted in lesser effectiveness of the MBHC compound compared to the erythromycin and fluconazole tablets. Molecular docking of the MBHC compound with the DNA gyrase protein exhibited the good binding affinity with energy of − 43.196 kcal/mol and docking score of − 6.266 and having good interaction with aminoacids – ASP81 and ARG84. - Highlights: • MBHC single crystal was grown by employing slow evaporation solution growth technique. • The compound crystallizes in monoclinic crystal system with space group P2_1/c. • The HOMO-LUMO band gap value was found to be 1.96 eV. • The compound has lesser antimicrobial activity when compared to erythromycin and fluconazole. • MBHC shows better binding affinity towards DNA gyrase protein.

  10. A hydrazone Schiff base single crystal (E)-Methyl N{sup ′}-(3,4,5-trimethoxybenzylidene) hydrazine carboxylate: Physicochemical, in vitro investigation of antimicrobial activities and molecular docking with DNA gyrase protein

    Energy Technology Data Exchange (ETDEWEB)

    Gomathi, G.; Gopalakrishnan, R., E-mail: krgkrishnan@annauniv.edu

    2016-07-01

    Hydrazone Schiff bases have been widely explored for their antimicrobial, anticancer, anticonvulsant properties. The aim of the present work is to investigate the spectroscopic, electrochemical, thermal properties, in vitro study of antimicrobial activity and molecular docking studies of the MBHC compound. Slow evaporation solution growth technique was used to grow the single crystal of the MBHC compound. Single crystal X-ray diffraction, FTIR and FT-Raman spectroscopic studies are performed and confirmed the grown MBHC compound. UV–Vis spectroscopy and electrochemical studies deduced the absorption region and HOMO-LUMO band gap value of the compound. Resazurin reduction assay method was utilized to perform antibacterial and antifungal studies which resulted in lesser effectiveness of the MBHC compound compared to the erythromycin and fluconazole tablets. Molecular docking of the MBHC compound with the DNA gyrase protein exhibited the good binding affinity with energy of − 43.196 kcal/mol and docking score of − 6.266 and having good interaction with aminoacids – ASP81 and ARG84. - Highlights: • MBHC single crystal was grown by employing slow evaporation solution growth technique. • The compound crystallizes in monoclinic crystal system with space group P2{sub 1}/c. • The HOMO-LUMO band gap value was found to be 1.96 eV. • The compound has lesser antimicrobial activity when compared to erythromycin and fluconazole. • MBHC shows better binding affinity towards DNA gyrase protein.

  11. Computational methods for molecular docking

    Energy Technology Data Exchange (ETDEWEB)

    Klebe, G. [BASF AG, Ludwigshafen (Germany); Lengauer, T.

    1995-12-31

    This tutorial was one of eight tutorials selected to be presented at the Third International Conference on Intelligent Systems for Molecular Biology which was held in the United Kingdom from July 16 to 19, 1995. Recently, it has been demonstrated that the knowledge of the three-dimensional structure of the protein can be used to derive new protein ligands with improved binding properties. This tutorial focuses on the following questions: What is its binding affinity toward a particular receptor? What are putative conformations of a ligand at the binding site? What are the similarities of different ligands in terms of their recognition capabilities? Where and in which orientation will a ligand bind to the active site? How is a new putative protein ligand selected? An overview is presented of the algorithms which are presently used to handle and predict protein-ligand interactions and to dock small molecule ligands into proteins.

  12. Rosetta FlexPepDock ab-initio: simultaneous folding, docking and refinement of peptides onto their receptors.

    Science.gov (United States)

    Raveh, Barak; London, Nir; Zimmerman, Lior; Schueler-Furman, Ora

    2011-04-29

    Flexible peptides that fold upon binding to another protein molecule mediate a large number of regulatory interactions in the living cell and may provide highly specific recognition modules. We present Rosetta FlexPepDock ab-initio, a protocol for simultaneous docking and de-novo folding of peptides, starting from an approximate specification of the peptide binding site. Using the Rosetta fragments library and a coarse-grained structural representation of the peptide and the receptor, FlexPepDock ab-initio samples efficiently and simultaneously the space of possible peptide backbone conformations and rigid-body orientations over the receptor surface of a given binding site. The subsequent all-atom refinement of the coarse-grained models includes full side-chain modeling of both the receptor and the peptide, resulting in high-resolution models in which key side-chain interactions are recapitulated. The protocol was applied to a benchmark in which peptides were modeled over receptors in either their bound backbone conformations or in their free, unbound form. Near-native peptide conformations were identified in 18/26 of the bound cases and 7/14 of the unbound cases. The protocol performs well on peptides from various classes of secondary structures, including coiled peptides with unusual turns and kinks. The results presented here significantly extend the scope of state-of-the-art methods for high-resolution peptide modeling, which can now be applied to a wide variety of peptide-protein interactions where no prior information about the peptide backbone conformation is available, enabling detailed structure-based studies and manipulation of those interactions. © 2011 Raveh et al.

  13. Arc is a flexible modular protein capable of reversible self-oligomerization

    Science.gov (United States)

    Myrum, Craig; Baumann, Anne; Bustad, Helene J.; Flydal, Marte Innselset; Mariaule, Vincent; Alvira, Sara; Cuéllar, Jorge; Haavik, Jan; Soulé, Jonathan; Valpuesta, José Maria; Márquez, José Antonio; Martinez, Aurora; Bramham, Clive R.

    2015-01-01

    The immediate early gene product Arc (activity-regulated cytoskeleton-associated protein) is posited as a master regulator of long-term synaptic plasticity and memory. However, the physicochemical and structural properties of Arc have not been elucidated. In the present study, we expressed and purified recombinant human Arc (hArc) and performed the first biochemical and biophysical analysis of hArc's structure and stability. Limited proteolysis assays and MS analysis indicate that hArc has two major domains on either side of a central more disordered linker region, consistent with in silico structure predictions. hArc's secondary structure was estimated using CD, and stability was analysed by CD-monitored thermal denaturation and differential scanning fluorimetry (DSF). Oligomerization states under different conditions were studied by dynamic light scattering (DLS) and visualized by AFM and EM. Biophysical analyses show that hArc is a modular protein with defined secondary structure and loose tertiary structure. hArc appears to be pyramid-shaped as a monomer and is capable of reversible self-association, forming large soluble oligomers. The N-terminal domain of hArc is highly basic, which may promote interaction with cytoskeletal structures or other polyanionic surfaces, whereas the C-terminal domain is acidic and stabilized by ionic conditions that promote oligomerization. Upon binding of presenilin-1 (PS1) peptide, hArc undergoes a large structural change. A non-synonymous genetic variant of hArc (V231G) showed properties similar to the wild-type (WT) protein. We conclude that hArc is a flexible multi-domain protein that exists in monomeric and oligomeric forms, compatible with a diverse, hub-like role in plasticity-related processes. PMID:25748042

  14. Automated docking screens: a feasibility study.

    Science.gov (United States)

    Irwin, John J; Shoichet, Brian K; Mysinger, Michael M; Huang, Niu; Colizzi, Francesco; Wassam, Pascal; Cao, Yiqun

    2009-09-24

    Molecular docking is the most practical approach to leverage protein structure for ligand discovery, but the technique retains important liabilities that make it challenging to deploy on a large scale. We have therefore created an expert system, DOCK Blaster, to investigate the feasibility of full automation. The method requires a PDB code, sometimes with a ligand structure, and from that alone can launch a full screen of large libraries. A critical feature is self-assessment, which estimates the anticipated reliability of the automated screening results using pose fidelity and enrichment. Against common benchmarks, DOCK Blaster recapitulates the crystal ligand pose within 2 A rmsd 50-60% of the time; inferior to an expert, but respectrable. Half the time the ligand also ranked among the top 5% of 100 physically matched decoys chosen on the fly. Further tests were undertaken culminating in a study of 7755 eligible PDB structures. In 1398 cases, the redocked ligand ranked in the top 5% of 100 property-matched decoys while also posing within 2 A rmsd, suggesting that unsupervised prospective docking is viable. DOCK Blaster is available at http://blaster.docking.org .

  15. Molecular dynamics simulations of a flexible polyethylene: a protein-like behaviour in a water solvent

    International Nuclear Information System (INIS)

    Kretov, D.A.; Kholmurodov, Kh.T.

    2005-01-01

    We used molecular dynamics (MD) simulations to study the density and the temperature behaviour of a flexible polyethylene (PE) subjected to various heating conditions and to investigate the PE chain conformational changes in a water solvent. First, we have considered the influence of the heating process on the final state of the polymeric system and the sensitivity of its thermodynamic characteristics (density, energy, etc.) for different heating regimes. For this purpose three different simulations were performed: fast, moderate, and slow heating. Second, we have investigated the PE chain conformational dynamics in water solvent for various simulation conditions and various configurations of the environment. From the obtained results we have got the pictures of the PE dynamical motions in water. We have observed a protein-like behaviour of the PE chain, like that of the DNA and the proteins in water, and have also estimated the rates of the conformational changes. For the MD simulations we used the optimized general-purpose DL P OLY code and the generic DREIDING force field. The MD simulations were performed on the parallel computers and special-purpose MDGRAPE-2 machine

  16. Combination of Ambiguous and Unambiguous Data in the Restraint-driven Docking of Flexible Peptides with HADDOCK: The Binding of the Spider Toxin PcTx1 to the Acid Sensing Ion Channel (ASIC) 1a.

    Science.gov (United States)

    Deplazes, Evelyne; Davies, Josephine; Bonvin, Alexandre M J J; King, Glenn F; Mark, Alan E

    2016-01-25

    Peptides that bind to ion channels have attracted much interest as potential lead molecules for the development of new drugs and insecticides. However, the structure determination of large peptide-channel complexes using experimental methods is challenging. Thus structural models are often derived from combining experimental information with restraint-driven docking approaches. Using the complex formed by the venom peptide PcTx1 and the acid sensing ion channel (ASIC) 1a as a case study, we have examined the effect of different combinations of restraints and input structures on the statistical likelihood of (a) correctly predicting the structure of the binding interface and (b) the ability to predict which residues are involved in specific pairwise peptide-channel interactions. For this, we have analyzed over 200,000 water-refined docked structures obtained with various amounts and types of restraints of the peptide-channel complex predicted using the docking program HADDOCK. We found that increasing the number of restraints or even the use of pairwise interaction data resulted in only a modest improvement in the likelihood of finding a structure within a given accuracy. This suggests that shape complementarity and the force field make a large contribution to the accuracy of the predicted structure. The results also showed that there are large variations in the accuracy of the predicted structure depending on the precise combination of residues used as restraints. Finally, we reflect on the limitations of relying on geometric criteria such as root-mean square deviations to assess the accuracy of docking procedures. We propose that in addition to currently used measures, the likelihood of finding a structure within a given level of accuracy should be also used to evaluate docking methods.

  17. Extracellular Signal-Regulated Kinase 2 (ERK2) Phosphorylation Sites and Docking Domain on the Nuclear Pore Complex Protein Tpr Cooperatively Regulate ERK2-Tpr Interaction

    Czech Academy of Sciences Publication Activity Database

    Vomastek, Tomáš; Iwanicky, M. P.; Burack, W. R.; Tiwari, D.; Kumar, D.; Parsons, J. T.; Weber, M. J.; Nandicoori, V. K.

    2008-01-01

    Roč. 28, č. 22 (2008), s. 6954-6966 ISSN 0270-7306 R&D Projects: GA AV ČR IAA500200716 Institutional research plan: CEZ:AV0Z50200510 Keywords : erk * docking domain * cell growth Subject RIV: EE - Microbiology, Virology Impact factor: 5.942, year: 2008

  18. Covalent docking of selected boron-based serine beta-lactamase inhibitors

    Science.gov (United States)

    Sgrignani, Jacopo; Novati, Beatrice; Colombo, Giorgio; Grazioso, Giovanni

    2015-05-01

    AmpC β-lactamase is a hydrolytic enzyme conferring resistance to β-lactam antibiotics in multiple Gram-negative bacteria. Therefore, identification of non-β-lactam compounds able to inhibit the enzyme is crucial for the development of novel antibacterial therapies. In general, AmpC inhibitors have to engage the highly solvent-exposed catalytic site of the enzyme. Therefore, understanding the implications of ligand-protein induced-fit and water-mediated interactions behind the inhibitor-enzyme recognition process is fundamental for undertaking structure-based drug design process. Here, we focus on boronic acids, a promising class of beta-lactamase covalent inhibitors. First, we optimized a docking protocol able to reproduce the experimentally determined binding mode of AmpC inhibitors bearing a boronic group. This goal was pursued (1) performing rigid and flexible docking calculations aiming to establish the role of the side chain conformations; and (2) investigating the role of specific water molecules in shaping the enzyme active site and mediating ligand protein interactions. Our calculations showed that some water molecules, conserved in the majority of the considered X-ray structures, are needed to correctly predict the binding pose of known covalent AmpC inhibitors. On this basis, we formalized our findings in a docking and scoring protocol that could be useful for the structure-based design of new boronic acid AmpC inhibitors.

  19. CABS-flex 2.0: a web server for fast simulations of flexibility of protein structures.

    Science.gov (United States)

    Kuriata, Aleksander; Gierut, Aleksandra Maria; Oleniecki, Tymoteusz; Ciemny, Maciej Pawel; Kolinski, Andrzej; Kurcinski, Mateusz; Kmiecik, Sebastian

    2018-05-14

    Classical simulations of protein flexibility remain computationally expensive, especially for large proteins. A few years ago, we developed a fast method for predicting protein structure fluctuations that uses a single protein model as the input. The method has been made available as the CABS-flex web server and applied in numerous studies of protein structure-function relationships. Here, we present a major update of the CABS-flex web server to version 2.0. The new features include: extension of the method to significantly larger and multimeric proteins, customizable distance restraints and simulation parameters, contact maps and a new, enhanced web server interface. CABS-flex 2.0 is freely available at http://biocomp.chem.uw.edu.pl/CABSflex2.

  20. Docking screens: right for the right reasons?

    Science.gov (United States)

    Kolb, Peter; Irwin, John J

    2009-01-01

    Whereas docking screens have emerged as the most practical way to use protein structure for ligand discovery, an inconsistent track record raises questions about how well docking actually works. In its favor, a growing number of publications report the successful discovery of new ligands, often supported by experimental affinity data and controls for artifacts. Few reports, however, actually test the underlying structural hypotheses that docking makes. To be successful and not just lucky, prospective docking must not only rank a true ligand among the top scoring compounds, it must also correctly orient the ligand so the score it receives is biophysically sound. If the correct binding pose is not predicted, a skeptic might well infer that the discovery was serendipitous. Surveying over 15 years of the docking literature, we were surprised to discover how rarely sufficient evidence is presented to establish whether docking actually worked for the right reasons. The paucity of experimental tests of theoretically predicted poses undermines confidence in a technique that has otherwise become widely accepted. Of course, solving a crystal structure is not always possible, and even when it is, it can be a lot of work, and is not readily accessible to all groups. Even when a structure can be determined, investigators may prefer to gloss over an erroneous structural prediction to better focus on their discovery. Still, the absence of a direct test of theory by experiment is a loss for method developers seeking to understand and improve docking methods. We hope this review will motivate investigators to solve structures and compare them with their predictions whenever possible, to advance the field.

  1. Solvated protein–DNA docking using HADDOCK

    International Nuclear Information System (INIS)

    Dijk, Marc van; Visscher, Koen M.; Kastritis, Panagiotis L.; Bonvin, Alexandre M. J. J.

    2013-01-01

    Interfacial water molecules play an important role in many aspects of protein–DNA specificity and recognition. Yet they have been mostly neglected in the computational modeling of these complexes. We present here a solvated docking protocol that allows explicit inclusion of water molecules in the docking of protein–DNA complexes and demonstrate its feasibility on a benchmark of 30 high-resolution protein–DNA complexes containing crystallographically-determined water molecules at their interfaces. Our protocol is capable of reproducing the solvation pattern at the interface and recovers hydrogen-bonded water-mediated contacts in many of the benchmark cases. Solvated docking leads to an overall improvement in the quality of the generated protein–DNA models for cases with limited conformational change of the partners upon complex formation. The applicability of this approach is demonstrated on real cases by docking a representative set of 6 complexes using unbound protein coordinates, model-built DNA and knowledge-based restraints. As HADDOCK supports the inclusion of a variety of NMR restraints, solvated docking is also applicable for NMR-based structure calculations of protein–DNA complexes.

  2. Synthesis and molecular docking of pyrimidine incorporated novel ...

    Indian Academy of Sciences (India)

    APOORVA MISRA

    2018-03-09

    Mar 9, 2018 ... aDepartment of Chemistry, Banasthali Vidyapith, Banasthali, Rajasthan 304 022, India ... serotonin 5-HT6 receptor antagonist,22 hepatitis-A virus ..... Molecular docking structure and ligand protein binding sites of MTX- (a) ...

  3. A scalable and accurate method for classifying protein-ligand binding geometries using a MapReduce approach.

    Science.gov (United States)

    Estrada, T; Zhang, B; Cicotti, P; Armen, R S; Taufer, M

    2012-07-01

    We present a scalable and accurate method for classifying protein-ligand binding geometries in molecular docking. Our method is a three-step process: the first step encodes the geometry of a three-dimensional (3D) ligand conformation into a single 3D point in the space; the second step builds an octree by assigning an octant identifier to every single point in the space under consideration; and the third step performs an octree-based clustering on the reduced conformation space and identifies the most dense octant. We adapt our method for MapReduce and implement it in Hadoop. The load-balancing, fault-tolerance, and scalability in MapReduce allow screening of very large conformation spaces not approachable with traditional clustering methods. We analyze results for docking trials for 23 protein-ligand complexes for HIV protease, 21 protein-ligand complexes for Trypsin, and 12 protein-ligand complexes for P38alpha kinase. We also analyze cross docking trials for 24 ligands, each docking into 24 protein conformations of the HIV protease, and receptor ensemble docking trials for 24 ligands, each docking in a pool of HIV protease receptors. Our method demonstrates significant improvement over energy-only scoring for the accurate identification of native ligand geometries in all these docking assessments. The advantages of our clustering approach make it attractive for complex applications in real-world drug design efforts. We demonstrate that our method is particularly useful for clustering docking results using a minimal ensemble of representative protein conformational states (receptor ensemble docking), which is now a common strategy to address protein flexibility in molecular docking. Copyright © 2012 Elsevier Ltd. All rights reserved.

  4. Spacecraft rendezvous and docking

    DEFF Research Database (Denmark)

    Jørgensen, John Leif

    1999-01-01

    The phenomenons and problems encountered when a rendezvous manoeuvre, and possible docking, of two spacecrafts has to be performed, have been the topic for numerous studies, and, details of a variety of scenarios has been analysed. So far, all solutions that has been brought into realization has...... been based entirely on direct human supervision and control. This paper describes a vision-based system and methodology, that autonomously generates accurate guidance information that may assist a human operator in performing the tasks associated with both the rendezvous and docking navigation...

  5. CAB-Align: A Flexible Protein Structure Alignment Method Based on the Residue-Residue Contact Area.

    Directory of Open Access Journals (Sweden)

    Genki Terashi

    Full Text Available Proteins are flexible, and this flexibility has an essential functional role. Flexibility can be observed in loop regions, rearrangements between secondary structure elements, and conformational changes between entire domains. However, most protein structure alignment methods treat protein structures as rigid bodies. Thus, these methods fail to identify the equivalences of residue pairs in regions with flexibility. In this study, we considered that the evolutionary relationship between proteins corresponds directly to the residue-residue physical contacts rather than the three-dimensional (3D coordinates of proteins. Thus, we developed a new protein structure alignment method, contact area-based alignment (CAB-align, which uses the residue-residue contact area to identify regions of similarity. The main purpose of CAB-align is to identify homologous relationships at the residue level between related protein structures. The CAB-align procedure comprises two main steps: First, a rigid-body alignment method based on local and global 3D structure superposition is employed to generate a sufficient number of initial alignments. Then, iterative dynamic programming is executed to find the optimal alignment. We evaluated the performance and advantages of CAB-align based on four main points: (1 agreement with the gold standard alignment, (2 alignment quality based on an evolutionary relationship without 3D coordinate superposition, (3 consistency of the multiple alignments, and (4 classification agreement with the gold standard classification. Comparisons of CAB-align with other state-of-the-art protein structure alignment methods (TM-align, FATCAT, and DaliLite using our benchmark dataset showed that CAB-align performed robustly in obtaining high-quality alignments and generating consistent multiple alignments with high coverage and accuracy rates, and it performed extremely well when discriminating between homologous and nonhomologous pairs of proteins

  6. CAB-Align: A Flexible Protein Structure Alignment Method Based on the Residue-Residue Contact Area.

    Science.gov (United States)

    Terashi, Genki; Takeda-Shitaka, Mayuko

    2015-01-01

    Proteins are flexible, and this flexibility has an essential functional role. Flexibility can be observed in loop regions, rearrangements between secondary structure elements, and conformational changes between entire domains. However, most protein structure alignment methods treat protein structures as rigid bodies. Thus, these methods fail to identify the equivalences of residue pairs in regions with flexibility. In this study, we considered that the evolutionary relationship between proteins corresponds directly to the residue-residue physical contacts rather than the three-dimensional (3D) coordinates of proteins. Thus, we developed a new protein structure alignment method, contact area-based alignment (CAB-align), which uses the residue-residue contact area to identify regions of similarity. The main purpose of CAB-align is to identify homologous relationships at the residue level between related protein structures. The CAB-align procedure comprises two main steps: First, a rigid-body alignment method based on local and global 3D structure superposition is employed to generate a sufficient number of initial alignments. Then, iterative dynamic programming is executed to find the optimal alignment. We evaluated the performance and advantages of CAB-align based on four main points: (1) agreement with the gold standard alignment, (2) alignment quality based on an evolutionary relationship without 3D coordinate superposition, (3) consistency of the multiple alignments, and (4) classification agreement with the gold standard classification. Comparisons of CAB-align with other state-of-the-art protein structure alignment methods (TM-align, FATCAT, and DaliLite) using our benchmark dataset showed that CAB-align performed robustly in obtaining high-quality alignments and generating consistent multiple alignments with high coverage and accuracy rates, and it performed extremely well when discriminating between homologous and nonhomologous pairs of proteins in both

  7. Molecular Docking Study on Galantamine Derivatives as Cholinesterase Inhibitors.

    Science.gov (United States)

    Atanasova, Mariyana; Yordanov, Nikola; Dimitrov, Ivan; Berkov, Strahil; Doytchinova, Irini

    2015-06-01

    A training set of 22 synthetic galantamine derivatives binding to acetylcholinesterase was docked by GOLD and the protocol was optimized in terms of scoring function, rigidity/flexibility of the binding site, presence/absence of a water molecule inside and radius of the binding site. A moderate correlation was found between the affinities of compounds expressed as pIC50 values and their docking scores. The optimized docking protocol was validated by an external test set of 11 natural galantamine derivatives and the correlation coefficient between the docking scores and the pIC50 values was 0.800. The derived relationship was used to analyze the interactions between galantamine derivatives and AChE. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. Munc13-4 Is a Rab11-binding Protein That Regulates Rab11-positive Vesicle Trafficking and Docking at the Plasma Membrane.

    Science.gov (United States)

    Johnson, Jennifer L; He, Jing; Ramadass, Mahalakshmi; Pestonjamasp, Kersi; Kiosses, William B; Zhang, Jinzhong; Catz, Sergio D

    2016-02-12

    The small GTPase Rab11 and its effectors control trafficking of recycling endosomes, receptor replenishment and the up-regulation of adhesion and adaptor molecules at the plasma membrane. Despite recent advances in the understanding of Rab11-regulated mechanisms, the final steps mediating docking and fusion of Rab11-positive vesicles at the plasma membrane are not fully understood. Munc13-4 is a docking factor proposed to regulate fusion through interactions with SNAREs. In hematopoietic cells, including neutrophils, Munc13-4 regulates exocytosis in a Rab27a-dependent manner, but its possible regulation of other GTPases has not been explored in detail. Here, we show that Munc13-4 binds to Rab11 and regulates the trafficking of Rab11-containing vesicles. Using a novel Time-resolved Fluorescence Resonance Energy Transfer (TR-FRET) assay, we demonstrate that Munc13-4 binds to Rab11a but not to dominant negative Rab11a. Immunoprecipitation analysis confirmed the specificity of the interaction between Munc13-4 and Rab11, and super-resolution microscopy studies support the interaction of endogenous Munc13-4 with Rab11 at the single molecule level in neutrophils. Vesicular dynamic analysis shows the common spatio-temporal distribution of Munc13-4 and Rab11, while expression of a calcium binding-deficient mutant of Munc13-4 significantly affected Rab11 trafficking. Munc13-4-deficient neutrophils showed normal endocytosis, but the trafficking, up-regulation, and retention of Rab11-positive vesicles at the plasma membrane was significantly impaired. This correlated with deficient NADPH oxidase activation at the plasma membrane in response to Rab11 interference. Our data demonstrate that Munc13-4 is a Rab11-binding partner that regulates the final steps of Rab11-positive vesicle docking at the plasma membrane. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  9. Determining Complex Structures using Docking Method with Single Particle Scattering Data

    Directory of Open Access Journals (Sweden)

    Haiguang Liu

    2017-04-01

    Full Text Available Protein complexes are critical for many molecular functions. Due to intrinsic flexibility and dynamics of complexes, their structures are more difficult to determine using conventional experimental methods, in contrast to individual subunits. One of the major challenges is the crystallization of protein complexes. Using X-ray free electron lasers (XFELs, it is possible to collect scattering signals from non-crystalline protein complexes, but data interpretation is more difficult because of unknown orientations. Here, we propose a hybrid approach to determine protein complex structures by combining XFEL single particle scattering data with computational docking methods. Using simulations data, we demonstrate that a small set of single particle scattering data collected at random orientations can be used to distinguish the native complex structure from the decoys generated using docking algorithms. The results also indicate that a small set of single particle scattering data is superior to spherically averaged intensity profile in distinguishing complex structures. Given the fact that XFEL experimental data are difficult to acquire and at low abundance, this hybrid approach should find wide applications in data interpretations.

  10. Rendezvous and docking tracker

    Science.gov (United States)

    Ray, Art J.; Ross, Susan E.; Deming, Douglas R.

    1986-01-01

    A conceptual solid-state rendezvous and docking tracker (RDT) has been devised for generating range and attitude data for a docking vehicle relative to a target vehicle. Emphasis is placed on the approach of the Orbiter to a link with the Space Station. Three laser illuminators ring the optical axis of the lens a directed toward retroreflectors on the target vehicle. Each retroreflector is equipped with a bandpass filter for a designated illumination frequency. Data are collected sequentially over a 20 deg field of view as the range closes to 100-1000 m. A fourth ranging retroreflector 0.3 m from center is employed during close-in maneuvers. The system provides tracking data on motions with 6 deg of freedom, and furnishes 500 msec updates (to be enhanced to 100 msec) to the operator at a computer console.

  11. Multiple receptor conformers based molecular docking study of fluorine enhanced ethionamide with mycobacterium enoyl ACP reductase (InhA).

    Science.gov (United States)

    Khan, Akib Mahmud; Shawon, Jakaria; Halim, Mohammad A

    2017-10-01

    A major limitation in current molecular docking method is that of failure to account for receptor flexibility. Herein we report multiple receptor conformers based molecular docking as a practical alternative to account for the receptor flexibility. Multiple (forty) conformers of Mycobacterium Enoyl ACP Reductase (InhA) are generated from Molecular Dynamics simulation and twenty crystallographic structures of InhA bound to different inhibitors are obtained from the Protein Data Bank. Fluorine directed modifications are performed to currently available anti-tuberculosis drug ethionamide. The modified drugs are optimized using B3LYP 6-31G (d,p) level of theory. Dipole moment, frontier orbital gap and thermodynamical properties such as electronic energy, enthalpy and Gibbs free energy of these optimized drugs are investigated. These drugs are subsequently docked against the conformers of InhA. Molecular docking against multiple InhA conformations show variation in ligand binding affinity and suggest that Ser94, Gly96, Lys165 and Ile194 amino acids play critical role on strong drug-InhA interaction. Modified drug N1 showed greater binding affinity compared to EN in most conformations. Structure of PDB ID: 2NSD and snapshot conformer at 5.5ns show most favorable binding with N1 compared to other conformers. Fluorine participates in forming fluorine bonds and contributes significantly in increasing binding affinity. Our study reveal that addition of trifluoromethyl group explicitly shows promise in improving thermodynamic properties and in enhancing hydrogen bonding and non-bonded interactions. Molecular dynamics (MD) simulation show that EN and N1 remained in the binding pocket similar to the docked pose of EN-InhA and E1-InhA complexes and also suggested that InhA binds to its inhibitor in inhibitor-induced folding manner. ADMET calculations predict modified drugs to have improved pharmacokinetic properties. Our study concludes that multiple receptor conformers based

  12. Exponential Repulsion Improves Structural Predictability of Molecular Docking

    Czech Academy of Sciences Publication Activity Database

    Bazgier, Václav; Berka, K.; Otyepka, M.; Banáš, P.

    2016-01-01

    Roč. 37, č. 28 (2016), s. 2485-2494 ISSN 0192-8651 Institutional support: RVO:61389030 Keywords : cyclin-dependent kinases * structure-based design * scoring functions * cdk2 inhibitors * force-field * ligand interactions * drug discovery * purine * potent * protein-kinase-2 * molecular docking * dock 6.6 * drug design * cyclin-dependent kinase 2 * directory of decoys Subject RIV: CF - Physical ; Theoretical Chemistry Impact factor: 3.229, year: 2016

  13. New generation of docking programs: Supercomputer validation of force fields and quantum-chemical methods for docking.

    Science.gov (United States)

    Sulimov, Alexey V; Kutov, Danil C; Katkova, Ekaterina V; Ilin, Ivan S; Sulimov, Vladimir B

    2017-11-01

    Discovery of new inhibitors of the protein associated with a given disease is the initial and most important stage of the whole process of the rational development of new pharmaceutical substances. New inhibitors block the active site of the target protein and the disease is cured. Computer-aided molecular modeling can considerably increase effectiveness of new inhibitors development. Reliable predictions of the target protein inhibition by a small molecule, ligand, is defined by the accuracy of docking programs. Such programs position a ligand in the target protein and estimate the protein-ligand binding energy. Positioning accuracy of modern docking programs is satisfactory. However, the accuracy of binding energy calculations is too low to predict good inhibitors. For effective application of docking programs to new inhibitors development the accuracy of binding energy calculations should be higher than 1kcal/mol. Reasons of limited accuracy of modern docking programs are discussed. One of the most important aspects limiting this accuracy is imperfection of protein-ligand energy calculations. Results of supercomputer validation of several force fields and quantum-chemical methods for docking are presented. The validation was performed by quasi-docking as follows. First, the low energy minima spectra of 16 protein-ligand complexes were found by exhaustive minima search in the MMFF94 force field. Second, energies of the lowest 8192 minima are recalculated with CHARMM force field and PM6-D3H4X and PM7 quantum-chemical methods for each complex. The analysis of minima energies reveals the docking positioning accuracies of the PM7 and PM6-D3H4X quantum-chemical methods and the CHARMM force field are close to one another and they are better than the positioning accuracy of the MMFF94 force field. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Using Variable-Length Aligned Fragment Pairs and an Improved Transition Function for Flexible Protein Structure Alignment.

    Science.gov (United States)

    Cao, Hu; Lu, Yonggang

    2017-01-01

    With the rapid growth of known protein 3D structures in number, how to efficiently compare protein structures becomes an essential and challenging problem in computational structural biology. At present, many protein structure alignment methods have been developed. Among all these methods, flexible structure alignment methods are shown to be superior to rigid structure alignment methods in identifying structure similarities between proteins, which have gone through conformational changes. It is also found that the methods based on aligned fragment pairs (AFPs) have a special advantage over other approaches in balancing global structure similarities and local structure similarities. Accordingly, we propose a new flexible protein structure alignment method based on variable-length AFPs. Compared with other methods, the proposed method possesses three main advantages. First, it is based on variable-length AFPs. The length of each AFP is separately determined to maximally represent a local similar structure fragment, which reduces the number of AFPs. Second, it uses local coordinate systems, which simplify the computation at each step of the expansion of AFPs during the AFP identification. Third, it decreases the number of twists by rewarding the situation where nonconsecutive AFPs share the same transformation in the alignment, which is realized by dynamic programming with an improved transition function. The experimental data show that compared with FlexProt, FATCAT, and FlexSnap, the proposed method can achieve comparable results by introducing fewer twists. Meanwhile, it can generate results similar to those of the FATCAT method in much less running time due to the reduced number of AFPs.

  15. Scleroglucan-borax hydrogel: a flexible tool for redox protein immobilization.

    Science.gov (United States)

    Frasconi, Marco; Rea, Sara; Matricardi, Pietro; Favero, Gabriele; Mazzei, Franco

    2009-09-15

    A highly stable biological film was prepared by casting an aqueous dispersion of protein and composite hydrogel obtained from the polysaccharide Scleroglucan (Sclg) and borax as a cross-linking agent. Heme proteins, such as hemoglobin (Hb), myoglobin (Mb), and horseradish peroxidase (HRP), were chosen as model proteins to investigate the immobilized system. A pair of well-defined quasi-reversible redox peaks, characteristics of the protein heme FeII/FeIII redox couples, were obtained at the Sclg-borax/proteins films on pyrolytic graphite (PG) electrodes, as a consequence of the direct electron transfer between the protein and the PG electrode. A full characterization of the electron transfer kinetic was performed by opportunely modeling data obtained from cyclic voltammetry and square wave voltammetry experiments. The efficiency of our cross-linking approach was investigated by studying the influence of different borax groups percentage in the Sclg matrix, revealing the versatility of this hydrogel in the immobilization of redox proteins. The native conformation of the three heme proteins entrapped in the hydrogel films were proved to be unchanged, reflected by the unaltered Soret adsorption band and by the catalytic activity toward hydrogen peroxide (H2O2). The main kinetic parameters, such as the apparent Michaelis-Menten constant, for the electrocatalytic reaction were also evaluated. The peculiar characteristics of Sclg-borax matrix make it possible to find wide opportunities as proteins immobilizing agent for studies of direct electrochemistry and biosensors development.

  16. Raf Kinase Inhibitory Protein Function Is Regulated via a Flexible Pocket and Novel Phosphorylation-Dependent Mechanism▿ †

    Science.gov (United States)

    Granovsky, Alexey E.; Clark, Matthew C.; McElheny, Dan; Heil, Gary; Hong, Jia; Liu, Xuedong; Kim, Youngchang; Joachimiak, Grazyna; Joachimiak, Andrzej; Koide, Shohei; Rosner, Marsha Rich

    2009-01-01

    Raf kinase inhibitory protein (RKIP/PEBP1), a member of the phosphatidylethanolamine binding protein family that possesses a conserved ligand-binding pocket, negatively regulates the mammalian mitogen-activated protein kinase (MAPK) signaling cascade. Mutation of a conserved site (P74L) within the pocket leads to a loss or switch in the function of yeast or plant RKIP homologues. However, the mechanism by which the pocket influences RKIP function is unknown. Here we show that the pocket integrates two regulatory signals, phosphorylation and ligand binding, to control RKIP inhibition of Raf-1. RKIP association with Raf-1 is prevented by RKIP phosphorylation at S153. The P74L mutation increases kinase interaction and RKIP phosphorylation, enhancing Raf-1/MAPK signaling. Conversely, ligand binding to the RKIP pocket inhibits kinase interaction and RKIP phosphorylation by a noncompetitive mechanism. Additionally, ligand binding blocks RKIP association with Raf-1. Nuclear magnetic resonance studies reveal that the pocket is highly dynamic, rationalizing its capacity to interact with distinct partners and be involved in allosteric regulation. Our results show that RKIP uses a flexible pocket to integrate ligand binding- and phosphorylation-dependent interactions and to modulate the MAPK signaling pathway. This mechanism is an example of an emerging theme involving the regulation of signaling proteins and their interaction with effectors at the level of protein dynamics. PMID:19103740

  17. Raf kinase inhibitory protein function is regulated via a flexible pocket and novel phosphorylation-dependent mechanism.

    Science.gov (United States)

    Granovsky, Alexey E; Clark, Matthew C; McElheny, Dan; Heil, Gary; Hong, Jia; Liu, Xuedong; Kim, Youngchang; Joachimiak, Grazyna; Joachimiak, Andrzej; Koide, Shohei; Rosner, Marsha Rich

    2009-03-01

    Raf kinase inhibitory protein (RKIP/PEBP1), a member of the phosphatidylethanolamine binding protein family that possesses a conserved ligand-binding pocket, negatively regulates the mammalian mitogen-activated protein kinase (MAPK) signaling cascade. Mutation of a conserved site (P74L) within the pocket leads to a loss or switch in the function of yeast or plant RKIP homologues. However, the mechanism by which the pocket influences RKIP function is unknown. Here we show that the pocket integrates two regulatory signals, phosphorylation and ligand binding, to control RKIP inhibition of Raf-1. RKIP association with Raf-1 is prevented by RKIP phosphorylation at S153. The P74L mutation increases kinase interaction and RKIP phosphorylation, enhancing Raf-1/MAPK signaling. Conversely, ligand binding to the RKIP pocket inhibits kinase interaction and RKIP phosphorylation by a noncompetitive mechanism. Additionally, ligand binding blocks RKIP association with Raf-1. Nuclear magnetic resonance studies reveal that the pocket is highly dynamic, rationalizing its capacity to interact with distinct partners and be involved in allosteric regulation. Our results show that RKIP uses a flexible pocket to integrate ligand binding- and phosphorylation-dependent interactions and to modulate the MAPK signaling pathway. This mechanism is an example of an emerging theme involving the regulation of signaling proteins and their interaction with effectors at the level of protein dynamics.

  18. Remote docking apparatus

    International Nuclear Information System (INIS)

    Dent, T.H.; Sumpman, W.C.; Wilhelm, J.J.

    1981-01-01

    The remote docking apparatus comprises a support plate with locking devices mounted thereon. The locking devices are capable of being inserted into tubular members for suspending the support plate therefrom. A vertical member is attached to the support plate with an attachment mechanism attached to the vertical member. A remote access manipulator is capable of being attached to the attachment mechanism so that the vertical member can position the remote access manipulator so that the remote access manipulator can be initially attached to the tubular members in a well defined manner

  19. Molecular dynamics modeling the synthetic and biological polymers interactions pre-studied via docking: anchors modified polyanions interference with the HIV-1 fusion mediator.

    Science.gov (United States)

    Tsvetkov, Vladimir B; Serbin, Alexander V

    2014-06-01

    In previous works we reported the design, synthesis and in vitro evaluations of synthetic anionic polymers modified by alicyclic pendant groups (hydrophobic anchors), as a novel class of inhibitors of the human immunodeficiency virus type 1 (HIV-1) entry into human cells. Recently, these synthetic polymers interactions with key mediator of HIV-1 entry-fusion, the tri-helix core of the first heptad repeat regions [HR1]3 of viral envelope protein gp41, were pre-studied via docking in terms of newly formulated algorithm for stepwise approximation from fragments of polymeric backbone and side-group models toward real polymeric chains. In the present article the docking results were verified under molecular dynamics (MD) modeling. In contrast with limited capabilities of the docking, the MD allowed of using much more large models of the polymeric ligands, considering flexibility of both ligand and target simultaneously. Among the synthesized polymers the dinorbornen anchors containing alternating copolymers of maleic acid were selected as the most representative ligands (possessing the top anti-HIV activity in vitro in correlation with the highest binding energy in the docking). To verify the probability of binding of the polymers with the [HR1]3 in the sites defined via docking, various starting positions of polymer chains were tried. The MD simulations confirmed the main docking-predicted priority for binding sites, and possibilities for axial and belting modes of the ligands-target interactions. Some newly MD-discovered aspects of the ligand's backbone and anchor units dynamic cooperation in binding the viral target clarify mechanisms of the synthetic polymers anti-HIV activity and drug resistance prevention.

  20. Role of the vaccinia virus O3 protein in cell entry can be fulfilled by its Sequence flexible transmembrane domain

    Energy Technology Data Exchange (ETDEWEB)

    Satheshkumar, P.S.; Chavre, James; Moss, Bernard, E-mail: bmoss@nih.gov

    2013-09-15

    The vaccinia virus O3 protein, a component of the entry–fusion complex, is encoded by all chordopoxviruses. We constructed truncation mutants and demonstrated that the transmembrane domain, which comprises two-thirds of this 35 amino acid protein, is necessary and sufficient for interaction with the entry–fusion complex and function in cell entry. Nevertheless, neither single amino acid substitutions nor alanine scanning mutagenesis revealed essential amino acids within the transmembrane domain. Moreover, replication-competent mutant viruses were generated by randomization of 10 amino acids of the transmembrane domain. Of eight unique viruses, two contained only two amino acids in common with wild type and the remainder contained one or none within the randomized sequence. Although these mutant viruses formed normal size plaques, the entry–fusion complex did not co-purify with the mutant O3 proteins suggesting a less stable interaction. Thus, despite low specific sequence requirements, the transmembrane domain is sufficient for function in entry. - Highlights: • The 35 amino acid O3 protein is required for efficient vaccinia virus entry. • The transmembrane domain of O3 is necessary and sufficient for entry. • Mutagenesis demonstrated extreme sequence flexibility compatible with function.

  1. The crystal structure of the Dachshund domain of human SnoN reveals flexibility in the putative protein interaction surface.

    Directory of Open Access Journals (Sweden)

    Tomas Nyman

    2010-09-01

    Full Text Available The human SnoN is an oncoprotein that interacts with several transcription-regulatory proteins such as the histone-deacetylase, N-CoR containing co-repressor complex and Smad proteins. This study presents the crystal structure of the Dachshund homology domain of human SnoN. The structure reveals a groove composed of conserved residues with characteristic properties of a protein-interaction surface. A comparison of the 12 monomers in the asymmetric unit reveals the presence of two major conformations: an open conformation with a well accessible groove and a tight conformation with a less accessible groove. The variability in the backbone between the open and the tight conformations matches the differences seen in previously determined structures of individual Dachshund homology domains, suggesting a general plasticity within this fold family. The flexibility observed in the putative protein binding groove may enable SnoN to recognize multiple interaction partners.This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available in Text S1.

  2. The Role of Conformational Flexibility on Protein Supercharging in Native Electrospray Ionization

    Science.gov (United States)

    Sterling, Harry J.; Cassou, Catherine A.; Trnka, Michael J.; Burlingame, A. L.; Krantz, Bryan A.; Williams, Evan R.

    2012-01-01

    Effects of covalent intramolecular bonds, either native disulfide bridges or chemical crosslinks, on ESI supercharging of proteins from aqueous solutions were investigated. Chemically modifying cytochrome c with up to seven crosslinks or ubiquitin with up to two crosslinks did not affect the average or maximum charge states of these proteins in the absence of m-nitrobenzyl alcohol (m-NBA), but the extent of supercharging induced by m-NBA increased with decreasing numbers of crosslinks. For the model random coil polypeptide reduced/alkylated RNase A, a decrease in charging with increasing m-NBA concentration attributable to reduced surface tension of the ESI droplet was observed, whereas native RNase A electrosprayed from these same solutions exhibited enhanced charging. The inverse relationship between the extent of supercharging and the number of intramolecular crosslinks for folded proteins, as well as the absence of supercharging for proteins that are random coils in aqueous solution, indicate that conformational restrictions induced by the crosslinks reduce the extent of supercharging. These results provide additional evidence that protein and protein complex supercharging from aqueous solution is primarily due to partial or significant unfolding that occurs as a result of chemical and/or thermal denaturation induced by the supercharging reagent late in the ESI droplet lifetime. PMID:21399817

  3. Prediction of mutational tolerance in HIV-1 protease and reverse transcriptase using flexible backbone protein design.

    Directory of Open Access Journals (Sweden)

    Elisabeth Humphris-Narayanan

    Full Text Available Predicting which mutations proteins tolerate while maintaining their structure and function has important applications for modeling fundamental properties of proteins and their evolution; it also drives progress in protein design. Here we develop a computational model to predict the tolerated sequence space of HIV-1 protease reachable by single mutations. We assess the model by comparison to the observed variability in more than 50,000 HIV-1 protease sequences, one of the most comprehensive datasets on tolerated sequence space. We then extend the model to a second protein, reverse transcriptase. The model integrates multiple structural and functional constraints acting on a protein and uses ensembles of protein conformations. We find the model correctly captures a considerable fraction of protease and reverse-transcriptase mutational tolerance and shows comparable accuracy using either experimentally determined or computationally generated structural ensembles. Predictions of tolerated sequence space afforded by the model provide insights into stability-function tradeoffs in the emergence of resistance mutations and into strengths and limitations of the computational model.

  4. Coumarin derivatives bearing benzoheterocycle moiety: synthesis, cholinesterase inhibitory, and docking simulation study

    Directory of Open Access Journals (Sweden)

    Kimia Hirbod

    2017-06-01

    Full Text Available Objective(s: To investigate the efficiency of a novel series of coumarin derivatives bearing benzoheterocycle moiety as novel cholinesterase inhibitors. Materials and Methods: Different 7-hydroxycoumarin derivatives were synthesized via Pechmann or Knoevenagel condensation and conjugated to different benzoheterocycle (8-hydroxyquinoline, 2-mercaptobenzoxazole or 2-mercaptobenzimidazole using dibromoalkanes 3a-m. Final compounds were evaluated against acetylcholinesterase (AChE and butyrylcholinesterase (BuChE by Ellman's method. Kinetic study of AChE inhibition and ligand-protein docking simulation were also carried out for the most potent compound 3b. Results: Some of the compounds revealed potent and selective activity against AChE. Compound 3b containing the quinoline group showed the best activity with an IC50 value of 8.80 µM against AChE. Kinetic study of AChE inhibition revealed the mixed-type inhibition of the enzyme by compound 3b. Ligand-protein docking simulation also showed that the flexibility of the hydrophobic five carbons linker allows the quinoline ring to form π-π interaction with Trp279 in the PAS. Conclusion: We suggest these synthesized compounds could become potential leads for AChE inhibition and prevention of AD symptoms.

  5. Space Shuttle Program (SSP) Dual Docked Operations (DDO)

    Science.gov (United States)

    Sills, Joel W., Jr.; Bruno, Erica E.

    2016-01-01

    This document describes the concept definition, studies, and analysis results generated by the Space Shuttle Program (SSP), International Space Station (ISS) Program (ISSP), and Mission Operations Directorate for implementing Dual Docked Operations (DDO) during mated Orbiter/ISS missions. This work was performed over a number of years. Due to the ever increasing visiting vehicle traffic to and from the ISS, it became apparent to both the ISSP and the SSP that there would arise occasions where conflicts between a visiting vehicle docking and/or undocking could overlap with a planned Space Shuttle launch and/or during docked operations. This potential conflict provided the genesis for evaluating risk mitigations to gain maximum flexibility for managing potential visiting vehicle traffic to and from the ISS and to maximize launch and landing opportunities for all visiting vehicles.

  6. Insights into regioselective metabolism of mefenamic acid by cytochrome P450 BM3 mutants through crystallography, docking, molecular dynamics, and free energy calculations

    DEFF Research Database (Denmark)

    Capoferri, Luigi; Leth, Rasmus; Ter Haar, Ernst

    2016-01-01

    of the protein mutant M11 was expressed, purified, and crystallized, and its X-ray structure was used as template for modeling. A multistep approach was used that combines molecular docking, molecular dynamics (MD) simulation, and binding free-energy calculations to address protein flexibility. In this way...... active-site mutations such as V87I were reported to invert regioselectivity in NSAID hydroxylation. In this work, we combine crystallography and molecular simulation to study the effect of single mutations on binding and regioselective metabolism of mefenamic acid by M11 mutants. The heme domain...... of mefenamic acid by M11 and its mutants by including protein flexibility and dynamics in free-energy computation. In addition, we could obtain structural insights into the change in regioselectivity of mefenamic acid hydroxylation due to single active-site mutations. Our findings confirm that use of MD...

  7. Evidence supporting a role for astrocytes in the regulation of cognitive flexibility and neuronal oscillations through the Ca2+ binding protein S100β.

    Science.gov (United States)

    Brockett, Adam T; Kane, Gary A; Monari, Patrick K; Briones, Brandy A; Vigneron, Pierre-Antoine; Barber, Gabriela A; Bermudez, Andres; Dieffenbach, Uma; Kloth, Alexander D; Buschman, Timothy J; Gould, Elizabeth

    2018-01-01

    The medial prefrontal cortex (mPFC) is important for cognitive flexibility, the ability to switch between two task-relevant dimensions. Changes in neuronal oscillations and alterations in the coupling across frequency ranges have been correlated with attention and cognitive flexibility. Here we show that astrocytes in the mPFC of adult male Sprague Dawley rats, participate in cognitive flexibility through the astrocyte-specific Ca2+ binding protein S100β, which improves cognitive flexibility and increases phase amplitude coupling between theta and gamma oscillations. We further show that reduction of astrocyte number in the mPFC impairs cognitive flexibility and diminishes delta, alpha and gamma power. Conversely, chemogenetic activation of astrocytic intracellular Ca2+ signaling in the mPFC enhances cognitive flexibility, while inactivation of endogenous S100β among chemogenetically activated astrocytes in the mPFC prevents this improvement. Collectively, our work suggests that astrocytes make important contributions to cognitive flexibility and that they do so by releasing a Ca2+ binding protein which in turn enhances coordinated neuronal oscillations.

  8. The Fanconi anemia gene product FANCF is a flexible adaptor protein.

    NARCIS (Netherlands)

    Leveille, F.; Blom, E.; Medhurst, A.L. dr.; Bier, P; Laghmani, elH; Johnson, M.; Rooimans, M.A.; Sobeck, A; Waisfisz, Q.; Arwert, F.; Patel, KJ; Hoatlin, M.E.; Joenje, H.; Winter, de J.P.

    2004-01-01

    The Fanconi anemia (FA) protein FANCF is an essential component of a nuclear core complex that protects the genome against chromosomal instability, but the specific function of FANCF is still poorly understood. Based upon the homology between human and Xenopus laevis FANCF, we carried out an

  9. Flexible method for fabricating protein patterns on superhydrophobic platforms controlled by magnetic field.

    Science.gov (United States)

    Wang, Jian; Li, Hao; Zou, Haoyang; Wang, Chenmiao; Zhang, Hao; Mano, João F; Song, Wenlong

    2017-02-28

    Inspired by the rolling of water droplets on lotus leaves, we developed a novel, magnetic field-controlled patterning method for water-soluble proteins and other functional materials on superhydrophobic platforms. This simple method can be used to fabricate biochips and open micro-fluidic devices in a simple way.

  10. Water molecule network and active site flexibility of apo protein tyrosine phosphatase 1B

    DEFF Research Database (Denmark)

    Pedersen, A.K.; Peters, Günther H.J.; Møller, K.B.

    2004-01-01

    Protein tyrosine phosphatase 1B (PTP1B) plays a key role as a negative regulator of insulin and leptin signalling and is therefore considered to be an important molecular target for the treatment of type 2 diabetes and obesity. Detailed structural information about the structure of PTP1B, including...

  11. Improving Docking Performance Using Negative Image-Based Rescoring.

    Science.gov (United States)

    Kurkinen, Sami T; Niinivehmas, Sanna; Ahinko, Mira; Lätti, Sakari; Pentikäinen, Olli T; Postila, Pekka A

    2018-01-01

    Despite the large computational costs of molecular docking, the default scoring functions are often unable to recognize the active hits from the inactive molecules in large-scale virtual screening experiments. Thus, even though a correct binding pose might be sampled during the docking, the active compound or its biologically relevant pose is not necessarily given high enough score to arouse the attention. Various rescoring and post-processing approaches have emerged for improving the docking performance. Here, it is shown that the very early enrichment (number of actives scored higher than 1% of the highest ranked decoys) can be improved on average 2.5-fold or even 8.7-fold by comparing the docking-based ligand conformers directly against the target protein's cavity shape and electrostatics. The similarity comparison of the conformers is performed without geometry optimization against the negative image of the target protein's ligand-binding cavity using the negative image-based (NIB) screening protocol. The viability of the NIB rescoring or the R-NiB, pioneered in this study, was tested with 11 target proteins using benchmark libraries. By focusing on the shape/electrostatics complementarity of the ligand-receptor association, the R-NiB is able to improve the early enrichment of docking essentially without adding to the computing cost. By implementing consensus scoring, in which the R-NiB and the original docking scoring are weighted for optimal outcome, the early enrichment is improved to a level that facilitates effective drug discovery. Moreover, the use of equal weight from the original docking scoring and the R-NiB scoring improves the yield in most cases.

  12. Clustering Molecular Dynamics Trajectories for Optimizing Docking Experiments

    Directory of Open Access Journals (Sweden)

    Renata De Paris

    2015-01-01

    Full Text Available Molecular dynamics simulations of protein receptors have become an attractive tool for rational drug discovery. However, the high computational cost of employing molecular dynamics trajectories in virtual screening of large repositories threats the feasibility of this task. Computational intelligence techniques have been applied in this context, with the ultimate goal of reducing the overall computational cost so the task can become feasible. Particularly, clustering algorithms have been widely used as a means to reduce the dimensionality of molecular dynamics trajectories. In this paper, we develop a novel methodology for clustering entire trajectories using structural features from the substrate-binding cavity of the receptor in order to optimize docking experiments on a cloud-based environment. The resulting partition was selected based on three clustering validity criteria, and it was further validated by analyzing the interactions between 20 ligands and a fully flexible receptor (FFR model containing a 20 ns molecular dynamics simulation trajectory. Our proposed methodology shows that taking into account features of the substrate-binding cavity as input for the k-means algorithm is a promising technique for accurately selecting ensembles of representative structures tailored to a specific ligand.

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

    Science.gov (United States)

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

    2011-04-12

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

  14. Correlated motion of protein subdomains and large-scale conformational flexibility of RecA protein filament

    Science.gov (United States)

    Yu, Garmay; A, Shvetsov; D, Karelov; D, Lebedev; A, Radulescu; M, Petukhov; V, Isaev-Ivanov

    2012-02-01

    Based on X-ray crystallographic data available at Protein Data Bank, we have built molecular dynamics (MD) models of homologous recombinases RecA from E. coli and D. radiodurans. Functional form of RecA enzyme, which is known to be a long helical filament, was approximated by a trimer, simulated in periodic water box. The MD trajectories were analyzed in terms of large-scale conformational motions that could be detectable by neutron and X-ray scattering techniques. The analysis revealed that large-scale RecA monomer dynamics can be described in terms of relative motions of 7 subdomains. Motion of C-terminal domain was the major contributor to the overall dynamics of protein. Principal component analysis (PCA) of the MD trajectories in the atom coordinate space showed that rotation of C-domain is correlated with the conformational changes in the central domain and N-terminal domain, that forms the monomer-monomer interface. Thus, even though C-terminal domain is relatively far from the interface, its orientation is correlated with large-scale filament conformation. PCA of the trajectories in the main chain dihedral angle coordinate space implicates a co-existence of a several different large-scale conformations of the modeled trimer. In order to clarify the relationship of independent domain orientation with large-scale filament conformation, we have performed analysis of independent domain motion and its implications on the filament geometry.

  15. Downstream of tyrosine kinase/docking protein 6, as a novel substrate of tropomyosin-related kinase C receptor, is involved in neurotrophin 3-mediated neurite outgrowth in mouse cortex neurons

    Directory of Open Access Journals (Sweden)

    Yuan Jian

    2010-06-01

    Full Text Available Abstract Background The downstream of tyrosine kinase/docking protein (Dok adaptor protein family has seven members, Dok1 to Dok7, that act as substrates of multiple receptor tyrosine kinase and non-receptor tyrosine kinase. The tropomyosin-related kinase (Trk receptor family, which has three members (TrkA, TrkB and TrkC, are receptor tyrosine kinases that play pivotal roles in many stages of nervous system development, such as differentiation, migration, axon and dendrite projection and neuron patterning. Upon related neurotrophin growth factor stimulation, dimerisation and autophosphorylation of Trk receptors can occur, recruiting adaptor proteins to mediate signal transduction. Results In this report, by using yeast two-hybrid assays, glutathione S-transferase (GST precipitation assays and coimmunoprecipitation (Co-IP experiments, we demonstrate that Dok6 selectively binds to the NPQY motif of TrkC through its phosphotyrosine-binding (PTB domain in a kinase activity-dependent manner. We further confirmed their interaction by coimmunoprecipitation and colocalisation in E18.5 mouse cortex neurons, which provided more in vivo evidence. Next, we demonstrated that Dok6 is involved in neurite outgrowth in mouse cortex neurons via the RNAi method. Knockdown of Dok6 decreased neurite outgrowth in cortical neurons upon neurotrophin 3 (NT-3 stimulation. Conclusions We conclude that Dok6 interacts with the NPQY motif of the TrkC receptor through its PTB domain in a kinase activity-dependent manner, and works as a novel substrate of the TrkC receptor involved in NT-3-mediated neurite outgrowth in mouse cortex neurons.

  16. Eps15R is a tyrosine kinase substrate with characteristics of a docking protein possibly involved in coated pits-mediated internalization

    DEFF Research Database (Denmark)

    Coda, L; Salcini, A E; Confalonieri, S

    1998-01-01

    in NIH-3T3 cells overexpressing the receptor, even at low levels of receptor occupancy, thus behaving as physiological substrates. A role for eps15R in clathrin-mediated endocytosis is suggested by its localization in plasma membrane-coated pits and in vivo association to the coated pits' adapter protein...... AP-2. Finally, we demonstrate that a sizable fraction of eps15R exists in the cell as a complex with eps15 and that its EH domains exhibit binding specificities that are partially distinct from those of eps15. We propose that eps15 and eps15R are multifunctional binding proteins that serve...

  17. Flexible segments modulate co-folding of dUTPase and nucleocapsid proteins

    Czech Academy of Sciences Publication Activity Database

    Németh-Pongrácz, V.; Barabás, O.; Fuxreiter, M.; Simon, I.; Pichová, Iva; Rumlová, Michaela; Zábranská, Helena; Svergun, D.; Petoukhov, M.; Harmat, V.; Klement, E.; Hunyadi-Gulyás, E.; Medzihradszky, K. F.; Kónya, E.; Vértessy, B. G.

    2007-01-01

    Roč. 35, č. 2 (2007), s. 495-505 ISSN 0305-1048 R&D Projects: GA MŠk 1M0508 Grant - others:6th Framework Programme(XE) LSHC-CT-2005-012127 Institutional research plan: CEZ:AV0Z40550506 Source of funding: R - rámcový projekt EK Keywords : dUTPase * Mason-Pfizer monkey virus * structure * fusion protein NC-dUTPase Subject RIV: CE - Biochemistry Impact factor: 6.954, year: 2007

  18. Structural insights into the evolution of a sexy protein: novel topology and restricted backbone flexibility in a hypervariable pheromone from the red-legged salamander, Plethodon shermani.

    Science.gov (United States)

    Wilburn, Damien B; Bowen, Kathleen E; Doty, Kari A; Arumugam, Sengodagounder; Lane, Andrew N; Feldhoff, Pamela W; Feldhoff, Richard C

    2014-01-01

    In response to pervasive sexual selection, protein sex pheromones often display rapid mutation and accelerated evolution of corresponding gene sequences. For proteins, the general dogma is that structure is maintained even as sequence or function may rapidly change. This phenomenon is well exemplified by the three-finger protein (TFP) superfamily: a diverse class of vertebrate proteins co-opted for many biological functions - such as components of snake venoms, regulators of the complement system, and coordinators of amphibian limb regeneration. All of the >200 structurally characterized TFPs adopt the namesake "three-finger" topology. In male red-legged salamanders, the TFP pheromone Plethodontid Modulating Factor (PMF) is a hypervariable protein such that, through extensive gene duplication and pervasive sexual selection, individual male salamanders express more than 30 unique isoforms. However, it remained unclear how this accelerated evolution affected the protein structure of PMF. Using LC/MS-MS and multidimensional NMR, we report the 3D structure of the most abundant PMF isoform, PMF-G. The high resolution structural ensemble revealed a highly modified TFP structure, including a unique disulfide bonding pattern and loss of secondary structure, that define a novel protein topology with greater backbone flexibility in the third peptide finger. Sequence comparison, models of molecular evolution, and homology modeling together support that this flexible third finger is the most rapidly evolving segment of PMF. Combined with PMF sequence hypervariability, this structural flexibility may enhance the plasticity of PMF as a chemical signal by permitting potentially thousands of structural conformers. We propose that the flexible third finger plays a critical role in PMF:receptor interactions. As female receptors co-evolve, this flexibility may allow PMF to still bind its receptor(s) without the immediate need for complementary mutations. Consequently, this unique

  19. Structural insights into the evolution of a sexy protein: novel topology and restricted backbone flexibility in a hypervariable pheromone from the red-legged salamander, Plethodon shermani.

    Directory of Open Access Journals (Sweden)

    Damien B Wilburn

    Full Text Available In response to pervasive sexual selection, protein sex pheromones often display rapid mutation and accelerated evolution of corresponding gene sequences. For proteins, the general dogma is that structure is maintained even as sequence or function may rapidly change. This phenomenon is well exemplified by the three-finger protein (TFP superfamily: a diverse class of vertebrate proteins co-opted for many biological functions - such as components of snake venoms, regulators of the complement system, and coordinators of amphibian limb regeneration. All of the >200 structurally characterized TFPs adopt the namesake "three-finger" topology. In male red-legged salamanders, the TFP pheromone Plethodontid Modulating Factor (PMF is a hypervariable protein such that, through extensive gene duplication and pervasive sexual selection, individual male salamanders express more than 30 unique isoforms. However, it remained unclear how this accelerated evolution affected the protein structure of PMF. Using LC/MS-MS and multidimensional NMR, we report the 3D structure of the most abundant PMF isoform, PMF-G. The high resolution structural ensemble revealed a highly modified TFP structure, including a unique disulfide bonding pattern and loss of secondary structure, that define a novel protein topology with greater backbone flexibility in the third peptide finger. Sequence comparison, models of molecular evolution, and homology modeling together support that this flexible third finger is the most rapidly evolving segment of PMF. Combined with PMF sequence hypervariability, this structural flexibility may enhance the plasticity of PMF as a chemical signal by permitting potentially thousands of structural conformers. We propose that the flexible third finger plays a critical role in PMF:receptor interactions. As female receptors co-evolve, this flexibility may allow PMF to still bind its receptor(s without the immediate need for complementary mutations. Consequently

  20. Biallelic loss-of-function variants in DOCK3 cause muscle hypotonia, ataxia, and intellectual disability.

    Science.gov (United States)

    Helbig, K L; Mroske, C; Moorthy, D; Sajan, S A; Velinov, M

    2017-10-01

    DOCK3 encodes the dedicator of cytokinesis 3 protein, a member of the DOCK180 family of proteins that are characterized by guanine-nucleotide exchange factor activity. DOCK3 is expressed exclusively in the central nervous system and plays an important role in axonal outgrowth and cytoskeleton reorganization. Dock3 knockout mice exhibit motor deficiencies with abnormal ataxic gait and impaired learning. We report 2 siblings with biallelic loss-of-function variants in DOCK3. Diagnostic whole-exome sequencing (WES) and chromosomal microarray were performed on a proband with severe developmental disability, hypotonia, and ataxic gait. Testing was also performed on the proband's similarly affected brother. A paternally inherited 458 kb deletion in chromosomal region 3p21.2 disrupting the DOCK3 gene was identified in both affected siblings. WES identified a nonsense variant c.382C>G (p.Gln128*) in the DOCK3 gene (NM_004947) on the maternal allele in both siblings. Common features in both affected individuals include severe developmental disability, ataxic gait, and severe hypotonia, which recapitulates the Dock3 knockout mouse phenotype. We show that complete DOCK3 deficiency in humans leads to developmental disability with significant hypotonia and gait ataxia, probably due to abnormal axonal development. © 2017 The Authors. Clinical Genetics published by John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  1. Aromatic interactions impact ligand binding and function at serotonin 5-HT2C G protein-coupled receptors: receptor homology modelling, ligand docking, and molecular dynamics results validated by experimental studies

    Science.gov (United States)

    Córdova-Sintjago, Tania; Villa, Nancy; Fang, Lijuan; Booth, Raymond G.

    2014-02-01

    The serotonin (5-hydroxytryptamine, 5-HT) 5-HT2 G protein-coupled receptor (GPCR) family consists of types 2A, 2B, and 2C that share ∼75% transmembrane (TM) sequence identity. Agonists for 5-HT2C receptors are under development for psychoses; whereas, at 5-HT2A receptors, antipsychotic effects are associated with antagonists - in fact, 5-HT2A agonists can cause hallucinations and 5-HT2B agonists cause cardiotoxicity. It is known that 5-HT2A TM6 residues W6.48, F6.51, and F6.52 impact ligand binding and function; however, ligand interactions with these residues at the 5-HT2C receptor have not been reported. To predict and validate molecular determinants for 5-HT2C-specific activation, results from receptor homology modelling, ligand docking, and molecular dynamics simulation studies were compared with experimental results for ligand binding and function at wild type and W6.48A, F6.51A, and F6.52A point-mutated 5-HT2C receptors.

  2. Autonomous spacecraft rendezvous and docking

    Science.gov (United States)

    Tietz, J. C.; Almand, B. J.

    A storyboard display is presented which summarizes work done recently in design and simulation of autonomous video rendezvous and docking systems for spacecraft. This display includes: photographs of the simulation hardware, plots of chase vehicle trajectories from simulations, pictures of the docking aid including image processing interpretations, and drawings of the control system strategy. Viewgraph-style sheets on the display bulletin board summarize the simulation objectives, benefits, special considerations, approach, and results.

  3. Neurodegeneration and unfolded-protein response in mice expressing a membrane-tethered flexible tail of PrP.

    Directory of Open Access Journals (Sweden)

    Paolo Dametto

    Full Text Available The cellular prion protein (PrPC consists of a flexible N-terminal tail (FT, aa 23-128 hinged to a membrane-anchored globular domain (GD, aa 129-231. Ligation of the GD with antibodies induces rapid neurodegeneration, which is prevented by deletion or functional inactivation of the FT. Therefore, the FT is an allosteric effector of neurotoxicity. To explore its mechanism of action, we generated transgenic mice expressing the FT fused to a GPI anchor, but lacking the GD (PrPΔ141-225, or "FTgpi". Here we report that FTgpi mice develop a progressive, inexorably lethal neurodegeneration morphologically and biochemically similar to that triggered by anti-GD antibodies. FTgpi was mostly retained in the endoplasmic reticulum, where it triggered a conspicuous unfolded protein response specifically activating the PERK pathway leading to phosphorylation of eIF2α and upregulation of CHOP ultimately leading to neurodegeration similar to what was observed in prion infection.

  4. Crystal structure and conformational flexibility of the unligated FK506-binding protein FKBP12.6

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Hui; Mustafi, Sourajit M. [New York State Department of Health, Empire State Plaza, Albany, NY 12201 (United States); LeMaster, David M. [New York State Department of Health, Empire State Plaza, Albany, NY 12201 (United States); University at Albany – SUNY, Empire State Plaza, Albany, NY 12201 (United States); Li, Zhong [New York State Department of Health, Empire State Plaza, Albany, NY 12201 (United States); Héroux, Annie [Brookhaven National Laboratory, Upton, NY 11973 (United States); Li, Hongmin; Hernández, Griselda, E-mail: griselda@wadsworth.org [New York State Department of Health, Empire State Plaza, Albany, NY 12201 (United States); University at Albany – SUNY, Empire State Plaza, Albany, NY 12201 (United States)

    2014-03-01

    Two crystal forms of unligated FKBP12.6 exhibit multiple conformations in the active site and in the 80s loop, the primary site for known protein-recognition interactions. The previously unreported NMR backbone assignment of FKBP12.6 revealed extensive doubling of amide resonances, which reflects a slow conformational transition centered in the 80s loop. The primary known physiological function of FKBP12.6 involves its role in regulating the RyR2 isoform of ryanodine receptor Ca{sup 2+} channels in cardiac muscle, pancreatic β islets and the central nervous system. With only a single previously reported X-ray structure of FKBP12.6, bound to the immunosuppressant rapamycin, structural inferences for this protein have been drawn from the more extensive studies of the homologous FKBP12. X-ray structures at 1.70 and 1.90 Å resolution from P2{sub 1} and P3{sub 1}21 crystal forms are reported for an unligated cysteine-free variant of FKBP12.6 which exhibit a notable diversity of conformations. In one monomer from the P3{sub 1}21 crystal form, the aromatic ring of Phe59 at the base of the active site is rotated perpendicular to its typical orientation, generating a steric conflict for the immunosuppressant-binding mode. The peptide unit linking Gly89 and Val90 at the tip of the protein-recognition ‘80s loop’ is flipped in the P2{sub 1} crystal form. Unlike the >30 reported FKBP12 structures, the backbone conformation of this loop closely follows that of the first FKBP domain of FKBP51. The NMR resonances for 21 backbone amides of FKBP12.6 are doubled, corresponding to a slow conformational transition centered near the tip of the 80s loop, as recently reported for 31 amides of FKBP12. The comparative absence of doubling for residues along the opposite face of the active-site pocket in FKBP12.6 may in part reflect attenuated structural coupling owing to increased conformational plasticity around the Phe59 ring.

  5. Molecular interactions of agonist and inverse agonist ligands at serotonin 5-HT2C G protein-coupled receptors: computational ligand docking and molecular dynamics studies validated by experimental mutagenesis results

    Science.gov (United States)

    Córdova-Sintjago, Tania C.; Liu, Yue; Booth, Raymond G.

    2015-02-01

    To understand molecular determinants for ligand activation of the serotonin 5-HT2C G protein-coupled receptor (GPCR), a drug target for obesity and neuropsychiatric disorders, a 5-HT2C homology model was built according to an adrenergic β2 GPCR (β2AR) structure and validated using a 5-HT2B GPCR crystal structure. The models were equilibrated in a simulated phosphatidyl choline membrane for ligand docking and molecular dynamics studies. Ligands included (2S, 4R)-(-)-trans-4-(3'-bromo- and trifluoro-phenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalene-2-amine (3'-Br-PAT and 3'-CF3-PAT), a 5-HT2C agonist and inverse agonist, respectively. Distinct interactions of 3'-Br-PAT and 3'-CF3-PAT at the wild-type (WT) 5-HT2C receptor model were observed and experimental 5-HT2C receptor mutagenesis studies were undertaken to validate the modelling results. For example, the inverse agonist 3'-CF3-PAT docked deeper in the WT 5-HT2C binding pocket and altered the orientation of transmembrane helices (TM) 6 in comparison to the agonist 3'-Br-PAT, suggesting that changes in TM orientation that result from ligand binding impact function. For both PATs, mutation of 5-HT2C residues S3.36, T3.37, and F5.47 to alanine resulted in significantly decreased affinity, as predicted from modelling results. It was concluded that upon PAT binding, 5-HT2C residues T3.37 and F5.47 in TMs 3 and 5, respectively, engage in inter-helical interactions with TMs 4 and 6, respectively. The movement of TMs 5 and 6 upon agonist and inverse agonist ligand binding observed in the 5-HT2C receptor modelling studies was similar to movements reported for the activation and deactivation of the β2AR, suggesting common mechanisms among aminergic neurotransmitter GPCRs.

  6. Virtual screening with AutoDock Vina and the common pharmacophore engine of a low diversity library of fragments and hits against the three allosteric sites of HIV integrase: participation in the SAMPL4 protein-ligand binding challenge.

    Science.gov (United States)

    Perryman, Alexander L; Santiago, Daniel N; Forli, Stefano; Martins, Diogo Santos; Olson, Arthur J

    2014-04-01

    To rigorously assess the tools and protocols that can be used to understand and predict macromolecular recognition, and to gain more structural insight into three newly discovered allosteric binding sites on a critical drug target involved in the treatment of HIV infections, the Olson and Levy labs collaborated on the SAMPL4 challenge. This computational blind challenge involved predicting protein-ligand binding against the three allosteric sites of HIV integrase (IN), a viral enzyme for which two drugs (that target the active site) have been approved by the FDA. Positive control cross-docking experiments were utilized to select 13 receptor models out of an initial ensemble of 41 different crystal structures of HIV IN. These 13 models of the targets were selected using our new "Rank Difference Ratio" metric. The first stage of SAMPL4 involved using virtual screens to identify 62 active, allosteric IN inhibitors out of a set of 321 compounds. The second stage involved predicting the binding site(s) and crystallographic binding mode(s) for 57 of these inhibitors. Our team submitted four entries for the first stage that utilized: (1) AutoDock Vina (AD Vina) plus visual inspection; (2) a new common pharmacophore engine; (3) BEDAM replica exchange free energy simulations, and a Consensus approach that combined the predictions of all three strategies. Even with the SAMPL4's very challenging compound library that displayed a significantly lower amount of structural diversity than most libraries that are conventionally employed in prospective virtual screens, these approaches produced hit rates of 24, 25, 34, and 27 %, respectively, on a set with 19 % declared binders. Our only entry for the second stage challenge was based on the results of AD Vina plus visual inspection, and it ranked third place overall according to several different metrics provided by the SAMPL4 organizers. The successful results displayed by these approaches highlight the utility of the computational

  7. Virtual screening with AutoDock Vina and the common pharmacophore engine of a low diversity library of fragments and hits against the three allosteric sites of HIV integrase: participation in the SAMPL4 protein-ligand binding challenge

    Science.gov (United States)

    Perryman, Alexander L.; Santiago, Daniel N.; Forli, Stefano; Santos-Martins, Diogo; Olson, Arthur J.

    2014-04-01

    To rigorously assess the tools and protocols that can be used to understand and predict macromolecular recognition, and to gain more structural insight into three newly discovered allosteric binding sites on a critical drug target involved in the treatment of HIV infections, the Olson and Levy labs collaborated on the SAMPL4 challenge. This computational blind challenge involved predicting protein-ligand binding against the three allosteric sites of HIV integrase (IN), a viral enzyme for which two drugs (that target the active site) have been approved by the FDA. Positive control cross-docking experiments were utilized to select 13 receptor models out of an initial ensemble of 41 different crystal structures of HIV IN. These 13 models of the targets were selected using our new "Rank Difference Ratio" metric. The first stage of SAMPL4 involved using virtual screens to identify 62 active, allosteric IN inhibitors out of a set of 321 compounds. The second stage involved predicting the binding site(s) and crystallographic binding mode(s) for 57 of these inhibitors. Our team submitted four entries for the first stage that utilized: (1) AutoDock Vina (AD Vina) plus visual inspection; (2) a new common pharmacophore engine; (3) BEDAM replica exchange free energy simulations, and a Consensus approach that combined the predictions of all three strategies. Even with the SAMPL4's very challenging compound library that displayed a significantly lower amount of structural diversity than most libraries that are conventionally employed in prospective virtual screens, these approaches produced hit rates of 24, 25, 34, and 27 %, respectively, on a set with 19 % declared binders. Our only entry for the second stage challenge was based on the results of AD Vina plus visual inspection, and it ranked third place overall according to several different metrics provided by the SAMPL4 organizers. The successful results displayed by these approaches highlight the utility of the computational

  8. GOMoDo: A GPCRs online modeling and docking webserver.

    Directory of Open Access Journals (Sweden)

    Massimo Sandal

    Full Text Available G-protein coupled receptors (GPCRs are a superfamily of cell signaling membrane proteins that include >750 members in the human genome alone. They are the largest family of drug targets. The vast diversity and relevance of GPCRs contrasts with the paucity of structures available: only 21 unique GPCR structures have been experimentally determined as of the beginning of 2013. User-friendly modeling and small molecule docking tools are thus in great demand. While both GPCR structural predictions and docking servers exist separately, with GOMoDo (GPCR Online Modeling and Docking, we provide a web server to seamlessly model GPCR structures and dock ligands to the models in a single consistent pipeline. GOMoDo can automatically perform template choice, homology modeling and either blind or information-driven docking by combining together proven, state of the art bioinformatic tools. The web server gives the user the possibility of guiding the whole procedure. The GOMoDo server is freely accessible at http://molsim.sci.univr.it/gomodo.

  9. Synthesis, Docking and Biological Activities of Novel Hybrids Celecoxib and Anthraquinone Analogs as Potent Cytotoxic Agents

    Directory of Open Access Journals (Sweden)

    Maha S. Almutairi

    2014-12-01

    Full Text Available Herein, novel hybrid compounds of celecoxib and 2-aminoanthraquinone derivatives have been synthesized using condensation reactions of celecoxib with 2-aminoanthraquinone derivatives or 2-aminoanthraquinon with celecoxib derivatives. Celecoxib was reacted with different acid chlorides, 2-chloroethylisocyanate and bis (2-chloroethyl amine hydrochloride. These intermediates were then reacted with 2-aminoanthraquinone. Also the same different acid chlorides and 2-chloroethylisocyanate were reacted with 2-aminoanthraquinone and the resulting intermediates were reacted with celecoxib to give isomers for the previous compounds. The antitumor activities against hepatic carcinoma tumor cell line (HEPG2 have been investigated in vitro, and all these compounds showed promising activities, especially compound 3c, 7, and 12. Flexible docking studies involving AutoDock 4.2 was investigated to identify the potential binding affinities and the mode of interaction of the hybrid compounds into two protein tyrosine kinases namely, SRC (Pp60v-src and platelet-derived growth factor receptor, PDGFR (c-Kit. The compounds in this study have a preferential affinity for the c-Kit PDGFR PTK over the non-receptor tyrosine kinase SRC (Pp60v-src.

  10. Synthesis, Docking and Biological Activities of Novel Hybrids Celecoxib and Anthraquinone Analogs as Potent Cytotoxic Agents

    Science.gov (United States)

    Almutairi, Maha S.; Hegazy, Gehan H.; Haiba, Mogedda E.; Ali, Hamed I.; Khalifa, Nagy M.; Soliman, Abd El-mohsen M.

    2014-01-01

    Herein, novel hybrid compounds of celecoxib and 2-aminoanthraquinone derivatives have been synthesized using condensation reactions of celecoxib with 2-aminoanthraquinone derivatives or 2-aminoanthraquinon with celecoxib derivatives. Celecoxib was reacted with different acid chlorides, 2-chloroethylisocyanate and bis (2-chloroethyl) amine hydrochloride. These intermediates were then reacted with 2-aminoanthraquinone. Also the same different acid chlorides and 2-chloroethylisocyanate were reacted with 2-aminoanthraquinone and the resulting intermediates were reacted with celecoxib to give isomers for the previous compounds. The antitumor activities against hepatic carcinoma tumor cell line (HEPG2) have been investigated in vitro, and all these compounds showed promising activities, especially compound 3c, 7, and 12. Flexible docking studies involving AutoDock 4.2 was investigated to identify the potential binding affinities and the mode of interaction of the hybrid compounds into two protein tyrosine kinases namely, SRC (Pp60v-src) and platelet-derived growth factor receptor, PDGFR (c-Kit). The compounds in this study have a preferential affinity for the c-Kit PDGFR PTK over the non-receptor tyrosine kinase SRC (Pp60v-src). PMID:25490139

  11. Selective binding of pyrene in subdomain IB of human serum albumin: Combining energy transfer spectroscopy and molecular modelling to understand protein binding flexibility

    Science.gov (United States)

    Ling, Irene; Taha, Mohamed; Al-Sharji, Nada A.; Abou-Zied, Osama K.

    2018-04-01

    The ability of human serum albumin (HSA) to bind medium-sized hydrophobic molecules is important for the distribution, metabolism, and efficacy of many drugs. Herein, the interaction between pyrene, a hydrophobic fluorescent probe, and HSA was thoroughly investigated using steady-state and time-resolved fluorescence techniques, ligand docking, and molecular dynamics (MD) simulations. A slight quenching of the fluorescence signal from Trp214 (the sole tryptophan residue in the protein) in the presence of pyrene was used to determine the ligand binding site in the protein, using Förster's resonance energy transfer (FRET) theory. The estimated FRET apparent distance between pyrene and Trp214 was 27 Å, which was closely reproduced by the docking analysis (29 Å) and MD simulation (32 Å). The highest affinity site for pyrene was found to be in subdomain IB from the docking results. The calculated equilibrium structure of the complex using MD simulation shows that the ligand is largely stabilized by hydrophobic interaction with Phe165, Phe127, and the nonpolar moieties of Tyr138 and Tyr161. The fluorescence vibronic peak ratio I1/I3 of bound pyrene inside HSA indicates the presence of polar effect in the local environment of pyrene which is less than that of free pyrene in buffer. This was clarified by the MD simulation results in which an average of 5.7 water molecules were found within 0.5 nm of pyrene in the binding site. Comparing the fluorescence signals and lifetimes of pyrene inside HSA to that free in buffer, the high tendency of pyrene to form dimer was almost completely suppressed inside HSA, indicating a high selectivity of the binding pocket toward pyrene monomer. The current results emphasize the ability of HSA, as a major carrier of several drugs and ligands in blood, to bind hydrophobic molecules in cavities other than subdomain IIA which is known to bind most hydrophobic drugs. This ability stems from the nature of the amino acids forming the binding

  12. A crystal structure of the Dengue virus NS5 protein reveals a novel inter-domain interface essential for protein flexibility and virus replication.

    Directory of Open Access Journals (Sweden)

    Yongqian Zhao

    2015-03-01

    Full Text Available Flavivirus RNA replication occurs within a replication complex (RC that assembles on ER membranes and comprises both non-structural (NS viral proteins and host cofactors. As the largest protein component within the flavivirus RC, NS5 plays key enzymatic roles through its N-terminal methyltransferase (MTase and C-terminal RNA-dependent-RNA polymerase (RdRp domains, and constitutes a major target for antivirals. We determined a crystal structure of the full-length NS5 protein from Dengue virus serotype 3 (DENV3 at a resolution of 2.3 Å in the presence of bound SAH and GTP. Although the overall molecular shape of NS5 from DENV3 resembles that of NS5 from Japanese Encephalitis Virus (JEV, the relative orientation between the MTase and RdRp domains differs between the two structures, providing direct evidence for the existence of a set of discrete stable molecular conformations that may be required for its function. While the inter-domain region is mostly disordered in NS5 from JEV, the NS5 structure from DENV3 reveals a well-ordered linker region comprising a short 310 helix that may act as a swivel. Solution Hydrogen/Deuterium Exchange Mass Spectrometry (HDX-MS analysis reveals an increased mobility of the thumb subdomain of RdRp in the context of the full length NS5 protein which correlates well with the analysis of the crystallographic temperature factors. Site-directed mutagenesis targeting the mostly polar interface between the MTase and RdRp domains identified several evolutionarily conserved residues that are important for viral replication, suggesting that inter-domain cross-talk in NS5 regulates virus replication. Collectively, a picture for the molecular origin of NS5 flexibility is emerging with profound implications for flavivirus replication and for the development of therapeutics targeting NS5.

  13. Protein flexibility and ligand rigidity : a thermodynamic and kinetic study of ITAM-based ligand binding to Syk tandem SH2

    NARCIS (Netherlands)

    de Mol, Nico J; Catalina, M Isabel; Dekker, Frank J; Fischer, Marcel J E; Heck, Albert J R; Liskamp, Rob M J; Dekker, Frank

    2005-01-01

    The Syk tandem Src homology 2 domain (Syk tSH2) constitutes a flexible protein module involved in the regulation of Syk kinase activity. The Syk tSH2 domain is assumed to function by adapting the distance between its two SH2 domains upon bivalent binding to diphosphotyrosine ligands. A thermodynamic

  14. Synthesis, biological evaluation and molecular docking studies of ...

    African Journals Online (AJOL)

    Synthesis, biological evaluation and molecular docking studies of Mannich bases derived from 1, 3, 4-oxadiazole- 2-thiones as potential urease inhibitors. ... Mannich bases (5-17) were subjected to in silico screening as urease inhibitors, using crystal structure of urease (Protein Data Bank ID: 5FSE) as a model enzyme.

  15. Application of the docking program SOL for CSAR benchmark.

    Science.gov (United States)

    Sulimov, Alexey V; Kutov, Danil C; Oferkin, Igor V; Katkova, Ekaterina V; Sulimov, Vladimir B

    2013-08-26

    This paper is devoted to results obtained by the docking program SOL and the post-processing program DISCORE at the CSAR benchmark. SOL and DISCORE programs are described. SOL is the original docking program developed on the basis of the genetic algorithm, MMFF94 force field, rigid protein, precalculated energy grid including desolvation in the frame of simplified GB model, vdW, and electrostatic interactions and taking into account the ligand internal strain energy. An important SOL feature is the single- or multi-processor performance for up to hundreds of CPUs. DISCORE improves the binding energy scoring by the local energy optimization of the ligand docked pose and a simple linear regression on the base of available experimental data. The docking program SOL has demonstrated a good ability for correct ligand positioning in the active sites of the tested proteins in most cases of CSAR exercises. SOL and DISCORE have not demonstrated very exciting results on the protein-ligand binding free energy estimation. Nevertheless, for some target proteins, SOL and DISCORE were among the first in prediction of inhibition activity. Ways to improve SOL and DISCORE are discussed.

  16. Molecular Dynamics and Docking of Biphenyl: A Potential ...

    African Journals Online (AJOL)

    Purpose: To develop a new drug that inhibits viral attachment and entry for the treatment of HIV/AIDS patients. Methods: Two Protein Databank (PDB) crystal structures of HIV-1 gp120-CD4 complexes, namely, 1RZK and 1G9N, were mutated at amino acid position 43 to a biphenylalanine (biPhe-43) residue. FireDock web ...

  17. Enrichment of Druggable Conformations from Apo Protein Structures Using Cosolvent-Accelerated Molecular Dynamics

    Directory of Open Access Journals (Sweden)

    Andrew Kalenkiewicz

    2015-04-01

    Full Text Available Here we describe the development of an improved workflow for utilizing experimental and simulated protein conformations in the structure-based design of inhibitors for anti-apoptotic Bcl-2 family proteins. Traditional structure-based approaches on similar targets are often constrained by the sparsity of available structures and difficulties in finding lead compounds that dock against flat, flexible protein-protein interaction surfaces. By employing computational docking of known small molecule inhibitors, we have demonstrated that structural ensembles derived from either accelerated MD (aMD or MD in the presence of an organic cosolvent generally give better scores than those assessed from analogous conventional MD. Furthermore, conformations obtained from combined cosolvent aMD simulations started with the apo-Bcl-xL structure yielded better average and minimum docking scores for known binders than an ensemble of 72 experimental apo- and ligand-bound Bcl-xL structures. A detailed analysis of the simulated conformations indicates that the aMD effectively enhanced conformational sampling of the flexible helices flanking the main Bcl-xL binding groove, permitting the cosolvent acting as small ligands to penetrate more deeply into the binding pocket and shape ligand-bound conformations not evident in conventional simulations. We believe this approach could be useful for identifying inhibitors against other protein-protein interaction systems involving highly flexible binding sites, particularly for targets with less accumulated structural data.

  18. CT-docking patient stretcher

    International Nuclear Information System (INIS)

    Mirvis, S.E.; Owens, E.; Maslyn, J.; Rizutto, M.

    1990-01-01

    This paper assesses the use of a patient stretcher that directly docks to a CT scanner for acutely injured and/or critically ill patients. The stretcher permits performance of radiography and acts as a platform for critical care monitoring and patient support devices. During a 1-year period, the prototype CT-docking stretcher was used for 35 patients sustaining acute trauma and 25 patients from critical care units. Observations were elicited from physicians, nurses and technologists concerning the advantages or disadvantages of the docking stretcher. Advantages of the CT-docking stretcher included time saved in moving patients to the CT table from the admitting/emergency ward, transfer of critically ill patients onto the stretcher in the controlled environment of the intensive care unit rather than the CT suite, increasing CT throughput by direct docking of the patient stretcher to the CT scanner rather than manual transfer of complex support and monitoring devices with the patient, decreased risk associated with physical movement of patients with potentially unstable spinal injuries or unstable physiologic status, and decrease in potential for injury to medical personnel performing patient transfer

  19. Dry dock gate stability modelling

    Science.gov (United States)

    Oktoberty; Widiyanto; Sasono, E. J.; Pramono, S.; Wandono, A. T.

    2018-03-01

    The development of marine transportation needs in Indonesia increasingly opens national shipyard business opportunities to provide shipbuilding services to the shipbuilding vessels. That emphasizes the stability of prime. The ship's decking door becomes an integral part of the efficient place and the specification of the use of the asset of its operational ease. This study aims to test the stability of Dry Dock gate with the length of 35.4 meters using Maxsurf and Hydromax in analyzing the calculation were in its assessment using interval per 500 mm length so that it can get detail data toward longitudinal and transverse such as studying Ship planning in general. The test result shows dry dock gate meets IMO standard with ballast construction containing 54% and 68% and using fix ballast can produce GMt 1,924 m, tide height 11,357m. The GMt value indicates dry dick gate can be stable and firmly erect at the base of the mouth dry dock. When empty ballast produces GMt 0.996 which means dry dock date is stable, but can easily be torn down. The condition can be used during dry dock gate treatment.

  20. The novel 2Fe–2S outer mitochondrial protein mitoNEET displays conformational flexibility in its N-terminal cytoplasmic tethering domain

    International Nuclear Information System (INIS)

    Conlan, Andrea R.; Paddock, Mark L.; Axelrod, Herbert L.; Cohen, Aina E.; Abresch, Edward C.; Wiley, Sandra; Roy, Melinda; Nechushtai, Rachel; Jennings, Patricia A.

    2009-01-01

    The crystal structure of the anti-diabetic drug target mitoNEET obtained from a GFP fusion construct (1.4 Å resolution, R factor = 20.2%) shows that the CDGSH 2Fe–2S binding domains are superimposable with previously determined non-fused constructs. However, there is considerable flexibility in the position of the outer mitochondrial tethering arms resulting in two different conformations in the crystal structure. A primary role for mitochondrial dysfunction is indicated in the pathogenesis of insulin resistance. A widely used drug for the treatment of type 2 diabetes is pioglitazone, a member of the thiazolidinedione class of molecules. MitoNEET, a 2Fe–2S outer mitochondrial membrane protein, binds pioglitazone [Colca et al. (2004 ▶), Am. J. Physiol. Endocrinol. Metab.286, E252–E260]. The soluble domain of the human mitoNEET protein has been expressed C-terminal to the superfolder green fluorescent protein and the mitoNEET protein has been isolated. Comparison of the crystal structure of mitoNEET isolated from cleavage of the fusion protein (1.4 Å resolution, R factor = 20.2%) with other solved structures shows that the CDGSH domains are superimposable, indicating proper assembly of mitoNEET. Furthermore, there is considerable flexibility in the position of the cytoplasmic tethering arms, resulting in two different conformations in the crystal structure. This flexibility affords multiple orientations on the outer mitochondrial membrane

  1. Residue 259 in protein-tyrosine phosphatase PTP1B and PTPα determines the flexibility of glutamine 262

    DEFF Research Database (Denmark)

    Peters, Günther H.j.; Iversen, L.F.; Andersen, H.S.

    2004-01-01

    To study the flexibility of the substrate-binding site and in particular of Gln262, we have performed adiabatic conformational search and molecular dynamics simulations on the crystal structure of the catalytic domain of wild-type protein-tyrosine phosphatase (PTP) 1B, a mutant PTP1B(R47V),(D48N...... and second step of the phosphate hydrolysis. Analyses of the trajectories revealed that in the cysteine-phosphor complex of PTP1B, Gln262 oscillates freely between the bound phosphate group and Gly259 frequently forming, as observed in the crystal structure, a hydrogen bond with the backbone oxygen of Gly259...... around Gln262 and the active site Cys215 reveals that the probability of finding a water molecule correctly positioned for catalysis is much larger in PTP1B than in PTP1B(R47V),(D48N),(M258C),(G259Q) and PTPalpha, in accordance with experiments....

  2. Human and server docking prediction for CAPRI round 30-35 using LZerD with combined scoring functions.

    Science.gov (United States)

    Peterson, Lenna X; Kim, Hyungrae; Esquivel-Rodriguez, Juan; Roy, Amitava; Han, Xusi; Shin, Woong-Hee; Zhang, Jian; Terashi, Genki; Lee, Matt; Kihara, Daisuke

    2017-03-01

    We report the performance of protein-protein docking predictions by our group for recent rounds of the Critical Assessment of Prediction of Interactions (CAPRI), a community-wide assessment of state-of-the-art docking methods. Our prediction procedure uses a protein-protein docking program named LZerD developed in our group. LZerD represents a protein surface with 3D Zernike descriptors (3DZD), which are based on a mathematical series expansion of a 3D function. The appropriate soft representation of protein surface with 3DZD makes the method more tolerant to conformational change of proteins upon docking, which adds an advantage for unbound docking. Docking was guided by interface residue prediction performed with BindML and cons-PPISP as well as literature information when available. The generated docking models were ranked by a combination of scoring functions, including PRESCO, which evaluates the native-likeness of residues' spatial environments in structure models. First, we discuss the overall performance of our group in the CAPRI prediction rounds and investigate the reasons for unsuccessful cases. Then, we examine the performance of several knowledge-based scoring functions and their combinations for ranking docking models. It was found that the quality of a pool of docking models generated by LZerD, that is whether or not the pool includes near-native models, can be predicted by the correlation of multiple scores. Although the current analysis used docking models generated by LZerD, findings on scoring functions are expected to be universally applicable to other docking methods. Proteins 2017; 85:513-527. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  3. Site-directed mutagenesis under the direction of in silico protein docking modeling reveals the active site residues of 3-ketosteroid-Δ1-dehydrogenase from Mycobacterium neoaurum.

    Science.gov (United States)

    Qin, Ning; Shen, Yanbing; Yang, Xu; Su, Liqiu; Tang, Rui; Li, Wei; Wang, Min

    2017-07-01

    3-Ketosteroid-Δ 1 -dehydrogenases (KsdD) from Mycobacterium neoaurum could transform androst-4-ene-3,17-dione (AD) to androst-1,4-diene-3,17-dione. This reaction has a significant effect on the product of pharmaceutical steroid. The crystal structure and active site residues information of KsdD from Mycobacterium is not yet available, which result in the engineering of KsdD is tedious. In this study, by the way of protein modeling and site-directed mutagenesis, we find that, Y122, Y125, S138, E140 and Y541 from the FAD-binding domain and Y365 from the catalytic domain play a key role in this transformation. Compared with the wild type, the decline in AD conversion for mutants illustrated that Y125, Y365, and Y541 were essential to the function of KsdD. Y122, S138 and E140 contributed to the catalysis of KsdD. The following analysis revealed the catalysis mechanism of these mutations in KsdD of Mycobacterium. These information presented here facilitate the manipulation of the catalytic properties of the enzyme to improve its application in the pharmaceutical steroid industry.

  4. NASA Docking System (NDS) Technical Integration Meeting

    Science.gov (United States)

    Lewis, James L.

    2010-01-01

    This slide presentation reviews the NASA Docking System (NDS) as NASA's implementation of the International Docking System Standard (IDSS). The goals of the NDS, is to build on proven technologies previously demonstrated in flight and to advance the state of the art of docking systems by incorporating Low Impact Docking System (LIDS) technology into the NDS. A Hardware Demonstration was included in the meeting, and there was discussion about software, NDS major system interfaces, integration information, schedule, and future upgrades.

  5. Identification of the quinolinedione inhibitor binding site in Cdc25 phosphatase B through docking and molecular dynamics simulations

    Science.gov (United States)

    Ge, Yushu; van der Kamp, Marc; Malaisree, Maturos; Liu, Dan; Liu, Yi; Mulholland, Adrian J.

    2017-11-01

    Cdc25 phosphatase B, a potential target for cancer therapy, is inhibited by a series of quinones. The binding site and mode of quinone inhibitors to Cdc25B remains unclear, whereas this information is important for structure-based drug design. We investigated the potential binding site of NSC663284 [DA3003-1 or 6-chloro-7-(2-morpholin-4-yl-ethylamino)-quinoline-5, 8-dione] through docking and molecular dynamics simulations. Of the two main binding sites suggested by docking, the molecular dynamics simulations only support one site for stable binding of the inhibitor. Binding sites in and near the Cdc25B catalytic site that have been suggested previously do not lead to stable binding in 50 ns molecular dynamics (MD) simulations. In contrast, a shallow pocket between the C-terminal helix and the catalytic site provides a favourable binding site that shows high stability. Two similar binding modes featuring protein-inhibitor interactions involving Tyr428, Arg482, Thr547 and Ser549 are identified by clustering analysis of all stable MD trajectories. The relatively flexible C-terminal region of Cdc25B contributes to inhibitor binding. The binding mode of NSC663284, identified through MD simulation, likely prevents the binding of protein substrates to Cdc25B. The present results provide useful information for the design of quinone inhibitors and their mechanism of inhibition.

  6. Identification of the quinolinedione inhibitor binding site in Cdc25 phosphatase B through docking and molecular dynamics simulations.

    Science.gov (United States)

    Ge, Yushu; van der Kamp, Marc; Malaisree, Maturos; Liu, Dan; Liu, Yi; Mulholland, Adrian J

    2017-11-01

    Cdc25 phosphatase B, a potential target for cancer therapy, is inhibited by a series of quinones. The binding site and mode of quinone inhibitors to Cdc25B remains unclear, whereas this information is important for structure-based drug design. We investigated the potential binding site of NSC663284 [DA3003-1 or 6-chloro-7-(2-morpholin-4-yl-ethylamino)-quinoline-5, 8-dione] through docking and molecular dynamics simulations. Of the two main binding sites suggested by docking, the molecular dynamics simulations only support one site for stable binding of the inhibitor. Binding sites in and near the Cdc25B catalytic site that have been suggested previously do not lead to stable binding in 50 ns molecular dynamics (MD) simulations. In contrast, a shallow pocket between the C-terminal helix and the catalytic site provides a favourable binding site that shows high stability. Two similar binding modes featuring protein-inhibitor interactions involving Tyr428, Arg482, Thr547 and Ser549 are identified by clustering analysis of all stable MD trajectories. The relatively flexible C-terminal region of Cdc25B contributes to inhibitor binding. The binding mode of NSC663284, identified through MD simulation, likely prevents the binding of protein substrates to Cdc25B. The present results provide useful information for the design of quinone inhibitors and their mechanism of inhibition.

  7. An Efficient ABC_DE_Based Hybrid Algorithm for Protein–Ligand Docking

    Directory of Open Access Journals (Sweden)

    Boxin Guan

    2018-04-01

    Full Text Available Protein–ligand docking is a process of searching for the optimal binding conformation between the receptor and the ligand. Automated docking plays an important role in drug design, and an efficient search algorithm is needed to tackle the docking problem. To tackle the protein–ligand docking problem more efficiently, An ABC_DE_based hybrid algorithm (ADHDOCK, integrating artificial bee colony (ABC algorithm and differential evolution (DE algorithm, is proposed in the article. ADHDOCK applies an adaptive population partition (APP mechanism to reasonably allocate the computational resources of the population in each iteration process, which helps the novel method make better use of the advantages of ABC and DE. The experiment tested fifty protein–ligand docking problems to compare the performance of ADHDOCK, ABC, DE, Lamarckian genetic algorithm (LGA, running history information guided genetic algorithm (HIGA, and swarm optimization for highly flexible protein–ligand docking (SODOCK. The results clearly exhibit the capability of ADHDOCK toward finding the lowest energy and the smallest root-mean-square deviation (RMSD on most of the protein–ligand docking problems with respect to the other five algorithms.

  8. Spent fuel canister docking station

    International Nuclear Information System (INIS)

    Suikki, M.

    2006-01-01

    The working report for the spent fuel canister docking station presents a design for the operation and structure of the docking equipment located in the fuel handling cell for the spent fuel in the encapsulation plant. The report contains a description of the basic requirements for the docking station equipment and their implementation, the operation of the equipment, maintenance and a cost estimate. In the designing of the equipment all the problems related with the operation have been solved at the level of principle, nevertheless, detailed designing and the selection of final components have not yet been carried out. In case of defects and failures, solutions have been considered for postulated problems, and furthermore, the entire equipment was gone through by the means of systematic risk analysis (PFMEA). During the docking station designing we came across with needs to influence the structure of the actual disposal canister for spent nuclear fuel, too. Proposed changes for the structure of the steel lid fastening screw were included in the report. The report also contains a description of installation with the fuel handling cell structures. The purpose of the docking station for the fuel handling cell is to position and to seal the disposal canister for spent nuclear fuel into a penetration located on the cell floor and to provide suitable means for executing the loading of the disposal canister and the changing of atmosphere. The designed docking station consists of a docking ring, a covering hatch, a protective cone and an atmosphere-changing cap as well as the vacuum technology pertaining to the changing of atmosphere and the inert gas system. As far as the solutions are concerned, we have arrived at rather simple structures and most of the actuators of the system are situated outside of the actual fuel handling cell. When necessary, the equipment can also be used for the dismantling of a faulty disposal canister, cut from its upper end by machining. The

  9. Multi-structure docking analysis of BACE1 crystal structures and non-peptidic ligands.

    Science.gov (United States)

    Haghighijoo, Zahra; Hemmateenejad, Bahram; Edraki, Najmeh; Miri, Ramin; Emami, Saeed

    2017-09-01

    In order to design novel non-peptidic inhibitors of BACE1, many research groups have attempted using computational studies including docking analyses. Since there are too many 3D structures for BACE1 in the protein database, the selection of suitable crystal structures is a key prerequisite for the successful application of molecular docking. We employed a multi-structure docking protocol. In which 615 ligands' structures were docked into 150 BACE1 structures. The large number of the resultant docking scores were post-processed by different data analysis methods including exploratory data analysis, regression analysis and discriminant analysis. It was found that using one crystal structure for docking did not result in high accuracy for predicting activity of the BACE1 inhibitors. Instead, using of the multi-structural docking scores, post-processed by chemometrics methods arrived to highly accurate predictive models. In this regards, the PDB accession codes of 4B70, 4DVF and 2WEZ could discriminate between active and inactive compounds, with higher accuracy. Clustering of the BACE1 structures based on principal component analysis of the crystallographic structures the revealed that the discriminant structures are in the center of the clusters. Thus, these structures can be selected as predominant crystal structures for docking studies of non-peptidic BACE1 inhibitors. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Combining self- and cross-docking as benchmark tools: the performance of DockBench in the D3R Grand Challenge 2

    Science.gov (United States)

    Salmaso, Veronica; Sturlese, Mattia; Cuzzolin, Alberto; Moro, Stefano

    2018-01-01

    Molecular docking is a powerful tool in the field of computer-aided molecular design. In particular, it is the technique of choice for the prediction of a ligand pose within its target binding site. A multitude of docking methods is available nowadays, whose performance may vary depending on the data set. Therefore, some non-trivial choices should be made before starting a docking simulation. In the same framework, the selection of the target structure to use could be challenging, since the number of available experimental structures is increasing. Both issues have been explored within this work. The pose prediction of a pool of 36 compounds provided by D3R Grand Challenge 2 organizers was preceded by a pipeline to choose the best protein/docking-method couple for each blind ligand. An integrated benchmark approach including ligand shape comparison and cross-docking evaluations was implemented inside our DockBench software. The results are encouraging and show that bringing attention to the choice of the docking simulation fundamental components improves the results of the binding mode predictions.

  11. Sensitivity of molecular docking to induced fit effects in influenza virus neuraminidase

    Science.gov (United States)

    Birch, Louise; Murray, Christopher W.; Hartshorn, Michael J.; Tickle, Ian J.; Verdonk, Marcel L.

    2002-12-01

    Many proteins undergo small side chain or even backbone movements on binding of different ligands into the same protein structure. This is known as induced fit and is potentially problematic for virtual screening of databases against protein targets. In this report we investigate the limits of the rigid protein approximation used by the docking program, GOLD, through cross-docking using protein structures of influenza neuraminidase. Neuraminidase is known to exhibit small but significant induced fit effects on ligand binding. Some neuraminidase crystal structures caused concern due to the bound ligand conformation and GOLD performed poorly on these complexes. A `clean' set, which contained unique, unambiguous complexes, was defined. For this set, the lowest energy structure was correctly docked (i.e. RMSD < 1.5 Å away from the crystal reference structure) in 84% of proteins, and the most promiscuous protein (1mwe) was able to dock all 15 ligands accurately including those that normally required an induced fit movement. This is considerably better than the 70% success rate seen with GOLD against general validation sets. Inclusion of specific water molecules involved in water-mediated hydrogen bonds did not significantly improve the docking performance for ligands that formed water-mediated contacts but it did prevent docking of ligands that displaced these waters. Our data supports the use of a single protein structure for virtual screening with GOLD in some applications involving induced fit effects, although care must be taken to identify the protein structure that performs best against a wide variety of ligands. The performance of GOLD was significantly better than the GOLD implementation of ChemScore and the reasons for this are discussed. Overall, GOLD has shown itself to be an extremely good, robust docking program for this system.

  12. Flexible Bronchoscopy.

    Science.gov (United States)

    Miller, Russell J; Casal, Roberto F; Lazarus, Donald R; Ost, David E; Eapen, George A

    2018-03-01

    Flexible bronchoscopy has changed the course of pulmonary medicine. As technology advances, the role of the flexible bronchoscope for both diagnostic and therapeutic indications is continually expanding. This article reviews the historical development of the flexible bronchoscopy, fundamental uses of the flexible bronchoscope as a tool to examine the central airways and obtain diagnostic tissue, and the indications, complications, and contraindications to flexible bronchoscopy. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Transparent and flexible resistive switching memory devices with a very high ON/OFF ratio using gold nanoparticles embedded in a silk protein matrix

    Science.gov (United States)

    Gogurla, Narendar; Mondal, Suvra P.; Sinha, Arun K.; Katiyar, Ajit K.; Banerjee, Writam; Kundu, Subhas C.; Ray, Samit K.

    2013-08-01

    The growing demand for biomaterials for electrical and optical devices is motivated by the need to make building blocks for the next generation of printable bio-electronic devices. In this study, transparent and flexible resistive memory devices with a very high ON/OFF ratio incorporating gold nanoparticles into the Bombyx mori silk protein fibroin biopolymer are demonstrated. The novel electronic memory effect is based on filamentary switching, which leads to the occurrence of bistable states with an ON/OFF ratio larger than six orders of magnitude. The mechanism of this process is attributed to the formation of conductive filaments through silk fibroin and gold nanoparticles in the nanocomposite. The proposed hybrid bio-inorganic devices show promise for use in future flexible and transparent nanoelectronic systems.

  14. Transparent and flexible resistive switching memory devices with a very high ON/OFF ratio using gold nanoparticles embedded in a silk protein matrix

    International Nuclear Information System (INIS)

    Gogurla, Narendar; Mondal, Suvra P; Sinha, Arun K; Katiyar, Ajit K; Banerjee, Writam; Ray, Samit K; Kundu, Subhas C

    2013-01-01

    The growing demand for biomaterials for electrical and optical devices is motivated by the need to make building blocks for the next generation of printable bio-electronic devices. In this study, transparent and flexible resistive memory devices with a very high ON/OFF ratio incorporating gold nanoparticles into the Bombyx mori silk protein fibroin biopolymer are demonstrated. The novel electronic memory effect is based on filamentary switching, which leads to the occurrence of bistable states with an ON/OFF ratio larger than six orders of magnitude. The mechanism of this process is attributed to the formation of conductive filaments through silk fibroin and gold nanoparticles in the nanocomposite. The proposed hybrid bio-inorganic devices show promise for use in future flexible and transparent nanoelectronic systems. (paper)

  15. Dimerization of DOCK2 is essential for DOCK2-mediated Rac activation and lymphocyte migration.

    Directory of Open Access Journals (Sweden)

    Masao Terasawa

    Full Text Available The migratory properties of lymphocytes depend on DOCK2, an atypical Rac activator predominantly expressed in hematopoietic cells. Although DOCK2 does not contain the Dbl homology domain typically found in guanine nucleotide exchange factors (GEFs, DOCK2 mediates the GTP-GDP exchange reaction for Rac via its DOCK homology region (DHR-2 (also known as CZH2 or Docker domain. DOCK2 DHR-2 domain is composed of three lobes, and Rac binding site and catalytic center are generated entirely from lobes B and C. On the other hand, lobe A has been implicated in dimer formation, yet its physiological significance remains unknown. Here, we report that lobe A-mediated DOCK2 dimerization is crucial for Rac activation and lymphocyte migration. We found that unlike wild-type DOCK2, DOCK2 mutant lacking lobe A failed to restore motility and polarity when expressed in thymoma cells and primary T cells lacking endogenous expression of DOCK2. Similar results were obtained with the DOCK2 point mutant having a defect in dimerization. Deletion of lobe A from the DHR-2 domain did not affect Rac GEF activity in vitro. However, fluorescence resonance energy transfer analyses revealed that lobe A is required for DOCK2 to activate Rac effectively during cell migration. Our results thus indicate that DOCK2 dimerization is functionally important under the physiological condition where only limited amounts of DOCK2 and Rac are localized to the plasma membrane.

  16. GeauxDock: Accelerating Structure-Based Virtual Screening with Heterogeneous Computing

    Science.gov (United States)

    Fang, Ye; Ding, Yun; Feinstein, Wei P.; Koppelman, David M.; Moreno, Juana; Jarrell, Mark; Ramanujam, J.; Brylinski, Michal

    2016-01-01

    Computational modeling of drug binding to proteins is an integral component of direct drug design. Particularly, structure-based virtual screening is often used to perform large-scale modeling of putative associations between small organic molecules and their pharmacologically relevant protein targets. Because of a large number of drug candidates to be evaluated, an accurate and fast docking engine is a critical element of virtual screening. Consequently, highly optimized docking codes are of paramount importance for the effectiveness of virtual screening methods. In this communication, we describe the implementation, tuning and performance characteristics of GeauxDock, a recently developed molecular docking program. GeauxDock is built upon the Monte Carlo algorithm and features a novel scoring function combining physics-based energy terms with statistical and knowledge-based potentials. Developed specifically for heterogeneous computing platforms, the current version of GeauxDock can be deployed on modern, multi-core Central Processing Units (CPUs) as well as massively parallel accelerators, Intel Xeon Phi and NVIDIA Graphics Processing Unit (GPU). First, we carried out a thorough performance tuning of the high-level framework and the docking kernel to produce a fast serial code, which was then ported to shared-memory multi-core CPUs yielding a near-ideal scaling. Further, using Xeon Phi gives 1.9× performance improvement over a dual 10-core Xeon CPU, whereas the best GPU accelerator, GeForce GTX 980, achieves a speedup as high as 3.5×. On that account, GeauxDock can take advantage of modern heterogeneous architectures to considerably accelerate structure-based virtual screening applications. GeauxDock is open-sourced and publicly available at www.brylinski.org/geauxdock and https://figshare.com/articles/geauxdock_tar_gz/3205249. PMID:27420300

  17. GeauxDock: Accelerating Structure-Based Virtual Screening with Heterogeneous Computing.

    Directory of Open Access Journals (Sweden)

    Ye Fang

    Full Text Available Computational modeling of drug binding to proteins is an integral component of direct drug design. Particularly, structure-based virtual screening is often used to perform large-scale modeling of putative associations between small organic molecules and their pharmacologically relevant protein targets. Because of a large number of drug candidates to be evaluated, an accurate and fast docking engine is a critical element of virtual screening. Consequently, highly optimized docking codes are of paramount importance for the effectiveness of virtual screening methods. In this communication, we describe the implementation, tuning and performance characteristics of GeauxDock, a recently developed molecular docking program. GeauxDock is built upon the Monte Carlo algorithm and features a novel scoring function combining physics-based energy terms with statistical and knowledge-based potentials. Developed specifically for heterogeneous computing platforms, the current version of GeauxDock can be deployed on modern, multi-core Central Processing Units (CPUs as well as massively parallel accelerators, Intel Xeon Phi and NVIDIA Graphics Processing Unit (GPU. First, we carried out a thorough performance tuning of the high-level framework and the docking kernel to produce a fast serial code, which was then ported to shared-memory multi-core CPUs yielding a near-ideal scaling. Further, using Xeon Phi gives 1.9× performance improvement over a dual 10-core Xeon CPU, whereas the best GPU accelerator, GeForce GTX 980, achieves a speedup as high as 3.5×. On that account, GeauxDock can take advantage of modern heterogeneous architectures to considerably accelerate structure-based virtual screening applications. GeauxDock is open-sourced and publicly available at www.brylinski.org/geauxdock and https://figshare.com/articles/geauxdock_tar_gz/3205249.

  18. Combined spectroscopic, molecular docking and quantum mechanics study of β-casein and p-coumaric acid interactions following thermal treatment.

    Science.gov (United States)

    Kaur, Jasmeet; Katopo, Lita; Hung, Andrew; Ashton, John; Kasapis, Stefan

    2018-06-30

    The molecular nature of interactions between β-casein and p-coumaric acid was studied following exposure of their solutions to ultra-high temperature (UHT at 145 °C). Interactions were characterised by employing multi-spectroscopic methods, molecular docking and quantum mechanics calculations. FTIR demonstrates that the ligand lies in the vicinity of the protein, hence inverting the absorbance spectrum of the complex. This outcome changes the conformational characteristics of the protein leading to a flexible and open structure that accommodates the phenolic microconstituent. Results are supported by UV-vis, CD and fluorescence quenching showing considerable shifts in spectra with complexation. Molecular docking indicates that there is at least a hydrogen bond between p-coumaric acid and the peptide backbone of isoleucine (Ile27). Quantum mechanics calculations further argue that changes in experimental observations are also due to a covalent interaction in the protein-phenolic adduct, which according to the best predicted binding pose involves the side chain of lysine 47. Copyright © 2018. Published by Elsevier Ltd.

  19. Rigid Body Energy Minimization on Manifolds for Molecular Docking.

    Science.gov (United States)

    Mirzaei, Hanieh; Beglov, Dmitri; Paschalidis, Ioannis Ch; Vajda, Sandor; Vakili, Pirooz; Kozakov, Dima

    2012-11-13

    Virtually all docking methods include some local continuous minimization of an energy/scoring function in order to remove steric clashes and obtain more reliable energy values. In this paper, we describe an efficient rigid-body optimization algorithm that, compared to the most widely used algorithms, converges approximately an order of magnitude faster to conformations with equal or slightly lower energy. The space of rigid body transformations is a nonlinear manifold, namely, a space which locally resembles a Euclidean space. We use a canonical parametrization of the manifold, called the exponential parametrization, to map the Euclidean tangent space of the manifold onto the manifold itself. Thus, we locally transform the rigid body optimization to an optimization over a Euclidean space where basic optimization algorithms are applicable. Compared to commonly used methods, this formulation substantially reduces the dimension of the search space. As a result, it requires far fewer costly function and gradient evaluations and leads to a more efficient algorithm. We have selected the LBFGS quasi-Newton method for local optimization since it uses only gradient information to obtain second order information about the energy function and avoids the far more costly direct Hessian evaluations. Two applications, one in protein-protein docking, and the other in protein-small molecular interactions, as part of macromolecular docking protocols are presented. The code is available to the community under open source license, and with minimal effort can be incorporated into any molecular modeling package.

  20. Modeling holo-ACP:DH and holo-ACP:KR complexes of modular polyketide synthases: a docking and molecular dynamics study

    Directory of Open Access Journals (Sweden)

    Anand Swadha

    2012-05-01

    Full Text Available Abstract Background Modular polyketide synthases are multifunctional megasynthases which biosynthesize a variety of secondary metabolites using various combinations of dehydratase (DH, ketoreductase (KR and enoyl-reductase (ER domains. During the catalysis of various reductive steps these domains act on a substrate moiety which is covalently attached to the phosphopantetheine (P-pant group of the holo-Acyl Carrier Protein (holo-ACP domain, thus necessitating the formation of holo-ACP:DH and holo-ACP:KR complexes. Even though three dimensional structures are available for DH, KR and ACP domains, no structures are available for DH or KR domains in complex with ACP or substrate moieties. Since Ser of holo-ACP is covalently attached to a large phosphopantetheine group, obtaining complexes involving holo-ACP by standard protein-protein docking has been a difficult task. Results We have modeled the holo-ACP:DH and holo-ACP:KR complexes for identifying specific residues on DH and KR domains which are involved in interaction with ACP, phosphopantetheine and substrate moiety. A novel combination of protein-protein and protein-ligand docking has been used to first model complexes involving apo-ACP and then dock the phosphopantetheine and substrate moieties using covalent connectivity between ACP, phosphopantetheine and substrate moiety as constraints. The holo-ACP:DH and holo-ACP:KR complexes obtained from docking have been further refined by restraint free explicit solvent MD simulations to incorporate effects of ligand and receptor flexibilities. The results from 50 ns MD simulations reveal that substrate enters into a deep tunnel in DH domain while in case of KR domain the substrate binds a shallow surface exposed cavity. Interestingly, in case of DH domain the predicted binding site overlapped with the binding site in the inhibitor bound crystal structure of FabZ, the DH domain from E.Coli FAS. In case of KR domain, the substrate binding site

  1. Structural insight and flexible features of NS5 proteins from all four serotypes of Dengue virus in solution

    Energy Technology Data Exchange (ETDEWEB)

    Saw, Wuan Geok; Tria, Giancarlo; Grüber, Ardina; Subramanian Manimekalai, Malathy Sony; Zhao, Yongqian; Chandramohan, Arun; Srinivasan Anand, Ganesh; Matsui, Tsutomu; Weiss, Thomas M.; Vasudevan, Subhash G.; Grüber, Gerhard

    2015-10-31

    Infection by the four serotypes ofDengue virus(DENV-1 to DENV-4) causes an important arthropod-borne viral disease in humans. The multifunctional DENV nonstructural protein 5 (NS5) is essential for capping and replication of the viral RNA and harbours a methyltransferase (MTase) domain and an RNA-dependent RNA polymerase (RdRp) domain. In this study, insights into the overall structure and flexibility of the entire NS5 of all fourDengue virusserotypes in solution are presented for the first time. The solution models derived revealed an arrangement of the full-length NS5 (NS5FL) proteins with the MTase domain positioned at the top of the RdRP domain. The DENV-1 to DENV-4 NS5 forms are elongated and flexible in solution, with DENV-4 NS5 being more compact relative to NS5 from DENV-1, DENV-2 and DENV-3. Solution studies of the individual MTase and RdRp domains show the compactness of the RdRp domain as well as the contribution of the MTase domain and the ten-residue linker region to the flexibility of the entire NS5. Swapping the ten-residue linker between DENV-4 NS5FL and DENV-3 NS5FL demonstrated its importance in MTase–RdRp communication and in concerted interaction with viral and host proteins, as probed by amide hydrogen/deuterium mass spectrometry. Conformational alterations owing to RNA binding are presented.

  2. Pharmacophore Modeling and Molecular Docking Studies on Pinus roxburghii as a Target for Diabetes Mellitus

    Directory of Open Access Journals (Sweden)

    Pawan Kaushik

    2014-01-01

    Full Text Available The present study attempts to establish a relationship between ethnopharmacological claims and bioactive constituents present in Pinus roxburghii against all possible targets for diabetes through molecular docking and to develop a pharmacophore model for the active target. The process of molecular docking involves study of different bonding modes of one ligand with active cavities of target receptors protein tyrosine phosphatase 1-beta (PTP-1β, dipeptidyl peptidase-IV (DPP-IV, aldose reductase (AR, and insulin receptor (IR with help of docking software Molegro virtual docker (MVD. From the results of docking score values on different receptors for antidiabetic activity, it is observed that constituents, namely, secoisoresinol, pinoresinol, and cedeodarin, showed the best docking results on almost all the receptors, while the most significant results were observed on AR. Then, LigandScout was applied to develop a pharmacophore model for active target. LigandScout revealed that 2 hydrogen bond donors pointing towards Tyr 48 and His 110 are a major requirement of the pharmacophore generated. In our molecular docking studies, the active constituent, secoisoresinol, has also shown hydrogen bonding with His 110 residue which is a part of the pharmacophore. The docking results have given better insights into the development of better aldose reductase inhibitor so as to treat diabetes related secondary complications.

  3. Proposed docking interface between peptidoglycan and the target recognition domain of zoocin A

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Yinghua [Department of Chemistry, University of Alabama, Tuscaloosa, AL 35487 (United States); Simmonds, Robin S. [Department of Microbiology and Immunology, University of Otago, Dunedin (New Zealand); Timkovich, Russell, E-mail: rtimkovi@bama.ua.edu [Department of Chemistry, University of Alabama, Tuscaloosa, AL 35487 (United States)

    2013-11-15

    Highlights: •Peptidoglycan added to zoocin rTRD perturbs NMR resonances around W115. •Simulations predict docking to a shallow surface groove near W115. •The docking interface is similar to mammalian antibody–antigen sites. •EDTA binds to a distinct surface site. -- Abstract: A docking model is proposed for the target recognition domain of the lytic exoenzyme zoocin A with the peptidoglycan on the outer cell surface of sensitive bacterial strains. Solubilized fragments from such peptidoglycans perturb specific backbone and side chain amide resonances in the recombinant form of the domain designated rTRD as detected in two-dimensional {sup 1}H–{sup 15}N correlation NMR spectra. The affected residues comprise a shallow surface cleft on the protein surface near W115, N53, N117, and Q105 among others, which interacts with the peptide portion of the peptidoglycan. Calculations with AutoDock Vina provide models of the docking interface. There is approximate homology between the rTDR-peptidoglycan docking site and the antigen binding site of Fab antibodies with the immunoglobin fold. EDTA was also found to bind to rTRD, but at a site distinct from the proposed peptidoglycan docking site.

  4. Molecular docking of Glycine max and Medicago truncatula ureases with urea; bioinformatics approaches.

    Science.gov (United States)

    Filiz, Ertugrul; Vatansever, Recep; Ozyigit, Ibrahim Ilker

    2016-03-01

    Urease (EC 3.5.1.5) is a nickel-dependent metalloenzyme catalyzing the hydrolysis of urea into ammonia and carbon dioxide. It is present in many bacteria, fungi, yeasts and plants. Most species, with few exceptions, use nickel metalloenzyme urease to hydrolyze urea, which is one of the commonly used nitrogen fertilizer in plant growth thus its enzymatic hydrolysis possesses vital importance in agricultural practices. Considering the essentiality and importance of urea and urease activity in most plants, this study aimed to comparatively investigate the ureases of two important legume species such as Glycine max (soybean) and Medicago truncatula (barrel medic) from Fabaceae family. With additional plant species, primary and secondary structures of 37 plant ureases were comparatively analyzed using various bioinformatics tools. A structure based phylogeny was constructed using predicted 3D models of G. max and M. truncatula, whose crystallographic structures are not available, along with three additional solved urease structures from Canavalia ensiformis (PDB: 4GY7), Bacillus pasteurii (PDB: 4UBP) and Klebsiella aerogenes (PDB: 1FWJ). In addition, urease structures of these species were docked with urea to analyze the binding affinities, interacting amino acids and atom distances in urease-urea complexes. Furthermore, mutable amino acids which could potentially affect the protein active site, stability and flexibility as well as overall protein stability were analyzed in urease structures of G. max and M. truncatula. Plant ureases demonstrated similar physico-chemical properties with 833-878 amino acid residues and 89.39-90.91 kDa molecular weight with mainly acidic (5.15-6.10 pI) nature. Four protein domain structures such as urease gamma, urease beta, urease alpha and amidohydro 1 characterized the plant ureases. Secondary structure of plant ureases also demonstrated conserved protein architecture, with predominantly α-helix and random coil structures. In

  5. Systematic and efficient side chain optimization for molecular docking using a cheapest-path procedure.

    Science.gov (United States)

    Schumann, Marcel; Armen, Roger S

    2013-05-30

    Molecular docking of small-molecules is an important procedure for computer-aided drug design. Modeling receptor side chain flexibility is often important or even crucial, as it allows the receptor to adopt new conformations as induced by ligand binding. However, the accurate and efficient incorporation of receptor side chain flexibility has proven to be a challenge due to the huge computational complexity required to adequately address this problem. Here we describe a new docking approach with a very fast, graph-based optimization algorithm for assignment of the near-optimal set of residue rotamers. We extensively validate our approach using the 40 DUD target benchmarks commonly used to assess virtual screening performance and demonstrate a large improvement using the developed side chain optimization over rigid receptor docking (average ROC AUC of 0.693 vs. 0.623). Compared to numerous benchmarks, the overall performance is better than nearly all other commonly used procedures. Furthermore, we provide a detailed analysis of the level of receptor flexibility observed in docking results for different classes of residues and elucidate potential avenues for further improvement. Copyright © 2013 Wiley Periodicals, Inc.

  6. DockBench: An Integrated Informatic Platform Bridging the Gap between the Robust Validation of Docking Protocols and Virtual Screening Simulations

    Directory of Open Access Journals (Sweden)

    Alberto Cuzzolin

    2015-05-01

    Full Text Available Virtual screening (VS is a computational methodology that streamlines the drug discovery process by reducing costs and required resources through the in silico identification of potential drug candidates. Structure-based VS (SBVS exploits knowledge about the three-dimensional (3D structure of protein targets and uses the docking methodology as search engine for novel hits. The success of a SBVS campaign strongly depends upon the accuracy of the docking protocol used to select the candidates from large chemical libraries. The identification of suitable protocols is therefore a crucial step in the setup of SBVS experiments. Carrying out extensive benchmark studies, however, is usually a tangled task that requires users’ proficiency in handling different file formats and philosophies at the basis of the plethora of existing software packages. We present here DockBench 1.0, a platform available free of charge that eases the pipeline by automating the entire procedure, from docking benchmark to VS setups. In its current implementation, DockBench 1.0 handles seven docking software packages and offers the possibility to test up to seventeen different protocols. The main features of our platform are presented here and the results of the benchmark study of human Checkpoint kinase 1 (hChk1 are discussed as validation test.

  7. Conformational flexibility of aspartame.

    Science.gov (United States)

    Toniolo, Claudio; Temussi, Pierandrea

    2016-05-01

    L-Aspartyl-L-phenylalanine methyl ester, better known as aspartame, is not only one of the most used artificial sweeteners, but also a very interesting molecule with respect to the correlation between molecular structure and taste. The extreme conformational flexibility of this dipeptide posed a huge difficulty when researchers tried to use it as a lead compound to design new sweeteners. In particular, it was difficult to take advantage of its molecular model as a mold to infer the shape of the, then unknown, active site of the sweet taste receptor. Here, we follow the story of the 3D structural aspects of aspartame from early conformational studies to recent docking into homology models of the receptor. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 376-384, 2016. © 2016 Wiley Periodicals, Inc.

  8. On flexibility

    OpenAIRE

    Weiss, Christoph R.; Briglauer, Wolfgang

    2000-01-01

    By building on theoretical work by Mills and Schumann (1985) and Ungern-Sternberg (1990) this paper provides evidence on the determinants of two dimensions of flexibility, the flexibility in adjusting aggregate output over time (tactical flexibility) as well as the ability to switch quickly between products (operational flexibility). Econometric analysis of a sample of 40.000 farms in Upper-Austria for the period 1980 to 1990 suggests that larger full-time farms operated by younger, better ed...

  9. Experimental and Theoretical Study of the Movement of the Wpd Flexible Loop of Human Protein Tyrosine Phosphatase PTP1B in Complex with Halide Ions

    Science.gov (United States)

    Katz, Aline; Saenz-Méndez, Patricia; Cousido-Siah, Alexandra; Podjarny, Alberto D.; Ventura, Oscar N.

    2012-11-01

    Protein tyrosine phosphorylation is a post-translational modification mechanism, crucial for the regulation of nearly all aspects of cell life. This dynamic, reversible process is regulated by the balanced opposing activity of protein tyrosine kinases and protein tyrosine phosphatases. In particular, the protein tyrosine phosphatase 1B (PTP1B) is implicated in the regulation of the insulin-receptor activity, leptin-stimulated signal transduction pathways and other clinically relevant metabolic routes, and it has been found overexpressed or overregulated in human breasts, colon and ovary cancers. The WPD loop of the enzyme presents an inherent flexibility, and it plays a fundamental role in the enzymatic catalysis, turning it into a potential target in the design of new efficient PTP1B inhibitors. In order to determine the interactions that control the spatial conformation adopted by the WPD loop, complexes between the enzyme and halide ions (Br- and I- in particular) were crystallized and their crystallographic structure determined, and the collective movements of the aforementioned complexes were studied through Molecular Dynamics (MD) simulations. Both studies yielded concordant results, indicating the existence of a relationship between the identity of the ion present in the complex and the strength of the interactions it establishes with the surrounding protein residues.

  10. Computational modeling on the recognition of the HRE motif by HIF-1: molecular docking and molecular dynamics studies.

    Science.gov (United States)

    Sokkar, Pandian; Sathis, Vani; Ramachandran, Murugesan

    2012-05-01

    Hypoxia inducible factor-1 (HIF-1) is a bHLH-family transcription factor that controls genes involved in glycolysis, angiogenesis, migration, as well as invasion factors that are important for tumor progression and metastasis. HIF-1, a heterodimer of HIF-1α and HIF-1β, binds to the hypoxia responsive element (HRE) present in the promoter regions of hypoxia responsive genes, such as vascular endothelial growth factor (VEGF). Neither the structure of free HIF-1 nor that of its complex with HRE is available. Computational modeling of the transcription factor-DNA complex has always been challenging due to their inherent flexibility and large conformational space. The present study aims to model the interaction between the DNA-binding domain of HIF-1 and HRE. Experiments showed that rigid macromolecular docking programs (HEX and GRAMM-X) failed to predict the optimal dimerization of individually modeled HIF-1 subunits. Hence, the HIF-1 heterodimer was modeled based on the phosphate system positive regulatory protein (PHO4) homodimer. The duplex VEGF-DNA segment containing HRE with flanking nucleotides was modeled in the B form and equilibrated via molecular dynamics (MD) simulation. A rigid docking approach was used to predict the crude binding mode of HIF-1 dimer with HRE, in which the putative contacts were found to be present. An MD simulation (5 ns) of the HIF-1-HRE complex in explicit water was performed to account for its flexibility and to optimize its interactions. All of the conserved amino acid residues were found to play roles in the recognition of HRE. The present work, which sheds light on the recognition of HRE by HIF-1, could be beneficial in the design of peptide or small molecule therapeutics that can mimic HIF-1 and bind with the HRE sequence.

  11. The C Terminus of the Core β-Ladder Domain in Japanese Encephalitis Virus Nonstructural Protein 1 Is Flexible for Accommodation of Heterologous Epitope Fusion.

    Science.gov (United States)

    Yen, Li-Chen; Liao, Jia-Teh; Lee, Hwei-Jen; Chou, Wei-Yuan; Chen, Chun-Wei; Lin, Yi-Ling; Liao, Ching-Len

    2016-02-01

    NS1 is the only nonstructural protein that enters the lumen of the endoplasmic reticulum (ER), where NS1 is glycosylated, forms a dimer, and is subsequently secreted during flavivirus replication as dimers or hexamers, which appear to be highly immunogenic to the infected host, as protective immunity can be elicited against homologous flavivirus infections. Here, by using a trans-complementation assay, we identified the C-terminal end of NS1 derived from Japanese encephalitis virus (JEV), which was more flexible than other regions in terms of housing foreign epitopes without a significant impact on virus replication. This mapped flexible region is located in the conserved tip of the core β-ladder domain of the multimeric NS1 structure and is also known to contain certain linear epitopes, readily triggering specific antibody responses from the host. Despite becoming attenuated, recombinant JEV with insertion of a neutralizing epitope derived from enterovirus 71 (EV71) into the C-terminal end of NS1 not only could be normally released from infected cells, but also induced dual protective immunity for the host to counteract lethal challenge with either JEV or EV71 in neonatal mice. These results indicated that the secreted multimeric NS1 of flaviviruses may serve as a natural protein carrier to render epitopes of interest more immunogenic in the C terminus of the core β-ladder domain. The positive-sense RNA genomes of mosquito-borne flaviviruses appear to be flexible in terms of accommodating extra insertions of short heterologous antigens into their virus genes. Here, we illustrate that the newly identified C terminus of the core β-ladder domain in NS1 could be readily inserted into entities such as EV71 epitopes, and the resulting NS1-epitope fusion proteins appeared to maintain normal virus replication, secretion ability, and multimeric formation from infected cells. Nonetheless, such an insertion attenuated the recombinant JEV in mice, despite having retained

  12. Theory and Applications of Covalent Docking in Drug Discovery: Merits and Pitfalls

    Directory of Open Access Journals (Sweden)

    Hezekiel Mathambo Kumalo

    2015-01-01

    Full Text Available he present art of drug discovery and design of new drugs is based on suicidal irreversible inhibitors. Covalent inhibition is the strategy that is used to achieve irreversible inhibition. Irreversible inhibitors interact with their targets in a time-dependent fashion, and the reaction proceeds to completion rather than to equilibrium. Covalent inhibitors possessed some significant advantages over non-covalent inhibitors such as covalent warheads can target rare, non-conserved residue of a particular target protein and thus led to development of highly selective inhibitors, covalent inhibitors can be effective in targeting proteins with shallow binding cleavage which will led to development of novel inhibitors with increased potency than non-covalent inhibitors. Several computational approaches have been developed to simulate covalent interactions; however, this is still a challenging area to explore. Covalent molecular docking has been recently implemented in the computer-aided drug design workflows to describe covalent interactions between inhibitors and biological targets. In this review we highlight: (i covalent interactions in biomolecular systems; (ii the mathematical framework of covalent molecular docking; (iii implementation of covalent docking protocol in drug design workflows; (iv applications covalent docking: case studies and (v shortcomings and future perspectives of covalent docking. To the best of our knowledge; this review is the first account that highlights different aspects of covalent docking with its merits and pitfalls. We believe that the method and applications highlighted in this study will help future efforts towards the design of irreversible inhibitors.

  13. Bio-inspired algorithms applied to molecular docking simulations.

    Science.gov (United States)

    Heberlé, G; de Azevedo, W F

    2011-01-01

    Nature as a source of inspiration has been shown to have a great beneficial impact on the development of new computational methodologies. In this scenario, analyses of the interactions between a protein target and a ligand can be simulated by biologically inspired algorithms (BIAs). These algorithms mimic biological systems to create new paradigms for computation, such as neural networks, evolutionary computing, and swarm intelligence. This review provides a description of the main concepts behind BIAs applied to molecular docking simulations. Special attention is devoted to evolutionary algorithms, guided-directed evolutionary algorithms, and Lamarckian genetic algorithms. Recent applications of these methodologies to protein targets identified in the Mycobacterium tuberculosis genome are described.

  14. Ribosomal protein L5 has a highly twisted concave surface and flexible arms responsible for rRNA binding.

    OpenAIRE

    Nakashima, T; Yao, M; Kawamura, S; Iwasaki, K; Kimura, M; Tanaka, I

    2001-01-01

    Ribosomal protein L5 is a 5S rRNA binding protein in the large subunit and plays an essential role in the promotion of a particular conformation of 5S rRNA. The crystal structure of the ribosomal protein L5 from Bacillus stearothermophilus has been determined at 1.8 A resolution. The molecule consists of a five-stranded antiparallel beta-sheet and four alpha-helices, which fold in a way that is topologically similar to the ribonucleoprotein (RNP) domain. The molecular shape and electrostatic ...

  15. Improved performance in CAPRI round 37 using LZerD docking and template-based modeling with combined scoring functions.

    Science.gov (United States)

    Peterson, Lenna X; Shin, Woong-Hee; Kim, Hyungrae; Kihara, Daisuke

    2018-03-01

    We report our group's performance for protein-protein complex structure prediction and scoring in Round 37 of the Critical Assessment of PRediction of Interactions (CAPRI), an objective assessment of protein-protein complex modeling. We demonstrated noticeable improvement in both prediction and scoring compared to previous rounds of CAPRI, with our human predictor group near the top of the rankings and our server scorer group at the top. This is the first time in CAPRI that a server has been the top scorer group. To predict protein-protein complex structures, we used both multi-chain template-based modeling (TBM) and our protein-protein docking program, LZerD. LZerD represents protein surfaces using 3D Zernike descriptors (3DZD), which are based on a mathematical series expansion of a 3D function. Because 3DZD are a soft representation of the protein surface, LZerD is tolerant to small conformational changes, making it well suited to docking unbound and TBM structures. The key to our improved performance in CAPRI Round 37 was to combine multi-chain TBM and docking. As opposed to our previous strategy of performing docking for all target complexes, we used TBM when multi-chain templates were available and docking otherwise. We also describe the combination of multiple scoring functions used by our server scorer group, which achieved the top rank for the scorer phase. © 2017 Wiley Periodicals, Inc.

  16. Immunolocalization of keratin-associated beta-proteins (beta-keratins) in pad lamellae of geckos suggest that glycine-cysteine-rich proteins contribute to their flexibility and adhesiveness.

    Science.gov (United States)

    Alibardi, Lorenzo

    2013-03-01

    The epidermis of digital pads in geckos comprises superficial microornamentation from the oberhautchen layer that form long setae allowing these lizards to climb vertical surfaces. The beta-layer is reduced in pad lamellae but persists up to the apical free margin. Setae are made of different proteins including keratin-associated beta-proteins, formerly indicated as beta-keratins. In order to identify specific setal proteins the present ultrastructural study on geckos pad lamellae analyzes the immunolocalization of three beta-proteins previously found in the epidermis and adhesive setae of the green anolis. A protein rich in glycine but poor in cysteine (HgG5-like) is absent or masked in gecko pad lamellae. Another protein rich in glycine and cysteine (HgGC3-like) is weakly present in setae, oberhautchen and beta-layer. A glycine and cysteine medium rich beta-protein (HgGC10-like) is present in the lower part of the beta-layer but is absent in the oberhautchen, setae, and mesos layer. The latter two proteins may form intermolecular bonds that contribute to the flexibility of the corneous material sustaining the setae. The pliable alpha-layer present beneath the thin beta-layer and in the hinge region of the pad lamellae also contains HgGC10-like proteins. Based on the possibility that some HgGC3-like or other cys-rich beta-proteins are charged in the setae it is suggested that their charges influence the mechanism of adhesion increasing the induction of dipoles on the substrate and enhancing attractive van der Waals forces. Copyright © 2013 Wiley Periodicals, Inc.

  17. RNA-Seq and molecular docking reveal multi-level pesticide resistance in the bed bug

    Directory of Open Access Journals (Sweden)

    Mamidala Praveen

    2012-01-01

    Full Text Available Abstract Background Bed bugs (Cimex lectularius are hematophagous nocturnal parasites of humans that have attained high impact status due to their worldwide resurgence. The sudden and rampant resurgence of C. lectularius has been attributed to numerous factors including frequent international travel, narrower pest management practices, and insecticide resistance. Results We performed a next-generation RNA sequencing (RNA-Seq experiment to find differentially expressed genes between pesticide-resistant (PR and pesticide-susceptible (PS strains of C. lectularius. A reference transcriptome database of 51,492 expressed sequence tags (ESTs was created by combining the databases derived from de novo assembled mRNA-Seq tags (30,404 ESTs and our previous 454 pyrosequenced database (21,088 ESTs. The two-way GLMseq analysis revealed ~15,000 highly significant differentially expressed ESTs between the PR and PS strains. Among the top 5,000 differentially expressed ESTs, 109 putative defense genes (cuticular proteins, cytochrome P450s, antioxidant genes, ABC transporters, glutathione S-transferases, carboxylesterases and acetyl cholinesterase involved in penetration resistance and metabolic resistance were identified. Tissue and development-specific expression of P450 CYP3 clan members showed high mRNA levels in the cuticle, Malpighian tubules, and midgut; and in early instar nymphs, respectively. Lastly, molecular modeling and docking of a candidate cytochrome P450 (CYP397A1V2 revealed the flexibility of the deduced protein to metabolize a broad range of insecticide substrates including DDT, deltamethrin, permethrin, and imidacloprid. Conclusions We developed significant molecular resources for C. lectularius putatively involved in metabolic resistance as well as those participating in other modes of insecticide resistance. RNA-Seq profiles of PR strains combined with tissue-specific profiles and molecular docking revealed multi-level insecticide

  18. Effects of wood preservative leachates from docks

    Energy Technology Data Exchange (ETDEWEB)

    Wendt, P.H.; Van Dolah, R.F.; Bobo, M.Y.; Mathews, T.D. [South Carolina Marine Resources Research Inst., Charleston, SC (United States)

    1994-12-31

    Recent evidence indicates that the wood preservative commonly used in dock pilings (chromated copper arsenate or CCA) is highly toxic to several estuarine organisms in laboratory experiments. Increasing demand for residential docks prompted a field study intended to complement these earlier laboratory investigations. Objectives of the study were to: (1) examine concentrations of Cu, Cr, and As in sediments and oysters from intertidal locations in several creeks with and without high densities of docks; (2) examine the bioaccumulation of wood preservative leachates by laboratory-reared oysters transferred to field sites near and distant from newly constructed docks; and (3) investigate the acute toxicity of wood preservative leachates for several species of estuarine fishes and invertebrates exposed to these compounds in the field. Preliminary results indicate that sediment concentrations of all three metals were well below ER-L levels reported by Long and Morgan at all but one dock site. In an ancillary study, 24h LC{sub 50} bioassays were performed using rotifers (Brachionus plicatilis) which were exposed to pore water from sediments in creeks with and without docks. Toxicities of bulk sediments from the same sites were examined using Microtox which measures decreases in bioluminescence of marine bacteria (Photobacterium phosphoreum) as a function of sediment concentration. Neither the rotifer nor the Microtox bioassays showed any significant differences in toxicity between creeks with and without docks.

  19. A Steric-inhibition model for regulation of nucleotide exchange via the Dock180 family of GEFs.

    Science.gov (United States)

    Lu, Mingjian; Kinchen, Jason M; Rossman, Kent L; Grimsley, Cynthia; Hall, Matthew; Sondek, John; Hengartner, Michael O; Yajnik, Vijay; Ravichandran, Kodi S

    2005-02-22

    CDM (CED-5, Dock180, Myoblast city) family members have been recently identified as novel, evolutionarily conserved guanine nucleotide exchange factors (GEFs) for Rho-family GTPases . They regulate multiple processes, including embryonic development, cell migration, apoptotic-cell engulfment, tumor invasion, and HIV-1 infection, in diverse model systems . However, the mechanism(s) of regulation of CDM proteins has not been well understood. Here, our studies on the prototype member Dock180 reveal a steric-inhibition model for regulating the Dock180 family of GEFs. At basal state, the N-terminal SH3 domain of Dock180 binds to the distant catalytic Docker domain and negatively regulates the function of Dock180. Further studies revealed that the SH3:Docker interaction sterically blocks Rac access to the Docker domain. Interestingly, ELMO binding to the SH3 domain of Dock180 disrupted the SH3:Docker interaction, facilitated Rac access to the Docker domain, and contributed to the GEF activity of the Dock180/ELMO complex. Additional genetic rescue studies in C. elegans suggested that the regulation of the Docker-domain-mediated GEF activity by the SH3 domain and its adjoining region is evolutionarily conserved. This steric-inhibition model may be a general mechanism for regulating multiple SH3-domain-containing Dock180 family members and may have implications for a variety of biological processes.

  20. Transition Metal Ions Enable the Transition from Electrospun Prolamin Protein Fibers to Nitrogen-Doped Freestanding Carbon Films for Flexible Supercapacitors.

    Science.gov (United States)

    Wang, Yixiang; Yang, Jingqi; Du, Rongbing; Chen, Lingyun

    2017-07-19

    Flexible carbon ultrafine fibers are highly desirable in energy storage and conversion devices. Our previous finding showed that electrospun hordein/zein fibers stabilized by Ca 2+ were successfully transferred into nitrogen-doped carbon ultrafine fibers for supercapacitors. However, their relatively brittle nature needed to be improved. Inspired by this stabilizing effect of Ca 2+ , in this work, four transition metal divalent cations were used to assist the formation of flexible hordein/zein-derived carbon ultrafine fibers. Without alteration of the electrospinnability, adequate amounts of zinc acetate and cobalt acetate supported the fibrous structure during pyrolysis. This resulted in flexible freestanding carbon films consisting of well-defined fibers with nitrogen-doped graphitic layers and hierarchical pores. These carbon films were easily cut into small square pieces and directly applied as working electrode in the three-electrode testing system without the need for polymer binders or conducting agents. Notably, the hz-Zn0.3-p electrode, synthesized with 0.3 mol/L Zn 2+ and post-acid treatment, exhibited a specific capacitance of 393 F/g (at 1 A/g), a large rate capability (72.3% remained at 20 A/g), and a capacitance retention of ∼98% after 2000 charging-discharging cycles at 10 A/g. These superior electrochemical properties were attributed to the synergistic effects of the well-developed graphitic layers induced by Zn 2+ , the nitrogen-decorated carbon structure, and the interconnected channels generated by HCl treatment. This research advances potential applications for prolamin proteins as nitrogen-containing raw materials in developing carbon structures for high-performance supercapacitors.

  1. Dock/Nck facilitates PTP61F/PTP1B regulation of insulin signalling.

    Science.gov (United States)

    Wu, Chia-Lun; Buszard, Bree; Teng, Chun-Hung; Chen, Wei-Lin; Warr, Coral G; Tiganis, Tony; Meng, Tzu-Ching

    2011-10-01

    PTP1B (protein tyrosine phosphatase 1B) is a negative regulator of IR (insulin receptor) activation and glucose homoeostasis, but the precise molecular mechanisms governing PTP1B substrate selectivity and the regulation of insulin signalling remain unclear. In the present study we have taken advantage of Drosophila as a model organism to establish the role of the SH3 (Src homology 3)/SH2 adaptor protein Dock (Dreadlocks) and its mammalian counterpart Nck in IR regulation by PTPs. We demonstrate that the PTP1B orthologue PTP61F dephosphorylates the Drosophila IR in S2 cells in vitro and attenuates IR-induced eye overgrowth in vivo. Our studies indicate that Dock forms a stable complex with PTP61F and that Dock/PTP61F associate with the IR in response to insulin. We report that Dock is required for effective IR dephosphorylation and inactivation by PTP61F in vitro and in vivo. Furthermore, we demonstrate that Nck interacts with PTP1B and that the Nck/PTP1B complex inducibly associates with the IR for the attenuation of IR activation in mammalian cells. Our studies reveal for the first time that the adaptor protein Dock/Nck attenuates insulin signalling by recruiting PTP61F/PTP1B to its substrate, the IR.

  2. Vehicle routing with cross-docking

    DEFF Research Database (Denmark)

    Wen, Min; Larsen, Jesper; Clausen, Jens

    2009-01-01

    a set of homogeneous vehicles are used to transport orders from the suppliers to the corresponding customers via a cross-dock. The orders can be consolidated at the cross-dock but cannot be stored for very long because the cross-dock does not have long-term inventory-holding capabilities. The objective...... of the VRPCD is to minimize the total travel time while respecting time window constraints at the nodes and a time horizon for the whole transportation operation. In this paper, a mixed integer programming formulation for the VRPCD is proposed. A tabu search heuristic is embedded within an adaptive memory...... values) within very short computational time....

  3. Dietary balanced protein in broiler chickens. 1. A flexible and practical tool to predict dose-response curves

    NARCIS (Netherlands)

    Eits, R.M.; Kwakkel, R.P.; Verstegen, M.W.A.; Hartog, den L.A.

    2005-01-01

    1. An empirical model of exponential form was developed, different versions of which can be used to predict growth rate, feed conversion and carcase and breast meat yield of broiler chickens as a function of dietary balanced protein ( DBP) content. The model was developed to support decision- making

  4. F pocket flexibility influences the tapasin dependence of two differentially disease-associated MHC Class I proteins.

    Science.gov (United States)

    Abualrous, Esam T; Fritzsche, Susanne; Hein, Zeynep; Al-Balushi, Mohammed S; Reinink, Peter; Boyle, Louise H; Wellbrock, Ursula; Antoniou, Antony N; Springer, Sebastian

    2015-04-01

    The human MHC class I protein HLA-B*27:05 is statistically associated with ankylosing spondylitis, unlike HLA-B*27:09, which differs in a single amino acid in the F pocket of the peptide-binding groove. To understand how this unique amino acid difference leads to a different behavior of the proteins in the cell, we have investigated the conformational stability of both proteins using a combination of in silico and experimental approaches. Here, we show that the binding site of B*27:05 is conformationally disordered in the absence of peptide due to a charge repulsion at the bottom of the F pocket. In agreement with this, B*27:05 requires the chaperone protein tapasin to a greater extent than the conformationally stable B*27:09 in order to remain structured and to bind peptide. Taken together, our data demonstrate a method to predict tapasin dependence and physiological behavior from the sequence and crystal structure of a particular class I allotype. Also watch the Video Abstract. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  5. NMR experiments for resonance assignments of 13C, 15N doubly-labeled flexible polypeptides: Application to the human prion protein hPrP(23-230)

    International Nuclear Information System (INIS)

    Liu Aizhuo; Riek, Roland; Wider, Gerhard; Schroetter, Christine von; Zahn, Ralph; Wuethrich, Kurt

    2000-01-01

    A combination of three heteronuclear three-dimensional NMR experiments tailored for sequential resonance assignments in uniformly 15 N, 13 C-labeled flexible polypeptide chains is described. The 3D (H)N(CO-TOCSY)NH, 3D (H)CA(CO-TOCSY)NH and 3D (H)CBCA(CO-TOCSY)NH schemes make use of the favorable 15 N chemical shift dispersion in unfolded polypeptides, exploit the slow transverse 15 N relaxation rates of unfolded polypeptides in high resolution constant-time [ 1 H, 15 N]-correlation experiments, and use carbonyl carbon homonuclear isotropic mixing to transfer magnetization sequentially along the amino acid sequence. Practical applications are demonstrated with the 100-residue flexible tail of the recombinant human prion protein, making use of spectral resolution up to 0.6 Hz in the 15 N dimension, simultaneous correlation with the two adjacent amino acid residues to overcome problems associated with spectral overlap, and the potential of the presently described experiments to establish nearest-neighbor correlations across proline residues in the amino acid sequence

  6. Local Backbone Flexibility as a Determinant of the Apparent pKa Values of Buried Ionizable Groups in Proteins.

    Science.gov (United States)

    Peck, Meredith T; Ortega, Gabriel; De Luca-Johnson, Javier N; Schlessman, Jamie L; Robinson, Aaron C; García-Moreno E, Bertrand

    2017-10-10

    Ionizable groups buried in the hydrophobic interior of proteins are essential for energy transduction. These groups can have highly anomalous pK a values that reflect the incompatibility between charges and dehydrated environments. A systematic study of pK a values of buried ionizable groups in staphylococcal nuclease (SNase) suggests that these pK a values are determined in part by conformational reorganization of the protein. Lys-66 is one of the most deeply buried residues in SNase. We show that its apparent pK a of 5.7 reflects the average of the pK a values of Lys-66 in different conformational states of the protein. In the fully folded state, Lys-66 is deeply buried in the hydrophobic core of SNase and must titrate with a pK a of ≪5.7. In other states, the side chain of Lys-66 is fully solvent-exposed and has a normal pK a of ≈10.4. We show that the pK a of Lys-66 can be shifted from 5.7 toward a more normal value of 7.1 via the insertion of flanking Gly residues at positions 64 and 67 to promote an "open" conformation of SNase. Crystal structures and nuclear magnetic resonance spectroscopy show that in these Gly-containing variants Lys-66 can access bulk water as a consequence of overwinding of the C-terminal end of helix 1. These data illustrate that the apparent pK a values of buried groups in proteins are governed in part by the difference in free energy between different conformational states of the protein and by differences in the pK a values of the buried groups in the different conformations.

  7. A molecular docking study of phytochemical estrogen mimics from dietary herbal supplements.

    Science.gov (United States)

    Powers, Chelsea N; Setzer, William N

    2015-01-01

    The purpose of this study is to use a molecular docking approach to identify potential estrogen mimics or anti-estrogens in phytochemicals found in popular dietary herbal supplements. In this study, 568 phytochemicals found in 17 of the most popular herbal supplements sold in the United States were built and docked with two isoforms of the estrogen receptor, ERα and ERβ (a total of 27 different protein crystal structures). The docking results revealed six strongly docking compounds in Echinacea, three from milk thistle (Silybum marianum), three from Gingko biloba, one from Sambucus nigra, none from maca (Lepidium meyenii), five from chaste tree (Vitex agnus-castus), two from fenugreek (Trigonella foenum-graecum), and two from Rhodiola rosea. Notably, of the most popular herbal supplements for women, there were numerous compounds that docked strongly with the estrogen receptor: Licorice (Glycyrrhiza glabra) had a total of 26 compounds strongly docking to the estrogen receptor, 15 with wild yam (Dioscorea villosa), 11 from black cohosh (Actaea racemosa), eight from muira puama (Ptychopetalum olacoides or P. uncinatum), eight from red clover (Trifolium pratense), three from damiana (Turnera aphrodisiaca or T. diffusa), and three from dong quai (Angelica sinensis). Of possible concern were the compounds from men's herbal supplements that exhibited strong docking to the estrogen receptor: Gingko biloba had three compounds, gotu kola (Centella asiatica) had two, muira puama (Ptychopetalum olacoides or P. uncinatum) had eight, and Tribulus terrestris had six compounds. This molecular docking study has revealed that almost all popular herbal supplements contain phytochemical components that may bind to the human estrogen receptor and exhibit selective estrogen receptor modulation. As such, these herbal supplements may cause unwanted side effects related to estrogenic activity.

  8. Ranking multiple docking solutions based on the conservation of inter-residue contacts

    KAUST Repository

    Oliva, Romina M.

    2013-06-17

    Molecular docking is the method of choice for investigating the molecular basis of recognition in a large number of functional protein complexes. However, correctly scoring the obtained docking solutions (decoys) to rank native-like (NL) conformations in the top positions is still an open problem. Herein we present CONSRANK, a simple and effective tool to rank multiple docking solutions, which relies on the conservation of inter-residue contacts in the analyzed decoys ensemble. First it calculates a conservation rate for each inter-residue contact, then it ranks decoys according to their ability to match the more frequently observed contacts. We applied CONSRANK to 102 targets from three different benchmarks, RosettaDock, DOCKGROUND, and Critical Assessment of PRedicted Interactions (CAPRI). The method performs consistently well, both in terms of NL solutions ranked in the top positions and of values of the area under the receiver operating characteristic curve. Its ideal application is to solutions coming from different docking programs and procedures, as in the case of CAPRI targets. For all the analyzed CAPRI targets where a comparison is feasible, CONSRANK outperforms the CAPRI scorers. The fraction of NL solutions in the top ten positions in the RosettaDock, DOCKGROUND, and CAPRI benchmarks is enriched on average by a factor of 3.0, 1.9, and 9.9, respectively. Interestingly, CONSRANK is also able to specifically single out the high/medium quality (HMQ) solutions from the docking decoys ensemble: it ranks 46.2 and 70.8% of the total HMQ solutions available for the RosettaDock and CAPRI targets, respectively, within the top 20 positions. © 2013 Wiley Periodicals, Inc.

  9. Modeling complexes of modeled proteins.

    Science.gov (United States)

    Anishchenko, Ivan; Kundrotas, Petras J; Vakser, Ilya A

    2017-03-01

    Structural characterization of proteins is essential for understanding life processes at the molecular level. However, only a fraction of known proteins have experimentally determined structures. This fraction is even smaller for protein-protein complexes. Thus, structural modeling of protein-protein interactions (docking) primarily has to rely on modeled structures of the individual proteins, which typically are less accurate than the experimentally determined ones. Such "double" modeling is the Grand Challenge of structural reconstruction of the interactome. Yet it remains so far largely untested in a systematic way. We present a comprehensive validation of template-based and free docking on a set of 165 complexes, where each protein model has six levels of structural accuracy, from 1 to 6 Å C α RMSD. Many template-based docking predictions fall into acceptable quality category, according to the CAPRI criteria, even for highly inaccurate proteins (5-6 Å RMSD), although the number of such models (and, consequently, the docking success rate) drops significantly for models with RMSD > 4 Å. The results show that the existing docking methodologies can be successfully applied to protein models with a broad range of structural accuracy, and the template-based docking is much less sensitive to inaccuracies of protein models than the free docking. Proteins 2017; 85:470-478. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  10. Slit stimulation recruits Dock and Pak to the roundabout receptor and increases Rac activity to regulate axon repulsion at the CNS midline.

    Science.gov (United States)

    Fan, Xueping; Labrador, Juan Pablo; Hing, Huey; Bashaw, Greg J

    2003-09-25

    Drosophila Roundabout (Robo) is the founding member of a conserved family of repulsive axon guidance receptors that respond to secreted Slit proteins. Here we present evidence that the SH3-SH2 adaptor protein Dreadlocks (Dock), the p21-activated serine-threonine kinase (Pak), and the Rac1/Rac2/Mtl small GTPases can function during Robo repulsion. Loss-of-function and genetic interaction experiments suggest that limiting the function of Dock, Pak, or Rac partially disrupts Robo repulsion. In addition, Dock can directly bind to Robo's cytoplasmic domain, and the association of Dock and Robo is enhanced by stimulation with Slit. Furthermore, Slit stimulation can recruit a complex of Dock and Pak to the Robo receptor and trigger an increase in Rac1 activity. These results provide a direct physical link between the Robo receptor and an important cytoskeletal regulatory protein complex and suggest that Rac can function in both attractive and repulsive axon guidance.

  11. Conflicting flexibility

    NARCIS (Netherlands)

    De Jong, P.; Schaap, A.

    2011-01-01

    New buildings are designed for first users. For a sustainable approach there are many advantages in designing in flexibility and adjustability in order to enable and facilitate the other sequential users. For the first investor this flexibility is translated into improved exit values due to

  12. Molecular docking and molecular dynamics simulation studies on Thermus thermophilus leucyl-tRNA synthetase complexed with different amino acids and pre-transfer editing substrates

    Directory of Open Access Journals (Sweden)

    Rayevsky A. V.

    2016-02-01

    Full Text Available Aim. To investigate the structural bases for the amino acid selectivity of the Thermus thermophilus leucyl-tRNA synthetase (LeuRSTT aminoacylation site and to disclose the binding pattern of pre-transfer editing substrates. Methods. Eight amino acids proposed as semi-cognate substrates for aminoacylation and eight aminoacyl-adenylates (formed from AMP and eight amino acids were prepared in zwitterions form. The protein structure with a co-crystallized substrate in the aminoacylation site [PDBID: 1OBH] was taken from RCSB. Docking settings and evaluation of substrate efficiency were followed by twofold docking function analysis for each conformation with Gold CCDC. The molecular dynamics simulation was performed using Gromacs. The procedures of relaxation and binding study were separated in two different subsequent simulations for 50ns and 5ns. Results. The evaluation of substrate efficiency for 8 amino acids by twofold docking function analysis, based on score values,has shown that the ligands of LeuRSTT can be positioned in the following order: Leu>Nva>Hcy>Nle>Met>Cys>Ile >Val. MD simulation has revealed lower electrostatic interactions of isoleucine with the active site of the enzyme compared with those for norvaline and leucine. In the case of aminoacyl-adenylates no significant differences were found based on score values for both GoldScore and Asp functions. Molecular dynamics of leucyl-, isoleucyl- and norvalyl-adenylates showed that the most stable and conformationally favorable is leucine, then follow norvaline and isoleucine. It has been also found that the TYR43 of the active site covers carboxyl group of leucine and norvaline like a shield and deflected towards isoleucine, allowing water molecules to come closer. Conclusions. In this study we revealed some structural basis for screening unfavorable substrates by shape, size and flexibility of a radical. The results obtained for different amino acids by molecular docking and MD studies

  13. Transforming p21 ras protein: flexibility in the major variable region linking the catalytic and membrane-anchoring domains

    DEFF Research Database (Denmark)

    Willumsen, B M; Papageorge, A G; Hubbert, N

    1985-01-01

    or increasing it to 50 amino acids has relatively little effect on the capacity of the gene to induce morphological transformation of NIH 3T3 cells. Assays of GTP binding, GTPase and autophosphorylating activities of such mutant v-rasH-encoded proteins synthesized in bacteria indicated that the sequences...... that is required for post-translational processing, membrane localization and transforming activity of the proteins. We have now used the viral oncogene (v-rasH) of Harvey sarcoma virus to study the major variable region by deleting or duplicating parts of the gene. Reducing this region to five amino acids...... that encode these biochemical activities are located upstream from the major variable region. In the context of transformation, we propose that the region of sequence heterogeneity serves principally to connect the N-terminal catalytic domain with amino acids at the C terminus that are required to anchor...

  14. Design and Preliminary Testing of the International Docking Adapter's Peripheral Docking Target

    Science.gov (United States)

    Foster, Christopher W.; Blaschak, Johnathan; Eldridge, Erin A.; Brazzel, Jack P.; Spehar, Peter T.

    2015-01-01

    The International Docking Adapter's Peripheral Docking Target (PDT) was designed to allow a docking spacecraft to judge its alignment relative to the docking system. The PDT was designed to be compatible with relative sensors using visible cameras, thermal imagers, or Light Detection and Ranging (LIDAR) technologies. The conceptual design team tested prototype designs and materials to determine the contrast requirements for the features. This paper will discuss the design of the PDT, the methodology and results of the tests, and the conclusions pertaining to PDT design that were drawn from testing.

  15. Why are most EU pigs tail docked?

    DEFF Research Database (Denmark)

    D'eath, R.B.; Niemi, J.K.; Vosough Ahmadi, B.

    2016-01-01

    To limit tail biting incidence, most pig producers in Europe tail dock their piglets. This is despite EU Council Directive 2008/120/EC banning routine tail docking and allowing it only as a last resort. The paper aims to understand what it takes to fulfil the intentions of the Directive...... by examining economic results of four management and housing scenarios, and by discussing their consequences for animal welfare in the light of legal and ethical considerations. The four scenarios compared are: ‘Standard Docked’, a conventional housing scenario with tail docking meeting the recommendations...... for Danish production (0.7 m2/pig); ‘Standard Undocked’, which is the same as ‘Standard Docked’ but with no tail docking, ‘Efficient Undocked’ and ‘Enhanced Undocked’, which have increased solid floor area (0.9 and 1.0 m2/pig, respectively) provision of loose manipulable materials (100 and 200 g/straw per...

  16. Dockomatic - automated ligand creation and docking.

    Science.gov (United States)

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

    2010-11-08

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

  17. Dockomatic - automated ligand creation and docking

    Directory of Open Access Journals (Sweden)

    Hampikian Greg

    2010-11-01

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

  18. Ribosomal protein L5 has a highly twisted concave surface and flexible arms responsible for rRNA binding.

    Science.gov (United States)

    Nakashima, T; Yao, M; Kawamura, S; Iwasaki, K; Kimura, M; Tanaka, I

    2001-05-01

    Ribosomal protein L5 is a 5S rRNA binding protein in the large subunit and plays an essential role in the promotion of a particular conformation of 5S rRNA. The crystal structure of the ribosomal protein L5 from Bacillus stearothermophilus has been determined at 1.8 A resolution. The molecule consists of a five-stranded antiparallel beta-sheet and four alpha-helices, which fold in a way that is topologically similar to the ribonucleoprotein (RNP) domain. The molecular shape and electrostatic representation suggest that the concave surface and loop regions are involved in 5S rRNA binding. To identify amino acid residues responsible for 5S rRNA binding, we made use of Ala-scanning mutagenesis of evolutionarily conserved amino acids occurring in the beta-strands and loop regions. The mutations of Asn37 at the beta1-strand and Gln63 at the loop between helix 2 and beta3-strand as well as that of Phe77 at the tip of the loop structure between the beta2- and beta3-strands caused a significant reduction in 5S rRNA binding. In addition, the mutations of Thr90 on the beta3-strand and Ile141 and Asp144 at the loop between beta4- and beta5-strands moderately reduced the 5S rRNA-binding affinity. Comparison of these results with the more recently analyzed structure of the 50S subunit from Haloarcula marismortui suggests that there are significant differences in the structure at N- and C-terminal regions and probably in the 5S rRNA binding.

  19. Modeling, molecular dynamics, and docking assessment of transcription factor rho: a potential drug target in Brucella melitensis 16M

    Directory of Open Access Journals (Sweden)

    Pradeepkiran JA

    2015-03-01

    Full Text Available Jangampalli Adi Pradeepkiran,1 Konidala Kranthi Kumar,1 Yellapu Nanda Kumar,2 Matcha Bhaskar11Division of Animal Biotechnology, Department of Zoology, Sri Venkateswara University, Tirupati, 2Biomedical Informatics Centre, Vector Control Research Centre, Indian Council of Medical Research, Pondicherry, India Abstract: The zoonotic disease brucellosis, a chronic condition in humans affecting renal and cardiac systems and causing osteoarthritis, is caused by Brucella, a genus of Gram-negative, facultative, intracellular pathogens. The mode of transmission and the virulence of the pathogens are still enigmatic. Transcription regulatory elements, such as rho proteins, play an important role in the termination of transcription and/or the selection of genes in Brucella. Adverse effects of the transcription inhibitors play a key role in the non-successive transcription challenges faced by the pathogens. In the investigation presented here, we computationally predicted the transcription termination factor rho (TtFRho inhibitors against Brucella melitensis 16M via a structure-based method. In view the unknown nature of its crystal structure, we constructed a robust three-dimensional homology model of TtFRho’s structure by comparative modeling with the crystal structure of the Escherichia coli TtFRho (Protein Data Bank ID: 1PVO as a template in MODELLER (v 9.10. The modeled structure was optimized by applying a molecular dynamics simulation for 2 ns with the CHARMM (Chemistry at HARvard Macromolecular Mechanics 27 force field in NAMD (NAnoscale Molecular Dynamics program; v 2.9 and then evaluated by calculating the stereochemical quality of the protein. The flexible docking for the interaction phenomenon of the template consists of ligand-related inhibitor molecules from the ZINC (ZINC Is Not Commercial database using a structure-based virtual screening strategy against minimized TtFRho. Docking simulations revealed two inhibitors compounds – ZINC

  20. A new approach for investigating protein flexibility based on Constraint Logic Programming. The first application in the case of the estrogen receptor.

    Science.gov (United States)

    Dal Palú, Alessandro; Spyrakis, Francesca; Cozzini, Pietro

    2012-03-01

    We describe the potential of a novel method, based on Constraint Logic Programming (CLP), developed for an exhaustive sampling of protein conformational space. The CLP framework proposed here has been tested and applied to the estrogen receptor, whose activity and function is strictly related to its intrinsic, and well known, dynamics. We have investigated in particular the flexibility of H12, focusing on the pathways followed by the helix when moving from one stable crystallographic conformation to the others. Millions of geometrically feasible conformations were generated, selected and the traces connecting the different forms were determined by using a shortest path algorithm. The preliminary analyses showed a marked agreement between the crystallographic agonist-like, antagonist-like and hypothetical apo forms, and the corresponding conformations identified by the CLP framework. These promising results, together with the short computational time required to perform the analyses, make this constraint-based approach a valuable tool for the study of protein folding prediction. The CLP framework enables one to consider various structural and energetic scenarious, without changing the core algorithm. To show the feasibility of the method, we intentionally choose a pure geometric setting, neglecting the energetic evaluation of the poses, in order to be independent from a specific force field and to provide the possibility of comparing different behaviours associated with various energy models. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

  1. Scheduling Trucks in a Cross-Dock with Mixed Service Mode Dock Doors

    DEFF Research Database (Denmark)

    Bodnar, Peter; Azadeh, Kaveh; Koster, René de

    2017-01-01

    The problem considered in this paper is how to schedule inbound and outbound trucks subject to time windows at a multidoor cross-dock. Dock doors can either be dedicated to inbound or outbound trucks or be capable of handling both truck types. In addition, loads are allowed to be temporarily...

  2. Native Alanine Substitution in the Glycine Hinge Modulates Conformational Flexibility of Heme Nitric Oxide/Oxygen (H-NOX) Sensing Proteins.

    Science.gov (United States)

    Hespen, Charles W; Bruegger, Joel J; Guo, Yirui; Marletta, Michael A

    2018-06-15

    Heme nitric oxide/oxygen sensing (H-NOX) domains are direct NO sensors that regulate a variety of biological functions in both bacteria and eukaryotes. Previous work on H-NOX proteins has shown that upon NO binding, a conformational change occurs along two glycine residues on adjacent helices (termed the glycine hinge). Despite the apparent importance of the glycine hinge, it is not fully conserved in all H-NOX domains. Several H-NOX sensors from the family Flavobacteriaceae contain a native alanine substitution in one of the hinge residues. In this work, the effect of the increased steric bulk within the Ala-Gly hinge on H-NOX function was investigated. The hinge in Kordia algicida OT-1 ( Ka H-NOX) is composed of A71 and G145. Ligand-binding properties and signaling function for this H-NOX were characterized. The variant A71G was designed to convert the hinge region of Ka H-NOX to the typical Gly-Gly motif. In activity assays with its cognate histidine kinase (HnoK), the wild type displayed increased signal specificity compared to A71G. Increasing titrations of unliganded A71G gradually inhibits HnoK autophosphorylation, while increasing titrations of unliganded wild type H-NOX does not inhibit HnoK. Crystal structures of both wild type and A71G Ka H-NOX were solved to 1.9 and 1.6 Å, respectively. Regions of H-NOX domains previously identified as involved in protein-protein interactions with HnoK display significantly higher b-factors in A71G compared to wild-type H-NOX. Both biochemical and structural data indicate that the hinge region controls overall conformational flexibility of the H-NOX, affecting NO complex formation and regulation of its HnoK.

  3. High-throughput Molecular Docking Now in Reach for a Wider Biochemical Community

    NARCIS (Netherlands)

    Balan, D.M.; Malinauskas, T.; Prins, J.C.P.; Moller, S.

    2012-01-01

    In silico molecular docking is used to predict how a small molecule, the ligand, interacts with a target protein, its receptor. Together with experimental methods like NMR or X-ray crystallography, industrial and academic groups use it for their investigation of compounds with the potential to

  4. What in silico molecular docking can do for the 'bench-working ...

    Indian Academy of Sciences (India)

    RB, FL http://www.biosolveit.de/FlexX/. Commercial program available for Linux and Windows, part of the LeadIT software solution. Good user interface. Takes account of the metal coordination. It allows the user to select which atoms of the ligand and the protein are able to be joined by a covalent bound. Dock 6 (Kuntz et al.

  5. α-Synuclein may cross-bridge v-SNARE and acidic phospholipids to facilitate SNARE-dependent vesicle docking.

    Science.gov (United States)

    Lou, Xiaochu; Kim, Jaewook; Hawk, Brenden J; Shin, Yeon-Kyun

    2017-06-06

    Misfolded α-synuclein (A-syn) is widely recognized as the primal cause of neurodegenerative diseases including Parkinson's disease and dementia with Lewy bodies. The normal cellular function of A-syn has, however, been elusive. There is evidence that A-syn plays multiple roles in the exocytotic pathway in the neuron, but the underlying molecular mechanisms are unclear. A-syn has been known to interact with negatively charged phospholipids and with vesicle SNARE protein VAMP2. Using single-vesicle docking/fusion assays, we find that A-syn promotes SNARE-dependent vesicles docking significantly at 2.5 µM. When phosphatidylserine (PS) is removed from t-SNARE-bearing vesicles, the docking enhancement by A-syn disappears and A-syn instead acts as an inhibitor for docking. In contrast, subtraction of PS from the v-SNARE-carrying vesicles enhances vesicle docking even further. Moreover, when we truncate the C-terminal 45 residues of A-syn that participates in interacting with VAMP2, the promotion of vesicle docking is abrogated. Thus, the results suggest that the A-syn's interaction with v-SNARE through its C-terminal tail and its concurrent interaction with PS in trans through its amphipathic N-terminal domain facilitate SNARE complex formation, whereby A-syn aids SNARE-dependent vesicle docking. © 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.

  6. Multibody dynamical modeling for spacecraft docking process with spring-damper buffering device: A new validation approach

    Science.gov (United States)

    Daneshjou, Kamran; Alibakhshi, Reza

    2018-01-01

    In the current manuscript, the process of spacecraft docking, as one of the main risky operations in an on-orbit servicing mission, is modeled based on unconstrained multibody dynamics. The spring-damper buffering device is utilized here in the docking probe-cone system for micro-satellites. Owing to the impact occurs inevitably during docking process and the motion characteristics of multibody systems are remarkably affected by this phenomenon, a continuous contact force model needs to be considered. Spring-damper buffering device, keeping the spacecraft stable in an orbit when impact occurs, connects a base (cylinder) inserted in the chaser satellite and the end of docking probe. Furthermore, by considering a revolute joint equipped with torsional shock absorber, between base and chaser satellite, the docking probe can experience both translational and rotational motions simultaneously. Although spacecraft docking process accompanied by the buffering mechanisms may be modeled by constrained multibody dynamics, this paper deals with a simple and efficient formulation to eliminate the surplus generalized coordinates and solve the impact docking problem based on unconstrained Lagrangian mechanics. By an example problem, first, model verification is accomplished by comparing the computed results with those recently reported in the literature. Second, according to a new alternative validation approach, which is based on constrained multibody problem, the accuracy of presented model can be also evaluated. This proposed verification approach can be applied to indirectly solve the constrained multibody problems by minimum required effort. The time history of impact force, the influence of system flexibility and physical interaction between shock absorber and penetration depth caused by impact are the issues followed in this paper. Third, the MATLAB/SIMULINK multibody dynamic analysis software will be applied to build impact docking model to validate computed results and

  7. Rendezvous and Docking for Space Exploration

    Science.gov (United States)

    Machula, M. F.; Crain, T.; Sandhoo, G. S.

    2005-01-01

    To achieve the exploration goals, new approaches to exploration are being envisioned that include robotic networks, modular systems, pre-positioned propellants and in-space assembly in Earth orbit, Lunar orbit and other locations around the cosmos. A fundamental requirement for rendezvous and docking to accomplish in-space assembly exists in each of these locations. While existing systems and technologies can accomplish rendezvous and docking in low earth orbit, and rendezvous and docking with crewed systems has been successfully accomplished in low lunar orbit, our capability must extend toward autonomous rendezvous and docking. To meet the needs of the exploration vision in-space assembly requiring both crewed and uncrewed vehicles will be an integral part of the exploration architecture. This paper focuses on the intelligent application of autonomous rendezvous and docking technologies to meet the needs of that architecture. It also describes key technology investments that will increase the exploration program's ability to ensure mission success, regardless of whether the rendezvous are fully automated or have humans in the loop.

  8. Spectroscopic and molecular docking studies on the charge transfer complex of bovine serum albumin with quinone in aqueous medium and its influence on the ligand binding property of the protein

    Science.gov (United States)

    Satheshkumar, Angupillai; Elango, Kuppanagounder P.

    2014-09-01

    The spectral techniques such as UV-Vis, 1H NMR and fluorescence and electrochemical experiments have been employed to investigate the interaction between 2-methoxy-3,5,6-trichloro-1,4-benzoquinone (MQ; a water soluble quinone) and bovine serum albumin (BSA) in aqueous medium. The fluorescence of BSA was quenched by MQ via formation of a 1:1 BSA-MQ charge transfer adduct with a formation constant of 3.3 × 108 L mol-1. Based on the Forster’s theory the binding distance between them is calculated as 2.65 nm indicating high probability of binding. For the first time, influence of quinone on the binding property of various types of ligands such as aspirin, ascorbic acid, nicotinimide and sodium stearate has also been investigated. The results indicated that the strong and spontaneous binding existing between BSA and MQ, decreased the intensity of binding of these ligands with BSA. Since Tryptophan (Trp) is the basic residue present in BSA, a comparison between binding property of Trp-MQ adduct with that of BSA-MQ with these ligands has also been attempted. 1H NMR titration study indicated that the Trp forms a charge transfer complex with MQ, which reduces the interaction of Trp with the ligands. Molecular docking study supported the fact that the quinone interacts with the Trp212 unit of the BSA and the free energy change of binding (ΔG) for the BSA-MQ complex was found to be -46 kJ mol-1, which is comparable to our experimental free energy of binding (-49 kJ mol-1) obtained from fluorescence study.

  9. Electro-optical rendezvous and docking sensors

    Science.gov (United States)

    Tubbs, David J.; Kesler, Lynn O.; Sirko, Robert J.

    1991-01-01

    Electro-optical sensors provide unique and critical functionality for space missions requiring rendezvous, docking, and berthing. McDonnell Douglas is developing a complete rendezvous and docking system for both manned and unmanned missions. This paper examines our sensor development and the systems and missions which benefit from rendezvous and docking sensors. Simulation results quantifying system performance improvements in key areas are given, with associated sensor performance requirements. A brief review of NASA-funded development activities and the current performance of electro-optical sensors for space applications is given. We will also describe current activities at McDonnell Douglas for a fully functional demonstration to address specific NASA mission needs.

  10. SAMPL4 & DOCK3.7: lessons for automated docking procedures

    Science.gov (United States)

    Coleman, Ryan G.; Sterling, Teague; Weiss, Dahlia R.

    2014-03-01

    The SAMPL4 challenges were used to test current automated methods for solvation energy, virtual screening, pose and affinity prediction of the molecular docking pipeline DOCK 3.7. Additionally, first-order models of binding affinity were proposed as milestones for any method predicting binding affinity. Several important discoveries about the molecular docking software were made during the challenge: (1) Solvation energies of ligands were five-fold worse than any other method used in SAMPL4, including methods that were similarly fast, (2) HIV Integrase is a challenging target, but automated docking on the correct allosteric site performed well in terms of virtual screening and pose prediction (compared to other methods) but affinity prediction, as expected, was very poor, (3) Molecular docking grid sizes can be very important, serious errors were discovered with default settings that have been adjusted for all future work. Overall, lessons from SAMPL4 suggest many changes to molecular docking tools, not just DOCK 3.7, that could improve the state of the art. Future difficulties and projects will be discussed.

  11. Peptide–polymer ligands for a tandem WW-domain, an adaptive multivalent protein–protein interaction: lessons on the thermodynamic fitness of flexible ligands

    Directory of Open Access Journals (Sweden)

    Katharina Koschek

    2015-05-01

    Full Text Available Three polymers, poly(N-(2-hydroxypropylmethacrylamide (pHPMA, hyperbranched polyglycerol (hPG, and dextran were investigated as carriers for multivalent ligands targeting the adaptive tandem WW-domain of formin-binding protein (FBP21. Polymer carriers were conjugated with 3–9 copies of the proline-rich decapeptide GPPPRGPPPR-NH2 (P1. Binding of the obtained peptide–polymer conjugates to the tandem WW-domain was investigated employing isothermal titration calorimetry (ITC to determine the binding affinity, the enthalpic and entropic contributions to free binding energy, and the stoichiometry of binding for all peptide–polymer conjugates. Binding affinities of all multivalent ligands were in the µM range, strongly amplified compared to the monovalent ligand P1 with a KD > 1 mM. In addition, concise differences were observed, pHPMA and hPG carriers showed moderate affinity and bound 2.3–2.8 peptides per protein binding site resulting in the formation of aggregates. Dextran-based conjugates displayed affinities down to 1.2 µM, forming complexes with low stoichiometry, and no precipitation. Experimental results were compared with parameters obtained from molecular dynamics simulations in order to understand the observed differences between the three carrier materials. In summary, the more rigid and condensed peptide–polymer conjugates based on the dextran scaffold seem to be superior to induce multivalent binding and to increase affinity, while the more flexible and dendritic polymers, pHPMA and hPG are suitable to induce crosslinking upon binding.

  12. Identification of Novel Aldose Reductase Inhibitors from Spices: A Molecular Docking and Simulation Study.

    Directory of Open Access Journals (Sweden)

    Priya Antony

    Full Text Available Hyperglycemia in diabetic patients results in a diverse range of complications such as diabetic retinopathy, neuropathy, nephropathy and cardiovascular diseases. The role of aldose reductase (AR, the key enzyme in the polyol pathway, in these complications is well established. Due to notable side-effects of several drugs, phytochemicals as an alternative has gained considerable importance for the treatment of several ailments. In order to evaluate the inhibitory effects of dietary spices on AR, a collection of phytochemicals were identified from Zingiber officinale (ginger, Curcuma longa (turmeric Allium sativum (garlic and Trigonella foenum graecum (fenugreek. Molecular docking was performed for lead identification and molecular dynamics simulations were performed to study the dynamic behaviour of these protein-ligand interactions. Gingerenones A, B and C, lariciresinol, quercetin and calebin A from these spices exhibited high docking score, binding affinity and sustained protein-ligand interactions. Rescoring of protein ligand interactions at the end of MD simulations produced binding scores that were better than the initially docked conformations. Docking results, ligand interactions and ADMET properties of these molecules were significantly better than commercially available AR inhibitors like epalrestat, sorbinil and ranirestat. Thus, these natural molecules could be potent AR inhibitors.

  13. Identification of Novel Aldose Reductase Inhibitors from Spices: A Molecular Docking and Simulation Study.

    Science.gov (United States)

    Antony, Priya; Vijayan, Ranjit

    2015-01-01

    Hyperglycemia in diabetic patients results in a diverse range of complications such as diabetic retinopathy, neuropathy, nephropathy and cardiovascular diseases. The role of aldose reductase (AR), the key enzyme in the polyol pathway, in these complications is well established. Due to notable side-effects of several drugs, phytochemicals as an alternative has gained considerable importance for the treatment of several ailments. In order to evaluate the inhibitory effects of dietary spices on AR, a collection of phytochemicals were identified from Zingiber officinale (ginger), Curcuma longa (turmeric) Allium sativum (garlic) and Trigonella foenum graecum (fenugreek). Molecular docking was performed for lead identification and molecular dynamics simulations were performed to study the dynamic behaviour of these protein-ligand interactions. Gingerenones A, B and C, lariciresinol, quercetin and calebin A from these spices exhibited high docking score, binding affinity and sustained protein-ligand interactions. Rescoring of protein ligand interactions at the end of MD simulations produced binding scores that were better than the initially docked conformations. Docking results, ligand interactions and ADMET properties of these molecules were significantly better than commercially available AR inhibitors like epalrestat, sorbinil and ranirestat. Thus, these natural molecules could be potent AR inhibitors.

  14. Proximity Operations and Docking Sensor Development

    Science.gov (United States)

    Howard, Richard T.; Bryan, Thomas C.; Brewster, Linda L.; Lee, James E.

    2009-01-01

    The Next Generation Advanced Video Guidance Sensor (NGAVGS) has been under development for the last three years as a long-range proximity operations and docking sensor for use in an Automated Rendezvous and Docking (AR&D) system. The first autonomous rendezvous and docking in the history of the U.S. Space Program was successfully accomplished by Orbital Express, using the Advanced Video Guidance Sensor (AVGS) as the primary docking sensor. That flight proved that the United States now has a mature and flight proven sensor technology for supporting Crew Exploration Vehicles (CEV) and Commercial Orbital Transport Systems (COTS) Automated Rendezvous and Docking (AR&D). NASA video sensors have worked well in the past: the AVGS used on the Demonstration of Autonomous Rendezvous Technology (DART) mission operated successfully in spot mode out to 2 km, and the first generation rendezvous and docking sensor, the Video Guidance Sensor (VGS), was developed and successfully flown on Space Shuttle flights in 1997 and 1998. 12 Parts obsolescence issues prevent the construction of more AVGS units, and the next generation sensor was updated to allow it to support the CEV and COTS programs. The flight proven AR&D sensor has been redesigned to update parts and add additional capabilities for CEV and COTS with the development of the Next Generation AVGS at the Marshall Space Flight Center. The obsolete imager and processor are being replaced with new radiation tolerant parts. In addition, new capabilities include greater sensor range, auto ranging capability, and real-time video output. This paper presents some sensor hardware trades, use of highly integrated laser components, and addresses the needs of future vehicles that may rendezvous and dock with the International Space Station (ISS) and other Constellation vehicles. It also discusses approaches for upgrading AVGS to address parts obsolescence, and concepts for minimizing the sensor footprint, weight, and power requirements

  15. Structural deformation upon protein-protein interaction: a structural alphabet approach.

    Science.gov (United States)

    Martin, Juliette; Regad, Leslie; Lecornet, Hélène; Camproux, Anne-Claude

    2008-02-28

    In a number of protein-protein complexes, the 3D structures of bound and unbound partners significantly differ, supporting the induced fit hypothesis for protein-protein binding. In this study, we explore the induced fit modifications on a set of 124 proteins available in both bound and unbound forms, in terms of local structure. The local structure is described thanks to a structural alphabet of 27 structural letters that allows a detailed description of the backbone. Using a control set to distinguish induced fit from experimental error and natural protein flexibility, we show that the fraction of structural letters modified upon binding is significantly greater than in the control set (36% versus 28%). This proportion is even greater in the interface regions (41%). Interface regions preferentially involve coils. Our analysis further reveals that some structural letters in coil are not favored in the interface. We show that certain structural letters in coil are particularly subject to modifications at the interface, and that the severity of structural change also varies. These information are used to derive a structural letter substitution matrix that summarizes the local structural changes observed in our data set. We also illustrate the usefulness of our approach to identify common binding motifs in unrelated proteins. Our study provides qualitative information about induced fit. These results could be of help for flexible docking.

  16. Structural deformation upon protein-protein interaction: A structural alphabet approach

    Directory of Open Access Journals (Sweden)

    Lecornet Hélène

    2008-02-01

    Full Text Available Abstract Background In a number of protein-protein complexes, the 3D structures of bound and unbound partners significantly differ, supporting the induced fit hypothesis for protein-protein binding. Results In this study, we explore the induced fit modifications on a set of 124 proteins available in both bound and unbound forms, in terms of local structure. The local structure is described thanks to a structural alphabet of 27 structural letters that allows a detailed description of the backbone. Using a control set to distinguish induced fit from experimental error and natural protein flexibility, we show that the fraction of structural letters modified upon binding is significantly greater than in the control set (36% versus 28%. This proportion is even greater in the interface regions (41%. Interface regions preferentially involve coils. Our analysis further reveals that some structural letters in coil are not favored in the interface. We show that certain structural letters in coil are particularly subject to modifications at the interface, and that the severity of structural change also varies. These information are used to derive a structural letter substitution matrix that summarizes the local structural changes observed in our data set. We also illustrate the usefulness of our approach to identify common binding motifs in unrelated proteins. Conclusion Our study provides qualitative information about induced fit. These results could be of help for flexible docking.

  17. Workplace flexibility.

    Science.gov (United States)

    Scordato, C; Harris, J

    1990-01-01

    Whether your organization is in a growth pattern or downsizing, you are probably facing change. To gain some insight into your options, here is an in-depth look at the problems and benefits of some flexible work arrangements from a just published study by Catalyst.

  18. Flexibility conflict?

    NARCIS (Netherlands)

    Delsen, L.W.M.; Bauer, F.; Groß, H.; Sieglen, G.

    2002-01-01

    The chapter deals with the presupposed conflict of interests between employers and employees resulting from a decoupling of operating hours and working times. It starts from the notion that both long operating hours and flexibility are relative concepts. As there is some discretion, the ultimate

  19. A Novel Docking System for Modular Self-Reconfigurable Robots

    Directory of Open Access Journals (Sweden)

    Tan Zhang

    2017-10-01

    Full Text Available Existing self-reconfigurable robots achieve connections and disconnections by a separate drive of the docking system. In this paper, we present a new docking system with which the connections and disconnections are driven by locomotion actuators, without the need for a separate drive, which reduces the weight and the complexity of the modules. This self-reconfigurable robot consists of two types of fundamental modules, i.e., active and passive modules. By the docking system, two types of connections are formed with the fundamental modules, and the docking and undocking actions are achieved through simple control with less sensory feedback. This paper describes the design of the robotic modules, the docking system, the docking process, and the docking force analysis. An experiment is performed to demonstrate the self-reconfigurable robot with the docking system.

  20. Structural interface parameters are discriminatory in recognising near-native poses of protein-protein interactions.

    Directory of Open Access Journals (Sweden)

    Sony Malhotra

    Full Text Available Interactions at the molecular level in the cellular environment play a very crucial role in maintaining the physiological functioning of the cell. These molecular interactions exist at varied levels viz. protein-protein interactions, protein-nucleic acid interactions or protein-small molecules interactions. Presently in the field, these interactions and their mechanisms mark intensively studied areas. Molecular interactions can also be studied computationally using the approach named as Molecular Docking. Molecular docking employs search algorithms to predict the possible conformations for interacting partners and then calculates interaction energies. However, docking proposes number of solutions as different docked poses and hence offers a serious challenge to identify the native (or near native structures from the pool of these docked poses. Here, we propose a rigorous scoring scheme called DockScore which can be used to rank the docked poses and identify the best docked pose out of many as proposed by docking algorithm employed. The scoring identifies the optimal interactions between the two protein partners utilising various features of the putative interface like area, short contacts, conservation, spatial clustering and the presence of positively charged and hydrophobic residues. DockScore was first trained on a set of 30 protein-protein complexes to determine the weights for different parameters. Subsequently, we tested the scoring scheme on 30 different protein-protein complexes and native or near-native structure were assigned the top rank from a pool of docked poses in 26 of the tested cases. We tested the ability of DockScore to discriminate likely dimer interactions that differ substantially within a homologous family and also demonstrate that DOCKSCORE can distinguish correct pose for all 10 recent CAPRI targets.

  1. An Integrated Framework Advancing Membrane Protein Modeling and Design.

    Directory of Open Access Journals (Sweden)

    Rebecca F Alford

    2015-09-01

    Full Text Available Membrane proteins are critical functional molecules in the human body, constituting more than 30% of open reading frames in the human genome. Unfortunately, a myriad of difficulties in overexpression and reconstitution into membrane mimetics severely limit our ability to determine their structures. Computational tools are therefore instrumental to membrane protein structure prediction, consequently increasing our understanding of membrane protein function and their role in disease. Here, we describe a general framework facilitating membrane protein modeling and design that combines the scientific principles for membrane protein modeling with the flexible software architecture of Rosetta3. This new framework, called RosettaMP, provides a general membrane representation that interfaces with scoring, conformational sampling, and mutation routines that can be easily combined to create new protocols. To demonstrate the capabilities of this implementation, we developed four proof-of-concept applications for (1 prediction of free energy changes upon mutation; (2 high-resolution structural refinement; (3 protein-protein docking; and (4 assembly of symmetric protein complexes, all in the membrane environment. Preliminary data show that these algorithms can produce meaningful scores and structures. The data also suggest needed improvements to both sampling routines and score functions. Importantly, the applications collectively demonstrate the potential of combining the flexible nature of RosettaMP with the power of Rosetta algorithms to facilitate membrane protein modeling and design.

  2. The flexibility of a generic LC-MS/MS method for the quantitative analysis of therapeutic proteins based on human immunoglobulin G and related constructs in animal studies.

    Science.gov (United States)

    Lanshoeft, Christian; Wolf, Thierry; Walles, Markus; Barteau, Samuel; Picard, Franck; Kretz, Olivier; Cianférani, Sarah; Heudi, Olivier

    2016-11-30

    An increasing demand of new analytical methods is associated with the growing number of biotherapeutic programs being prosecuted in the pharmaceutical industry. Whilst immunoassay has been the standard method for decades, a great interest in assays based on liquid chromatography tandem mass spectrometry (LC-MS/MS) is evolving. In this present work, the development of a generic method for the quantitative analysis of therapeutic proteins based on human immunoglobulin G (hIgG) in rat serum is reported. The method is based on four generic peptides GPSVFPLAPSSK (GPS), TTPPVLDSDGSFFLYSK (TTP), VVSVLTVLHQDWLNGK (VVS) and FNWYVDGVEVHNAK (FNW) originating from different parts of the fraction crystallizable (Fc) region of a reference hIgG1 (hIgG1A). A tryptic pellet digestion of rat serum spiked with hIgG1A and a stable isotope labeled protein (hIgG1B) used as internal standard (ISTD) was applied prior LC-MS/MS analysis. The upper limit of quantification was at 1000μg/mL. The lower limit of quantitation was for GPS, TTP and VVS at 1.00μg/mL whereas for FNW at 5.00μg/mL. Accuracy and precision data met acceptance over three days. The presented method was further successfully applied to the quantitative analysis of other hIgG1s (hIgG1C and hIgG1D) and hIgG4-based therapeutic proteins on spiked quality control (QC) samples in monkey and rat serum using calibration standards (Cs) prepared with hIgG1A in rat serum. In order to extend the applicability of our generic approach, a bispecific-bivalent hIgG1 (bb-hIgG1) and two lysine conjugated antibody-drug conjugates (ADC1 and ADC2) were incorporated as well. The observed values on spiked QC samples in monkey serum were satisfactory with GPS for the determination of bb-hIgG1 whereas the FNW and TTP peptides were suitable for the ADCs. Moreover, comparable mean concentration-time profiles were obtained from monkeys previously dosed intravenously with ADC2 measured against Cs samples prepared either with hIgG1A in rat serum

  3. CLUB-MARTINI: Selecting Favourable Interactions amongst Available Candidates, a Coarse-Grained Simulation Approach to Scoring Docking Decoys.

    Directory of Open Access Journals (Sweden)

    Qingzhen Hou

    Full Text Available Large-scale identification of native binding orientations is crucial for understanding the role of protein-protein interactions in their biological context. Measuring binding free energy is the method of choice to estimate binding strength and reveal the relevance of particular conformations in which proteins interact. In a recent study, we successfully applied coarse-grained molecular dynamics simulations to measure binding free energy for two protein complexes with similar accuracy to full-atomistic simulation, but 500-fold less time consuming. Here, we investigate the efficacy of this approach as a scoring method to identify stable binding conformations from thousands of docking decoys produced by protein docking programs. To test our method, we first applied it to calculate binding free energies of all protein conformations in a CAPRI (Critical Assessment of PRedicted Interactions benchmark dataset, which included over 19000 protein docking solutions for 15 benchmark targets. Based on the binding free energies, we ranked all docking solutions to select the near-native binding modes under the assumption that the native-solutions have lowest binding free energies. In our top 100 ranked structures, for the 'easy' targets that have many near-native conformations, we obtain a strong enrichment of acceptable or better quality structures; for the 'hard' targets without near-native decoys, our method is still able to retain structures which have native binding contacts. Moreover, in our top 10 selections, CLUB-MARTINI shows a comparable performance when compared with other state-of-the-art docking scoring functions. As a proof of concept, CLUB-MARTINI performs remarkably well for many targets and is able to pinpoint near-native binding modes in the top selections. To the best of our knowledge, this is the first time interaction free energy calculated from MD simulations have been used to rank docking solutions at a large scale.

  4. The HADDOCK web server for data-driven biomolecular docking

    NARCIS (Netherlands)

    de Vries, S.J.|info:eu-repo/dai/nl/304837717; van Dijk, M.|info:eu-repo/dai/nl/325811113; Bonvin, A.M.J.J.|info:eu-repo/dai/nl/113691238

    2010-01-01

    Computational docking is the prediction or modeling of the three-dimensional structure of a biomolecular complex, starting from the structures of the individual molecules in their free, unbound form. HADDOC K is a popular docking program that takes a datadriven approach to docking, with support for

  5. CovalentDock Cloud: a web server for automated covalent docking.

    Science.gov (United States)

    Ouyang, Xuchang; Zhou, Shuo; Ge, Zemei; Li, Runtao; Kwoh, Chee Keong

    2013-07-01

    Covalent binding is an important mechanism for many drugs to gain its function. We developed a computational algorithm to model this chemical event and extended it to a web server, the CovalentDock Cloud, to make it accessible directly online without any local installation and configuration. It provides a simple yet user-friendly web interface to perform covalent docking experiments and analysis online. The web server accepts the structures of both the ligand and the receptor uploaded by the user or retrieved from online databases with valid access id. It identifies the potential covalent binding patterns, carries out the covalent docking experiments and provides visualization of the result for user analysis. This web server is free and open to all users at http://docking.sce.ntu.edu.sg/.

  6. Compodock, a new device for sterile docking

    NARCIS (Netherlands)

    van der Meer, P. F.; Biekart, F. T.; Pietersz, R. N.; Rebers, S. P.; Reesink, H. W.

    2000-01-01

    BACKGROUND: A new device for sterile docking, the Compodock (Fresenius NPBI Transfusion Technology), was developed for connecting PVC tubing for medical use while maintaining sterility. STUDY DESIGN AND METHODS: Sterility of the connections was assessed by welding tubing with a heavy exterior

  7. Operator learning effects in teleoperated rendezvous & docking

    Science.gov (United States)

    Wilde, M.; Harder, J.; Purschke, R.

    Teleoperation of spacecraft proximity operations and docking requires delicate timing and coordination of spacecraft maneuvers. Experience has shown that human operators show large performance fluctuations in these areas, which are a major factor to be addressed in operator training. In order to allow the quantification of the impact of these human fluctuations on control system performance and the human perception of this performance, a learning curve study was conducted with teleoperated final approach and docking scenarios. Over a period of ten experiment days, three test participants were tasked with repeatedly completing a set of three training scenarios. The scenarios were designed to contain different combinations of the major elements of any final approach and docking situation, and to feature an increasing difficulty level. The individual difficulty levels for the three operators furthermore differed in the level of operator support functions available in their human-machine interfaces. Operator performance in the test scenarios were evaluated in the fields approach success and precision, docking safety, and approach efficiency by a combination of recorded maneuver data and questionnaires. The results show that operator experience and the associated learning curves increase operator performance substantially, regardless of the support system used. The paper also shows that the fluctuations in operator performance and self-perception are substantial between as well as within experiment days, and must be reckoned with in teleoperation system design and mission planning.

  8. Rationalization of activity cliffs of a sulfonamide inhibitor of DNA methyltransferases with induced-fit docking.

    Science.gov (United States)

    Medina-Franco, José L; Méndez-Lucio, Oscar; Yoo, Jakyung

    2014-02-21

    Inhibitors of human DNA methyltransferases (DNMT) are of increasing interest to develop novel epi-drugs for the treatment of cancer and other diseases. As the number of compounds with reported DNMT inhibition is increasing, molecular docking is shedding light to elucidate their mechanism of action and further interpret structure-activity relationships. Herein, we present a structure-based rationalization of the activity of SW155246, a distinct sulfonamide compound recently reported as an inhibitor of human DNMT1 obtained from high-throughput screening. We used flexible and induce-fit docking to develop a binding model of SW155246 with a crystallographic structure of human DNMT1. Results were in excellent agreement with experimental information providing a three-dimensional structural interpretation of 'activity cliffs', e.g., analogues of SW155246 with a high structural similarity to the sulfonamide compound, but with no activity in the enzymatic assay.

  9. Rationalization of Activity Cliffs of a Sulfonamide Inhibitor of DNA Methyltransferases with Induced-Fit Docking

    Directory of Open Access Journals (Sweden)

    José L. Medina-Franco

    2014-02-01

    Full Text Available Inhibitors of human DNA methyltransferases (DNMT are of increasing interest to develop novel epi-drugs for the treatment of cancer and other diseases. As the number of compounds with reported DNMT inhibition is increasing, molecular docking is shedding light to elucidate their mechanism of action and further interpret structure–activity relationships. Herein, we present a structure-based rationalization of the activity of SW155246, a distinct sulfonamide compound recently reported as an inhibitor of human DNMT1 obtained from high-throughput screening. We used flexible and induce-fit docking to develop a binding model of SW155246 with a crystallographic structure of human DNMT1. Results were in excellent agreement with experimental information providing a three-dimensional structural interpretation of ‘activity cliffs’, e.g., analogues of SW155246 with a high structural similarity to the sulfonamide compound, but with no activity in the enzymatic assay.

  10. Flexible licensing

    Directory of Open Access Journals (Sweden)

    Martyn Jansen

    2012-07-01

    Full Text Available The case is presented for a more flexible approach to licensing online library resources. Today's distributed education environment creates pressure for UK higher and further education institutions (HEI/FEIs to form partnerships and to develop educational products and roll them out across the globe. Online library resources are a key component of distributed education and yet existing licensing agreements struggle to keep pace with the increasing range of users and purposes for which they are required. This article describes the process of developing a flexible approach to licensing and proposes a new model licence for online library resources which has the adaptability needed in this new global educational landscape. These ideas have been presented and discussed at various workshops across Eduserv's and JISC Collections' higher education and publisher communities, and further consultation is ongoing.

  11. Activated Cdc42 kinase regulates Dock localization in male germ cells during Drosophila spermatogenesis.

    Science.gov (United States)

    Abdallah, Abbas M; Zhou, Xin; Kim, Christine; Shah, Kushani K; Hogden, Christopher; Schoenherr, Jessica A; Clemens, James C; Chang, Henry C

    2013-06-15

    Deregulation of the non-receptor tyrosine kinase ACK1 (Activated Cdc42-associated kinase) correlates with poor prognosis in cancers and has been implicated in promoting metastasis. To further understand its in vivo function, we have characterized the developmental defects of a null mutation in Drosophila Ack, which bears a high degree of sequence similarity to mammalian ACK1 but lacks a CRIB domain. We show that Ack, while not essential for viability, is critical for sperm formation. This function depends on Ack tyrosine kinase activity and is required cell autonomously in differentiating male germ cells at or after the spermatocyte stage. Ack associates predominantly with endocytic clathrin sites in spermatocytes, but disruption of Ack function has no apparent effect on clathrin localization and receptor-mediated internalization of Boss (Bride of sevenless) protein in eye discs. Instead, Ack is required for the subcellular distribution of Dock (dreadlocks), the Drosophila homolog of the SH2- and SH3-containing adaptor protein Nck. Moreover, Dock forms a complex with Ack, and the localization of Dock in male germ cells depends on its SH2 domain. Together, our results suggest that Ack-dependent tyrosine phosphorylation recruits Dock to promote sperm differentiation. Copyright © 2013 Elsevier Inc. All rights reserved.

  12. Differential Regulation of Synaptic Vesicle Tethering and Docking by UNC-18 and TOM-1.

    Science.gov (United States)

    Gracheva, Elena O; Maryon, Ed B; Berthelot-Grosjean, Martine; Richmond, Janet E

    2010-01-01

    The assembly of SNARE complexes between syntaxin, SNAP-25 and synaptobrevin is required to prime synaptic vesicles for fusion. Since Munc18 and tomosyn compete for syntaxin interactions, the interplay between these proteins is predicted to be important in regulating synaptic transmission. We explored this possibility, by examining genetic interactions between C. elegans unc-18(Munc18), unc-64(syntaxin) and tom-1(tomosyn). We have previously demonstrated that unc-18 mutants have reduced synaptic transmission, whereas tom-1 mutants exhibit enhanced release. Here we show that the unc-18 mutant release defect is associated with loss of two morphologically distinct vesicle pools; those tethered within 25 nm of the plasma membrane and those docked with the plasma membrane. In contrast, priming defective unc-13 mutants accumulate tethered vesicles, while docked vesicles are greatly reduced, indicating tethering is UNC-18-dependent and occurs in the absence of priming. C. elegans unc-64 mutants phenocopy unc-18 mutants, losing both tethered and docked vesicles, whereas overexpression of open syntaxin preferentially increases vesicle docking, suggesting UNC-18/closed syntaxin interactions are responsible for vesicle tethering. Given the competition between vertebrate tomosyn and Munc18, for syntaxin binding, we hypothesized that C. elegans TOM-1 may inhibit both UNC-18-dependent vesicle targeting steps. Consistent with this hypothesis, tom-1 mutants exhibit enhanced UNC-18 plasma membrane localization and a concomitant increase in both tethered and docked synaptic vesicles. Furthermore, in tom-1;unc-18 double mutants the docked, primed vesicle pool is preferentially rescued relative to unc-18 single mutants. Together these data provide evidence for the differential regulation of two vesicle targeting steps by UNC-18 and TOM-1 through competitive interactions with syntaxin.

  13. Differential regulation of synaptic vesicle tethering and docking by UNC-18 and TOM-1

    Directory of Open Access Journals (Sweden)

    Elena O Gracheva

    2010-10-01

    Full Text Available The assembly of SNARE complexes between syntaxin, SNAP-25 and synaptobrevin is required to prime synaptic vesicles for fusion. Since Munc18 and tomosyn compete for syntaxin interactions, the interplay between these proteins is predicted to be important in regulating synaptic transmission. We explored this possibility, by examining genetic interactions between C. elegans unc-18(Munc18, unc-64(syntaxin and tom-1(tomosyn. We have previously demonstrated that unc-18 mutants have reduced synaptic transmission, whereas tom-1 mutants exhibit enhanced release. Here we show that the unc-18 mutant release defect is associated with loss of two morphologically distinct vesicle pools; those tethered within 25nm of the plasma membrane and those docked with the plasma membrane. In contrast, priming defective unc-13 mutants accumulate tethered vesicles, while docked vesicles are greatly reduced, indicating tethering is UNC-18-dependent and occurs in the absence of priming. C. elegans unc-64 mutants phenocopy unc-18 mutants, losing both tethered and docked vesicles, whereas overexpression of open syntaxin preferentially increases vesicle docking, suggesting UNC-18/closed syntaxin interactions are responsible for vesicle tethering. Given the competition between vertebrate tomosyn and Munc18, for syntaxin binding, we hypothesized that C. elegans TOM-1 may inhibit both UNC-18-dependent vesicle targeting steps. Consistent with this hypothesis, tom-1 mutants exhibit enhanced UNC-18 plasma membrane localization and a concomitant increase in both tethered and docked synaptic vesicles. Furthermore, in tom-1;unc-18 double mutants the docked, primed vesicle pool is preferentially rescued relative to unc-18 single mutants. Together these data provide evidence for the differential regulation of two vesicle targeting steps by UNC-18 and TOM-1 through competitive interactions with syntaxin

  14. GREEN: A program package for docking studies in rational drug design

    Science.gov (United States)

    Tomioka, Nobuo; Itai, Akiko

    1994-08-01

    A program package, GREEN, has been developed that enables docking studies between ligand molecules and a protein molecule. Based on the structure of the protein molecule, the physical and chemical environment of the ligand-binding site is expressed as three-dimensional grid-point data. The grid-point data are used for the real-time evaluation of the protein-ligand interaction energy, as well as for the graphical representation of the binding-site environment. The interactive docking operation is facilitated by various built-in functions, such as energy minimization, energy contribution analysis and logging of the manipulation trajectory. Interactive modeling functions are incorporated for designing new ligand molecules while considering the binding-site environment and the protein-ligand interaction. As an example of the application of GREEN, a docking study is presented on the complex between trypsin and a synthetic trypsin inhibitor. The program package will be useful for rational drug design, based on the 3D structure of the target protein.

  15. Insights into structural features of HDAC1 and its selectivity inhibition elucidated by Molecular dynamic simulation and Molecular Docking.

    Science.gov (United States)

    Sixto-López, Yudibeth; Bello, Martiniano; Correa-Basurto, José

    2018-03-06

    Histone deacetylases (HDACs) are a family of proteins whose main function is the removal of acetyl groups from lysine residues located on histone and non-histone substrates, which regulates gene transcription and other activities in cells. HDAC1 dysfunction has been implicated in cancer development and progression; thus, its inhibition has emerged as a new therapeutic strategy. Two additional metal binding sites (Site 1 and Site 2) in HDACs have been described that are primarily occupied by potassium ions, suggesting a possible structural role that affects HDAC activity. In this work, we explored the structural role of potassium ions in Site 1 and Site 2 and how they affect the interactions of compounds with high affinities for HDAC1 (AC1OCG0B, Chlamydocin, Dacinostat and Quisinostat) and SAHA (a pan-inhibitor) using molecular docking and molecular dynamics (MD) simulations in concert with a Molecular-Mechanics-Generalized-Born-Surface-Area (MMGBSA) approach. Four models were generated: one with a potassium ion (K + ) in both sites (HDAC1 k ), a second with K + only at site 1 (HDAC1 ks1 ), a third with K + only at site 2 (HDAC1 ks2 ) and a fourth with no K + (HDAC1 wk ). We found that the presence or absence of K + not only impacted the structural flexibility of HDAC1, but also its molecular recognition, consistent with experimental findings. These results could therefore be useful for further structure-based drug design studies addressing new HDAC1 inhibitors.

  16. Study of the interaction between two newly synthesized cyclometallated platinum (II) complexes and human serum albumin: Spectroscopic characterization and docking simulation

    Energy Technology Data Exchange (ETDEWEB)

    Yousefi, Reza, E-mail: ryousefi@shirazu.ac.ir [Protein Chemistry Laboratory (PCL), Department of Biology, College of Sciences, Shiraz University, Shiraz (Iran, Islamic Republic of); Mohammadi, Roghayeh [Protein Chemistry Laboratory (PCL), Department of Biology, College of Sciences, Shiraz University, Shiraz (Iran, Islamic Republic of); Taheri-Kafrani, Asghar [Department of Biotechnology, Faculty of Advanced Sciences and Technologies, University of Isfahan, Isfahan 81746-73441 (Iran, Islamic Republic of); Bagher Shahsavani, Mohammad [Protein Chemistry Laboratory (PCL), Department of Biology, College of Sciences, Shiraz University, Shiraz (Iran, Islamic Republic of); Dadkhah Aseman, Marzieh; Masoud Nabavizadeh, S.; Rashidi, Mehdi [Department of Chemistry, College of Sciences, Shiraz University, Shiraz (Iran, Islamic Republic of); Poursasan, Najmeh; Moosavi-Movahedi, Ali-Akbar [Institute of Biochemistry and Biophysics (IBB), the University of Tehran, Tehran (Iran, Islamic Republic of)

    2015-03-15

    This study describes HSA binding properties of two cyclometalated platinum (II) complexes with non-leaving lipophilic ligands; deprotonated 2-phenylpyridine (ppy): C{sub 1} and deprotonated benzo [h]quinolone (bhq): C{sub 2}, using UV–vis, fluorescence and circular dichroism (CD) spectroscopy. The absorption spectra of HSA decreased in the presence of increasing concentration of these complexes, reflecting HSA structural alteration after drug's binding. Also the thermodynamic parameters (ΔG, ΔH and ΔS) that obtained from Trp fluorescence study revealed that the interaction between these complexes and HSA were spontaneous. In addition, C{sub 1} with flexible chemical structure indicated significantly higher fluorescence quenching and binding affinity to HSA than C{sub 2} which possesses a higher structural rigidity. The ANS fluorescence results also indicated that two Pt (II) complexes were competing for binding to the hydrophobic regions of HSA. Moreover, CD results demonstrated that C{sub 2} complex induced alteration of HSA conformation to more significant extent compared to C{sub 1}. The molecular docking results revealed the involvement of π–π stacking and hydrophobic interaction between these complexes and the protein. Overall, this study may highlight the significance of structural flexibility in designing of future anticancer Pt (II) complexes with improved binding affinity for HSA. - Highlights: • HSA is a general transport carrier for a wide variety of ligands such as metabolites and pharmaceutical drugs. • The HSA binding properties of two structurally related cyclometallated platinum (II) complexes (C{sub 1} and C{sub 2}) were studied. • The complexes can bind to HSA and induce structural alteration in this protein. • The thermodynamic parameters revealed that the interactions were spontaneous and mainly hydrophobic driven. • C{sub 1} with flexible chemical structure indicated a higher binding affinity for HSA than C{sub 2}.

  17. Flexible Consumption

    DEFF Research Database (Denmark)

    Holm Jacobsen, Peter; Pallesen, Trine

    This report presents the first findings from our qualitative study of consumer behaviour vis-à-vis flexible consumption. The main of objective of this report is to present our first round of data from Bornholm, and to assist the design of products/services designed in WP6. In the report, we adopt...... the perspective of the consumer: what does living in a demand response setup look like to participants – and what kinds of behaviour and interest motivate – and emerge from – their participation in EcoGrid 2.0....

  18. Flexible Capitalism

    DEFF Research Database (Denmark)

    Approaching “work” as at heart a practice of exchange, this volume explores sociality in work environments marked by the kind of structural changes that have come to define contemporary “flexible” capitalism. It introduces anthropological exchange theory to a wider readership, and shows how...... the perspective offers new ways to enquire about the flexible capitalism’s social dimensions. The essays contribute to a trans-disciplinary scholarship on contemporary economic practice and change by documenting how, across diverse settings, “gift-like” socialities proliferate, and even sustain the intensified...

  19. A Drosophila protein-tyrosine phosphatase associates with an adapter protein required for axonal guidance.

    Science.gov (United States)

    Clemens, J C; Ursuliak, Z; Clemens, K K; Price, J V; Dixon, J E

    1996-07-19

    We have used the yeast two-hybrid system to isolate a novel Drosophila adapter protein, which interacts with the Drosophila protein-tyrosine phosphatase (PTP) dPTP61F. Absence of this protein in Drosophila causes the mutant photoreceptor axon phenotype dreadlocks (dock) (Garrity, P. A., Rao, Y., Salecker, I., and Zipursky, S. L.(1996) Cell 85, 639-650). Dock is similar to the mammalian oncoprotein Nck and contains three Src homology 3 (SH3) domains and one Src homology 2 (SH2) domain. The interaction of dPTP61F with Dock was confirmed in vivo by immune precipitation experiments. A sequence containing five PXXP motifs from the non-catalytic domain of the PTP is sufficient for interaction with Dock. This suggests that binding to the PTP is mediated by one or more of the SH3 domains of Dock. Immune precipitations of Dock also co-precipitate two tyrosine-phosphorylated proteins having molecular masses of 190 and 145 kDa. Interactions between Dock and these tyrosine-phosphorylated proteins are likely mediated by the Dock SH2 domain. These findings identify potential signal-transducing partners of Dock and propose a role for dPTP61F and the unidentified phosphoproteins in axonal guidance.

  20. Flexible nanovectors

    International Nuclear Information System (INIS)

    Pugno, Nicola M

    2008-01-01

    In this paper we show that the control of adhesion in highly flexible (a property that could be crucial for smart drug delivery but which is still ignored in the literature) nanovectors can help in smartly targeting and delivering the drug. The existence of and the conditions for activating and controlling a super-adhesive state are addressed. Even if such a state has never been observed in nanovectors, our calculations, as well as observations in spiders and geckos, suggest its existence and feasible control. Control of the competition between the drag and the adhesive force is exploited to improve the targeting ability and a hierarchical model is applied to describe a real vasculature. The high flexibility of the nanovector is used to smartly deliver the drug only during adhesion by nanopumping or, as a limiting case, by the new concept of 'adhesion induced nanovector implosion'; a liquid drop analogy is utilized for the calculations. Fast (pumping) and slow (diffusion) drug deliveries can thus be separately controlled by controlling the size and shape of the nanovector. Multiple stage nanovectors are also briefly discussed, mimicking aerospace vector strategies.

  1. Flexible nanovectors

    Science.gov (United States)

    Pugno, Nicola M.

    2008-11-01

    In this paper we show that the control of adhesion in highly flexible (a property that could be crucial for smart drug delivery but which is still ignored in the literature) nanovectors can help in smartly targeting and delivering the drug. The existence of and the conditions for activating and controlling a super-adhesive state are addressed. Even if such a state has never been observed in nanovectors, our calculations, as well as observations in spiders and geckos, suggest its existence and feasible control. Control of the competition between the drag and the adhesive force is exploited to improve the targeting ability and a hierarchical model is applied to describe a real vasculature. The high flexibility of the nanovector is used to smartly deliver the drug only during adhesion by nanopumping or, as a limiting case, by the new concept of 'adhesion induced nanovector implosion'; a liquid drop analogy is utilized for the calculations. Fast (pumping) and slow (diffusion) drug deliveries can thus be separately controlled by controlling the size and shape of the nanovector. Multiple stage nanovectors are also briefly discussed, mimicking aerospace vector strategies.

  2. Drosophila photoreceptor axon guidance and targeting requires the dreadlocks SH2/SH3 adapter protein.

    Science.gov (United States)

    Garrity, P A; Rao, Y; Salecker, I; McGlade, J; Pawson, T; Zipursky, S L

    1996-05-31

    Mutations in the Drosophila gene dreadlocks (dock) disrupt photoreceptor cell (R cell) axon guidance and targeting. Genetic mosaic analysis and cell-type-specific expression of dock transgenes demonstrate dock is required in R cells for proper innervation. Dock protein contains one SH2 and three SH3 domains, implicating it in tyrosine kinase signaling, and is highly related to the human proto-oncogene Nck. Dock expression is detected in R cell growth cones in the target region. We propose Dock transmits signals in the growth cone in response to guidance and targeting cues. These findings provide an important step for dissection of signaling pathways regulating growth cone motility.

  3. Same but not alike: Structure, flexibility and energetics of domains in multi-domain proteins are influenced by the presence of other domains.

    Science.gov (United States)

    Vishwanath, Sneha; de Brevern, Alexandre G; Srinivasan, Narayanaswamy

    2018-02-01

    The majority of the proteins encoded in the genomes of eukaryotes contain more than one domain. Reasons for high prevalence of multi-domain proteins in various organisms have been attributed to higher stability and functional and folding advantages over single-domain proteins. Despite these advantages, many proteins are composed of only one domain while their homologous domains are part of multi-domain proteins. In the study presented here, differences in the properties of protein domains in single-domain and multi-domain systems and their influence on functions are discussed. We studied 20 pairs of identical protein domains, which were crystallized in two forms (a) tethered to other proteins domains and (b) tethered to fewer protein domains than (a) or not tethered to any protein domain. Results suggest that tethering of domains in multi-domain proteins influences the structural, dynamic and energetic properties of the constituent protein domains. 50% of the protein domain pairs show significant structural deviations while 90% of the protein domain pairs show differences in dynamics and 12% of the residues show differences in the energetics. To gain further insights on the influence of tethering on the function of the domains, 4 pairs of homologous protein domains, where one of them is a full-length single-domain protein and the other protein domain is a part of a multi-domain protein, were studied. Analyses showed that identical and structurally equivalent functional residues show differential dynamics in homologous protein domains; though comparable dynamics between in-silico generated chimera protein and multi-domain proteins were observed. From these observations, the differences observed in the functions of homologous proteins could be attributed to the presence of tethered domain. Overall, we conclude that tethered domains in multi-domain proteins not only provide stability or folding advantages but also influence pathways resulting in differences in

  4. Synthesis, spectroscopic characterization and in vitro cytotoxicities of new organometallic palladium complexes with biologically active β-diketones; Biological evaluation probing of the interaction mechanism with DNA/Protein and molecular docking

    Science.gov (United States)

    Karami, Kazem; Rafiee, Mina; Lighvan, Zohreh Mehri; Zakariazadeh, Mostafa; Faal, Ali Yeganeh; Esmaeili, Seyed-Alireza; Momtazi-Borojeni, Amir Abbas

    2018-02-01

    [Pd{(C,N)sbnd C6H4CH (CH3)NH}(CUR)] (3) and [Pd2{(C,N)sbnd C6H4CH(CH3)NH2}2(μ-N3CS2)] (4) [cur = 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dion] novel organometallic complexes with biologically active ligands have been prepared and characterized via elemental analysis, multinuclear spectroscopic techniques (1H, and 13C NMR and IR) and their biological activities, including antitumoral activity and DNA-protein interactions have been investigated. Fluorescence spectroscopy used to study the interaction of the complexes with BSA have shown the affinity of the complexes for these proteins with relatively high binding constant values and the changed secondary structure of BSA in the presence of the complexes. In the meantime, spectroscopy and competitive titration have been applied to investigate the interaction of complexes with Warfarin and Ibuprofen site markers for sites I and II, respectively, with BSA. The results have suggested that the locations of complexes 3 and 4 are sites II and I, respectively. UV-Vis spectroscopy, emission titration and helix melting methods have been used to study the interaction of these complexes with CT-DNA, indicating that complexes are bound to CT-DNA by intercalation binding mode. In addition, good cytotoxic activity against MCF-7 (human breast cancer) and JURKAT (human leukemia) cell line has been shown by both complexes whereas low cytotoxicity was exerted on normal peripheral blood mononuclear cells.

  5. PTP1B inhibitor promotes endothelial cell motility by activating the DOCK180/Rac1 pathway.

    Science.gov (United States)

    Wang, Yuan; Yan, Feng; Ye, Qing; Wu, Xiao; Jiang, Fan

    2016-04-07

    Promoting endothelial cell (EC) migration is important not only for therapeutic angiogenesis, but also for accelerating re-endothelialization after vessel injury. Several recent studies have shown that inhibition of protein tyrosine phosphatase 1B (PTP1B) may promote EC migration and angiogenesis by enhancing the vascular endothelial growth factor receptor-2 (VEGFR2) signalling. In the present study, we demonstrated that PTP1B inhibitor could promote EC adhesion, spreading and migration, which were abolished by the inhibitor of Rac1 but not RhoA GTPase. PTP1B inhibitor significantly increased phosphorylation of p130Cas, and the interactions among p130Cas, Crk and DOCK180; whereas the phosphorylation levels of focal adhesion kinase, Src, paxillin, or Vav2 were unchanged. Gene silencing of DOCK180, but not Vav2, abrogated the effects of PTP1B inhibitor on EC motility. The effects of PTP1B inhibitor on EC motility and p130Cas/DOCK180 activation persisted in the presence of the VEGFR2 antagonist. In conclusion, we suggest that stimulation of the DOCK180 pathway represents an alternative mechanism of PTP1B inhibitor-stimulated EC motility, which does not require concomitant VEGFR2 activation as a prerequisite. Therefore, PTP1B inhibitor may be a useful therapeutic strategy for promoting EC migration in cardiovascular patients in which the VEGF/VEGFR functions are compromised.

  6. Peptides Trapping Dioxins: A Docking-Based Inverse Screening Approach

    Directory of Open Access Journals (Sweden)

    German Perez

    2013-01-01

    Full Text Available A rapid and cost-effective computational methodology for designing and rationalizing the selection of small peptides as receptors for dioxin-like compounds was proposed. The backbone of the dioxin Ah receptor binding site was used to design a series of penta- and hexapeptide libraries, with 1400 elements in total. Peptide flexibility was considered and 10 conformers were found to be a good option to represent peptide conformational space with fair speed-accuracy ratio. Each peptide conformer was treated as a possible receptor, generating a dedicated box and then running a docking process using as ligands a family of 76 dibenzo-p-dioxins and 113 dibenzofurans mono- and polychlorinated. Significant predictions were confirmed by comparing primary structure of top and bottom ranked peptides binding dioxins confirming that scrambled positions of the same amino acids gave completely different predicted binding. The hexapeptide EWFQPW, with the best binding score, was chosen as selective sorbent material in solid-phase extraction. The retention performances were tested using the 2,3,7,8-tetrachlorodibenzo-p-dioxin and two polychlorinated biphenyls in order to verify the hexapeptide specificity. The solid-phase extraction experimental procedure was optimized, and analytical parameters of hexapeptide sorbent material were compared with the resin without hexapeptide and a commercial reversed phase cartridge.

  7. Single-Point Mutation with a Rotamer Library Toolkit: Toward Protein Engineering.

    Science.gov (United States)

    Pottel, Joshua; Moitessier, Nicolas

    2015-12-28

    Protein engineers have long been hard at work to harness biocatalysts as a natural source of regio-, stereo-, and chemoselectivity in order to carry out chemistry (reactions and/or substrates) not previously achieved with these enzymes. The extreme labor demands and exponential number of mutation combinations have induced computational advances in this domain. The first step in our virtual approach is to predict the correct conformations upon mutation of residues (i.e., rebuilding side chains). For this purpose, we opted for a combination of molecular mechanics and statistical data. In this work, we have developed automated computational tools to extract protein structural information and created conformational libraries for each amino acid dependent on a variable number of parameters (e.g., resolution, flexibility, secondary structure). We have also developed the necessary tool to apply the mutation and optimize the conformation accordingly. For side-chain conformation prediction, we obtained overall average root-mean-square deviations (RMSDs) of 0.91 and 1.01 Å for the 18 flexible natural amino acids within two distinct sets of over 3000 and 1500 side-chain residues, respectively. The commonly used dihedral angle differences were also evaluated and performed worse than the state of the art. These two metrics are also compared. Furthermore, we generated a family-specific library for kinases that produced an average 2% lower RMSD upon side-chain reconstruction and a residue-specific library that yielded a 17% improvement. Ultimately, since our protein engineering outlook involves using our docking software, Fitted/Impacts, we applied our mutation protocol to a benchmarked data set for self- and cross-docking. Our side-chain reconstruction does not hinder our docking software, demonstrating differences in pose prediction accuracy of approximately 2% (RMSD cutoff metric) for a set of over 200 protein/ligand structures. Similarly, when docking to a set of over 100

  8. Customizable de novo design strategies for DOCK: Application to HIVgp41 and other therapeutic targets.

    Science.gov (United States)

    Allen, William J; Fochtman, Brian C; Balius, Trent E; Rizzo, Robert C

    2017-11-15

    De novo design can be used to explore vast areas of chemical space in computational lead discovery. As a complement to virtual screening, from-scratch construction of molecules is not limited to compounds in pre-existing vendor catalogs. Here, we present an iterative fragment growth method, integrated into the program DOCK, in which new molecules are built using rules for allowable connections based on known molecules. The method leverages DOCK's advanced scoring and pruning approaches and users can define very specific criteria in terms of properties or features to customize growth toward a particular region of chemical space. The code was validated using three increasingly difficult classes of calculations: (1) Rebuilding known X-ray ligands taken from 663 complexes using only their component parts (focused libraries), (2) construction of new ligands in 57 drug target sites using a library derived from ∼13M drug-like compounds (generic libraries), and (3) application to a challenging protein-protein interface on the viral drug target HIVgp41. The computational testing confirms that the de novo DOCK routines are robust and working as envisioned, and the compelling results highlight the potential utility for designing new molecules against a wide variety of important protein targets. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  9. Binding of ethyl pyruvate to bovine serum albumin: Calorimetric, spectroscopic and molecular docking studies

    Energy Technology Data Exchange (ETDEWEB)

    Pathak, Mallika [Department of Chemistry, Miranda House, University of Delhi, Delhi 11007 (India); Mishra, Rashmi; Agarwala, Paban K. [Department of Radiation Genetics and Epigenetics, Division of Radioprotective Drug Development Research, Institute of Nuclear Medicine and Allied Sciences, Delhi 110054 (India); Ojha, Himanshu, E-mail: himanshu.drdo@gmail.com [Department of Radiation Genetics and Epigenetics, Division of Radioprotective Drug Development Research, Institute of Nuclear Medicine and Allied Sciences, Delhi 110054 (India); Singh, Bhawna [Department of Radiation Genetics and Epigenetics, Division of Radioprotective Drug Development Research, Institute of Nuclear Medicine and Allied Sciences, Delhi 110054 (India); Singh, Anju; Kukreti, Shrikant [Nucleic Acid Research Laboratory, Department of Chemistry, University of Delhi, Delhi 11007 (India)

    2016-06-10

    Highlights: • ITC study showed binding of ethyl pyruvate with BSA with high binding affinity. • Ethyl pyruvate binding caused conformation alteration of BSA. • Fluorescence quenching mechanism is static in nature. • Electrostatic, hydrogen bonding and hydrophobic forces involved in binding. • Docking confirmed role of electrostatic, hydrogen bonding and hydrophobic forces. - Abstract: Various in vitro and in vivo studies have shown the anti-inflammatory and anticancer potential role of ethyl pyruvate. Bio-distribution of drugs is significantly influenced by the drug-serum protein binding. Therefore, the binding mechanism of the ethyl pyruvate with bovine serum albumin was investigated using UV–vis absorption, fluorescence, circular dichroism, isothermal titration calorimetry and molecular docking techniques. Absorption and fluorescence quenching studies indicated the binding of ethyl pyruvate with protein. Circular dichroism spectra of bovine serum albumin confirmed significant change in the conformation of protein upon binding. Thermodynamic data confirmed that ethyl pyruvate binds to bovine serum albumin at the two different sites with high affinity. Binding of ethyl pyruvate to bovine serum albumin involves hydrogen bonding, van der Waal and hydrophobic interactions. Further, docking studies indicated that ethyl pyruvate could bind significantly at the three binding sites. The results will definitely contribute to the development of ethyl pyruvate as drug.

  10. Seismic vulnerability assessment of an Italian historical masonry dry dock

    OpenAIRE

    Marco Zucca; Pietro Giuseppe Crespi; Nicola Longarini

    2017-01-01

    The paper presents the seismic vulnerability analysis of the military dry dock built in 1861 inside the Messina’s harbor. The study appears very important not only for the relevance of the dry dock itself, but also for its social, military and symbolic role. As a first step, the historical documentation about the dry dock delivered by the Military Technical Office, in charge of its maintenance, was thoroughly examined. This activity was fundamental to understand the construction methods, the ...

  11. Linear Actuator System for the NASA Docking System

    Science.gov (United States)

    Dick, Brandon N.; Oesch, Christopher; Rupp, Timothy W.

    2017-01-01

    The Linear Actuator System (LAS) is a major sub-system within the NASA Docking System (NDS). The NDS Block 1 will be used on the Boeing Crew Space Transportation (CST-100) system to achieve docking with the International Space Station. Critical functions in the Soft Capture aspect of docking are performed by the LAS. This paper describes the general function of the LAS, the system's key requirements and technical challenges, and the development and qualification approach for the system.

  12. CONSRANK: a server for the analysis, comparison and ranking of docking models based on inter-residue contacts

    KAUST Repository

    Chermak, Edrisse; Petta, A.; Serra, L.; Vangone, A.; Scarano, V.; Cavallo, Luigi; Oliva, R.

    2014-01-01

    Summary: Herein, we present CONSRANK, a web tool for analyzing, comparing and ranking protein–protein and protein–nucleic acid docking models, based on the conservation of inter-residue contacts and its visualization in 2D and 3D interactive contact maps.

  13. CONSRANK: a server for the analysis, comparison and ranking of docking models based on inter-residue contacts

    KAUST Repository

    Chermak, Edrisse

    2014-12-21

    Summary: Herein, we present CONSRANK, a web tool for analyzing, comparing and ranking protein–protein and protein–nucleic acid docking models, based on the conservation of inter-residue contacts and its visualization in 2D and 3D interactive contact maps.

  14. Specificity and affinity quantification of protein-protein interactions.

    Science.gov (United States)

    Yan, Zhiqiang; Guo, Liyong; Hu, Liang; Wang, Jin

    2013-05-01

    Most biological processes are mediated by the protein-protein interactions. Determination of the protein-protein structures and insight into their interactions are vital to understand the mechanisms of protein functions. Currently, compared with the isolated protein structures, only a small fraction of protein-protein structures are experimentally solved. Therefore, the computational docking methods play an increasing role in predicting the structures and interactions of protein-protein complexes. The scoring function of protein-protein interactions is the key responsible for the accuracy of the computational docking. Previous scoring functions were mostly developed by optimizing the binding affinity which determines the stability of the protein-protein complex, but they are often lack of the consideration of specificity which determines the discrimination of native protein-protein complex against competitive ones. We developed a scoring function (named as SPA-PP, specificity and affinity of the protein-protein interactions) by incorporating both the specificity and affinity into the optimization strategy. The testing results and comparisons with other scoring functions show that SPA-PP performs remarkably on both predictions of binding pose and binding affinity. Thus, SPA-PP is a promising quantification of protein-protein interactions, which can be implemented into the protein docking tools and applied for the predictions of protein-protein structure and affinity. The algorithm is implemented in C language, and the code can be downloaded from http://dl.dropbox.com/u/1865642/Optimization.cpp.

  15. MOLECULAR DOCKING OF COMPOUNDS FROM Chaetomium Sp. AGAINST HUMAN ESTROGEN RECEPTOR ALPHA IN SEARCHING ANTI BREAST CANCER

    Directory of Open Access Journals (Sweden)

    Maywan Hariono

    2016-05-01

    Full Text Available A study on molecular docking-based virtual screening has been conducted to select virtual hit of compounds, reported its existence in fungal endophytes of Chaetomium sp. as cytotoxic agent of breast cancer. The ligands were docked into Human Estrogen Receptor alpha (HERa as the protein which regulates the breast cancer growth via estradiol-estrogen receptor binding intervention. The results showed that two compounds bearing xanthone and two compounds bearing benzonaphtyridinedione scaffolds were selected as virtual hit ligands for HERa leading to the conclusion that these compounds were good to be developed as anti breast cancer.

  16. Novel Penicillin Analogues as Potential Antimicrobial Agents; Design, Synthesis and Docking Studies.

    Science.gov (United States)

    Ashraf, Zaman; Bais, Abdul; Manir, Md Maniruzzaman; Niazi, Umar

    2015-01-01

    A number of penicillin derivatives (4a-h) were synthesized by the condensation of 6-amino penicillinic acid (6-APA) with non-steroidal anti-inflammatory drugs as antimicrobial agents. In silico docking study of these analogues was performed against Penicillin Binding Protein (PDBID 1CEF) using AutoDock Tools 1.5.6 in order to investigate the antimicrobial data on structural basis. Penicillin binding proteins function as either transpeptidases or carboxypeptidases and in few cases demonstrate transglycosylase activity in bacteria. The excellent antibacterial potential was depicted by compounds 4c and 4e against Escherichia coli, Staphylococcus epidermidus and Staphylococcus aureus compared to the standard amoxicillin. The most potent penicillin derivative 4e exhibited same activity as standard amoxicillin against S. aureus. In the enzyme inhibitory assay the compound 4e inhibited E. coli MurC with an IC50 value of 12.5 μM. The docking scores of these compounds 4c and 4e also verified their greater antibacterial potential. The results verified the importance of side chain functionalities along with the presence of central penam nucleus. The binding affinities calculated from docking results expressed in the form of binding energies ranges from -7.8 to -9.2kcal/mol. The carboxylic group of penam nucleus in all these compounds is responsible for strong binding with receptor protein with the bond length ranges from 3.4 to 4.4 Ǻ. The results of present work ratify that derivatives 4c and 4e may serve as a structural template for the design and development of potent antimicrobial agents.

  17. Novel Penicillin Analogues as Potential Antimicrobial Agents; Design, Synthesis and Docking Studies.

    Directory of Open Access Journals (Sweden)

    Zaman Ashraf

    Full Text Available A number of penicillin derivatives (4a-h were synthesized by the condensation of 6-amino penicillinic acid (6-APA with non-steroidal anti-inflammatory drugs as antimicrobial agents. In silico docking study of these analogues was performed against Penicillin Binding Protein (PDBID 1CEF using AutoDock Tools 1.5.6 in order to investigate the antimicrobial data on structural basis. Penicillin binding proteins function as either transpeptidases or carboxypeptidases and in few cases demonstrate transglycosylase activity in bacteria. The excellent antibacterial potential was depicted by compounds 4c and 4e against Escherichia coli, Staphylococcus epidermidus and Staphylococcus aureus compared to the standard amoxicillin. The most potent penicillin derivative 4e exhibited same activity as standard amoxicillin against S. aureus. In the enzyme inhibitory assay the compound 4e inhibited E. coli MurC with an IC50 value of 12.5 μM. The docking scores of these compounds 4c and 4e also verified their greater antibacterial potential. The results verified the importance of side chain functionalities along with the presence of central penam nucleus. The binding affinities calculated from docking results expressed in the form of binding energies ranges from -7.8 to -9.2kcal/mol. The carboxylic group of penam nucleus in all these compounds is responsible for strong binding with receptor protein with the bond length ranges from 3.4 to 4.4 Ǻ. The results of present work ratify that derivatives 4c and 4e may serve as a structural template for the design and development of potent antimicrobial agents.

  18. Effects of tail docking and docking length on neuroanatomical changes in healed tail tips of pigs

    DEFF Research Database (Denmark)

    Herskin, M S; Thodberg, K; Jensen, Henrik Elvang

    2015-01-01

    % (n=19); or leaving 25% (n=11) of the tail length on the pigs. The piglets were docked between day 2 and 4 after birth using a gas-heated apparatus, and were kept under conventional conditions until slaughter at 22 weeks of age, where tails were removed and examined macroscopically and histologically...

  19. Sampling protein motion and solvent effect during ligand binding

    Science.gov (United States)

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

    2012-01-01

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

  20. Insights into catalytic activity of industrial enzyme Co-nitrile hydratase. Docking studies of nitriles and amides.

    Science.gov (United States)

    Peplowski, Lukasz; Kubiak, Karina; Nowak, Wieslaw

    2007-07-01

    Nitrile hydratase (NHase) is an enzyme containing non-corrin Co3+ in the non-standard active site. NHases from Pseudonocardia thermophila JCM 3095 catalyse hydration of nitriles to corresponding amides. The efficiency of the enzyme is 100 times higher for aliphatic nitriles then aromatic ones. In order to understand better this selectivity dockings of a series of aliphatic and aromatic nitriles and related amides into a model protein based on an X-ray structure were performed. Substantial differences in binding modes were observed, showing better conformational freedom of aliphatic compounds. Distinct interactions with postranslationally modified cysteines present in the active site of the enzyme were observed. Modeling shows that water molecule activated by a metal ion may easily directly attack the docked acrylonitrile to transform this molecule into acryloamide. Thus docking studies provide support for one of the reaction mechanisms discussed in the literature.

  1. Multilevel Parallelization of AutoDock 4.2

    Directory of Open Access Journals (Sweden)

    Norgan Andrew P

    2011-04-01

    Full Text Available Abstract Background Virtual (computational screening is an increasingly important tool for drug discovery. AutoDock is a popular open-source application for performing molecular docking, the prediction of ligand-receptor interactions. AutoDock is a serial application, though several previous efforts have parallelized various aspects of the program. In this paper, we report on a multi-level parallelization of AutoDock 4.2 (mpAD4. Results Using MPI and OpenMP, AutoDock 4.2 was parallelized for use on MPI-enabled systems and to multithread the execution of individual docking jobs. In addition, code was implemented to reduce input/output (I/O traffic by reusing grid maps at each node from docking to docking. Performance of mpAD4 was examined on two multiprocessor computers. Conclusions Using MPI with OpenMP multithreading, mpAD4 scales with near linearity on the multiprocessor systems tested. In situations where I/O is limiting, reuse of grid maps reduces both system I/O and overall screening time. Multithreading of AutoDock's Lamarkian Genetic Algorithm with OpenMP increases the speed of execution of individual docking jobs, and when combined with MPI parallelization can significantly reduce the execution time of virtual screens. This work is significant in that mpAD4 speeds the execution of certain molecular docking workloads and allows the user to optimize the degree of system-level (MPI and node-level (OpenMP parallelization to best fit both workloads and computational resources.

  2. Multilevel Parallelization of AutoDock 4.2.

    Science.gov (United States)

    Norgan, Andrew P; Coffman, Paul K; Kocher, Jean-Pierre A; Katzmann, David J; Sosa, Carlos P

    2011-04-28

    Virtual (computational) screening is an increasingly important tool for drug discovery. AutoDock is a popular open-source application for performing molecular docking, the prediction of ligand-receptor interactions. AutoDock is a serial application, though several previous efforts have parallelized various aspects of the program. In this paper, we report on a multi-level parallelization of AutoDock 4.2 (mpAD4). Using MPI and OpenMP, AutoDock 4.2 was parallelized for use on MPI-enabled systems and to multithread the execution of individual docking jobs. In addition, code was implemented to reduce input/output (I/O) traffic by reusing grid maps at each node from docking to docking. Performance of mpAD4 was examined on two multiprocessor computers. Using MPI with OpenMP multithreading, mpAD4 scales with near linearity on the multiprocessor systems tested. In situations where I/O is limiting, reuse of grid maps reduces both system I/O and overall screening time. Multithreading of AutoDock's Lamarkian Genetic Algorithm with OpenMP increases the speed of execution of individual docking jobs, and when combined with MPI parallelization can significantly reduce the execution time of virtual screens. This work is significant in that mpAD4 speeds the execution of certain molecular docking workloads and allows the user to optimize the degree of system-level (MPI) and node-level (OpenMP) parallelization to best fit both workloads and computational resources.

  3. Docking studies of antidepressants against single crystal structure of tryptophan 2, 3-dioxygenase using Molegro Virtual Docker software.

    Science.gov (United States)

    Dawood, Shazia; Zarina, Shamshad; Bano, Samina

    2014-09-01

    Tryptophan 2, 3-dioxygenase (TDO) a heme containing enzyme found in mammalian liver is responsible for tryptophan (Trp) catabolism. Trp is an essential amino acid that is degraded in to N-formylkynurenine by the action of TDO. The protein ligand interaction plays a significant role in structural based drug designing. The current study illustrates the binding of established antidepressants (ADs) against TDO enzyme using in-silico docking studies. For this purpose, Fluoxetine, Paroxetine, Sertraline, Fluvoxamine, Seproxetine, Citalopram, Moclobamide, Hyperforin and Amoxepine were selected. In-silico docking studies were carried out using Molegro Virtual Docker (MVD) software. Docking results show that all ADs fit well in the active site of TDO moreover Hyperforin and Paroxetine exhibited high docking scores of -152.484k cal/mol and -139.706k cal/mol, respectively. It is concluded that Hyperforin and Paroxetine are possible lead molecules because of their high docking scores as compared to other ADs examined. Therefore, these two ADs stand as potent inhibitors of TDO enzyme.

  4. Novel Bacterial Topoisomerase Inhibitors Exploit Asp83 and the Intrinsic Flexibility of the DNA Gyrase Binding Site

    Directory of Open Access Journals (Sweden)

    Sebastian Franco-Ulloa

    2018-02-01

    Full Text Available DNA gyrases are enzymes that control the topology of DNA in bacteria cells. This is a vital function for bacteria. For this reason, DNA gyrases are targeted by widely used antibiotics such as quinolones. Recently, structural and biochemical investigations identified a new class of DNA gyrase inhibitors called NBTIs (i.e., novel bacterial topoisomerase inhibitors. NBTIs are particularly promising because they are active against multi-drug resistant bacteria, an alarming clinical issue. Structural data recently demonstrated that these NBTIs bind tightly to a newly identified pocket at the dimer interface of the DNA–protein complex. In the present study, we used molecular dynamics (MD simulations and docking calculations to shed new light on the binding of NBTIs to this site. Interestingly, our MD simulations demonstrate the intrinsic flexibility of this binding site, which allows the pocket to adapt its conformation and form optimal interactions with the ligand. In particular, we examined two ligands, AM8085 and AM8191, which induced a repositioning of a key aspartate (Asp83B, whose side chain can rotate within the binding site. The conformational rearrangement of Asp83B allows the formation of a newly identified H-bond interaction with an NH on the bound NBTI, which seems important for the binding of NBTIs having such functionality. We validated these findings through docking calculations using an extended set of cognate oxabicyclooctane-linked NBTIs derivatives (~150, in total, screened against multiple target conformations. The newly identified H-bond interaction significantly improves the docking enrichment. These insights could be helpful for future virtual screening campaigns against DNA gyrase.

  5. How well do the substrates KISS the enzyme? Molecular docking program selection for feruloyl esterases

    DEFF Research Database (Denmark)

    Udatha, D. B. R. K. Gupta; Sugaya, Nobuyoshi; Olsson, Lisbeth

    2012-01-01

    Molecular docking is the most commonly used technique in the modern drug discovery process where computational approaches involving docking algorithms are used to dock small molecules into macromolecular target structures. Over the recent years several evaluation studies have been reported...

  6. Binding Studies of Andrographolide with Human serum albumin: Molecular Docking, Chromatographic and Spectroscopic studies.

    Science.gov (United States)

    Godugu, Deepika; Rupula, Karuna; Beedu, Sashidhar Rao

    2018-02-11

    Andrographolide, sourced from Andrographis paniculata, is an established therapeutic agent with variety of pharmacological properties in treatment of various diseases. The present study is designed to evaluate the interaction and binding affinity of andrographolide with HSA by docking and spectral studies. The docking study for screening the interaction of andrographolide with HSA protein was carried out using Auto Dock Vina software and the binding score of andrographolide was -8.7 kcal mol-1 and formed one hydrogen bond with Arg 218 residue of HSA in sub-domains IIA region. The formation of HSA-andrographolide complex was characterized by spectroscopic methods - UV absorption, HPLC, CD and FTIR analysis. The UV spectral analysis revealed a decrease in the absorption peak of HSA due to its interaction with andrographolide. A new peak was observed at retention time 7.45 min by HPLC analysis and the Bmax was found to be 7.5 ± 0.4 mg protein with a Kd value of 1.89 mM, indicating interaction of andrographolide with HSA. The CD spectra results suggested, a marginal decrease in the negative ellipticity without any significant shift in peak, indicating the stabilization of the HSA-andrographolide complex. The FTIR analysis further confirmed, a shift of amide I groups from 1646 to 1637 cm-1 and a peak at 1016 cm-1 in andrographolide, was observed in the complex, indicating the interaction. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  7. Spectroscopic, structural and drug docking studies of carbocysteine

    Science.gov (United States)

    Manivannan, M.; Rajeshwaran, K.; Govindhan, R.; Karthikeyan, B.

    2017-09-01

    Carbocysteine or carbocisteine having the empirical formula C5H9NO4S,is one of the most therapeutically prescribed expectorant, sold under the brand name viz., Mucodyne (UK and India), Rhinathiol and Mucolite. In pediatric respiratory pathology, it can relieve the symptoms of obstructive pulmonary disease (COPD) and bronchiectasis. On the consideration of its extensive pharmaceutical usage and medicinal value, we have investigated its chemical structure and composition by employing various spectral techniques like 1H, 13C NMR, FT-IR,Raman, UV-Visible spectroscopy and powder X-ray diffraction method. Density Functional Theoretical (DFT) studies on its electronic structure is also carried out. Drug docking studies were carried out to ascertain the nature of molecular interaction with the biological protein system. Furthermore theoretical Raman spectrum of this molecule has been computed and compared with the experimental Raman spectrum. The forbidden energy gap between its frontier molecular orbitals, viz., HOMO-LUMO is calculated and correlated with its observed λmax value. Atomic orbitals which are mainly contributes to the frontier molecular orbitals were identified. Molecular electrostatic potential diagram has been mapped to explain its chemical activity. Based on the results, a suitable mechanism of its protein binding mode and drug action has been discussed.

  8. Elucidating the interaction of clofazimine with bovine liver catalase; a comprehensive spectroscopic and molecular docking approach.

    Science.gov (United States)

    Zaman, Masihuz; Nusrat, Saima; Zakariya, Syed Mohammad; Khan, Mohsin Vahid; Ajmal, Mohammad Rehan; Khan, Rizwan Hasan

    2017-08-01

    Nowadays, understanding of interface between protein and drugs has become an active research area of interest. These types of interactions provide structural guidelines in drug design with greater clinical efficacy. Thus, structural changes in catalase induced by clofazimine were monitored by various biophysical techniques including UV-visible spectrometer, fluorescence spectroscopy, circular dichroism, and dynamic light scattering techniques. Increase in absorption spectra (UV-visible spectrum) confers the complex formation between drug and protein. Fluorescence quenching with a binding constants of 2.47 × 10 4  M -1 revealed that clofazimine binds with protein. Using fluorescence resonance energy transfer, the distance (r) between the protein (donor) and drug (acceptor) was found to be 2.89 nm. Negative Gibbs free energy change (ΔG°) revealed that binding process is spontaneous. In addition, an increase in α-helicity was observed by far-UV circular dichroism spectra by adding clofazimine to protein. Dynamic light scattering results indicate that topology of bovine liver catalase was slightly altered in the presence of clofazimine. Hydrophobic interactions are the main forces between clofazimine and catalase interaction as depicted by molecular docking studies. Apart from hydrophobic interactions, some hydrogen bonding was also observed during docking method. The results obtained from the present study may establish abundant in optimizing the properties of ligand-protein mixtures relevant for numerous formulations. Copyright © 2017 John Wiley & Sons, Ltd.

  9. Fragment-based modelling of single stranded RNA bound to RNA recognition motif containing proteins

    Science.gov (United States)

    de Beauchene, Isaure Chauvot; de Vries, Sjoerd J.; Zacharias, Martin

    2016-01-01

    Abstract Protein-RNA complexes are important for many biological processes. However, structural modeling of such complexes is hampered by the high flexibility of RNA. Particularly challenging is the docking of single-stranded RNA (ssRNA). We have developed a fragment-based approach to model the structure of ssRNA bound to a protein, based on only the protein structure, the RNA sequence and conserved contacts. The conformational diversity of each RNA fragment is sampled by an exhaustive library of trinucleotides extracted from all known experimental protein–RNA complexes. The method was applied to ssRNA with up to 12 nucleotides which bind to dimers of the RNA recognition motifs (RRMs), a highly abundant eukaryotic RNA-binding domain. The fragment based docking allows a precise de novo atomic modeling of protein-bound ssRNA chains. On a benchmark of seven experimental ssRNA–RRM complexes, near-native models (with a mean heavy-atom deviation of <3 Å from experiment) were generated for six out of seven bound RNA chains, and even more precise models (deviation < 2 Å) were obtained for five out of seven cases, a significant improvement compared to the state of the art. The method is not restricted to RRMs but was also successfully applied to Pumilio RNA binding proteins. PMID:27131381

  10. Novel α, β-Unsaturated Sophoridinic Derivatives: Design, Synthesis, Molecular Docking and Anti-Cancer Activities

    Directory of Open Access Journals (Sweden)

    Yiming Xu

    2017-11-01

    Full Text Available Using sophoridine 1 and chalcone 3 as the lead compounds, a series of novel α, β-unsaturated sophoridinic derivatives were designed, synthesized, and evaluated for their in vitro cytotoxicity. Structure-activity relationship (SAR analysis indicated that introduction of α, β-unsaturated ketone moiety and heterocyclic group might significantly enhance anticancer activity. Among the compounds, 2f and 2m exhibited potential effects against HepG-2 and CNE-2 human cancer cell lines. Furthermore, molecular docking studies were performed to understand possible docking sites of the molecules on the target proteins and the mode of binding. This work provides a theoretical basis for structural optimizations and exploring anticancer pathways of this kind of compound.

  11. Natural Products as New Treatment Options for Trichomoniasis: A Molecular Docking Investigation

    Directory of Open Access Journals (Sweden)

    Mary Snow Setzer

    2017-01-01

    Full Text Available Trichomoniasis, caused by the parasitic protozoan Trichomonas vaginalis, is the most common non-viral sexually-transmitted disease, and there can be severe complications from trichomoniasis. Antibiotic resistance in T. vaginalis is increasing, but there are currently no alternatives treatment options. There is a need to discover and develop new chemotherapeutic alternatives. Plant-derived natural products have long served as sources for new medicinal agents, as well as new leads for drug discovery and development. In this work, we have carried out an in silico screening of 952 antiprotozoal phytochemicals with specific protein drug targets of T. vaginalis. A total of 42 compounds showed remarkable docking properties to T. vaginalis methionine gamma-lyase (TvMGL and to T. vaginalis purine nucleoside phosphorylase (TvPNP. The most promising ligands were polyphenolic compounds, and several of these showed docking properties superior to either co-crystallized ligands or synthetic enzyme inhibitors.

  12. Molecular Dynamics and Docking of Biphenyl: A Potential ...

    African Journals Online (AJOL)

    Results: Molecular docking by FireDock web server showed that biPhe-43 and Trp-43-mutated CD4 inhibited the binding of ... In a 5ns MD simulation, biPhe-43 and Trp-43 mutated CD4 .... 'unbound' MD on UMHPC Linux Cluster SGIAltix.

  13. Synthesis of Diphenyl Pyridazinone-based flexible system for ...

    Indian Academy of Sciences (India)

    conformational studies through weak noncovalent interactions: Application in DNA ... Single crystal structure; DFT calculation; Hirshfeld surfaces; fingerprint analysis; docking simulation; DNA ... tion properties of nucleic acids, peptides and proteins as well as ... as, (i) electrostatic attractions with the anionic sugar- phosphate ...

  14. Flexible Electronics Research Facility

    Data.gov (United States)

    Federal Laboratory Consortium — The Flexible Electronics Research Facility designs, synthesizes, tests, and fabricates materials and devices compatible with flexible substrates for Army information...

  15. Caffeine and sulfadiazine interact differently with human serum albumin: A combined fluorescence and molecular docking study

    Science.gov (United States)

    Islam, Mullah Muhaiminul; Sonu, Vikash K.; Gashnga, Pynsakhiat Miki; Moyon, N. Shaemningwar; Mitra, Sivaprasad

    2016-01-01

    The interaction and binding behavior of the well-known drug sulfadiazine (SDZ) and psychoactive stimulant caffeine (CAF) with human serum albumin (HSA) was monitored by in vitro fluorescence titration and molecular docking calculations under physiological condition. The quenching of protein fluorescence on addition of CAF is due to the formation of protein-drug complex in the ground state; whereas in case of SDZ, the experimental results were explained on the basis of sphere of action model. Although both these compounds bind preferentially in Sudlow's site 1 of the protein, the association constant is approximately two fold higher in case of SDZ (∼4.0 × 104 M-1) in comparison with CAF (∼9.3 × 102 M-1) and correlates well with physico-chemical properties like pKa and lipophilicity of the drugs. Temperature dependent fluorescence study reveals that both SDZ and CAF bind spontaneously with HSA. However, the binding of SDZ with the protein is mainly governed by the hydrophobic forces in contrast with that of CAF; where, the interaction is best explained in terms of electrostatic mechanism. Molecular docking calculation predicts the binding of these drugs in different location of sub-domain IIA in the protein structure.

  16. Visual Sensory Signals Dominate Tactile Cues during Docked Feeding in Hummingbirds.

    Science.gov (United States)

    Goller, Benjamin; Segre, Paolo S; Middleton, Kevin M; Dickinson, Michael H; Altshuler, Douglas L

    2017-01-01

    Animals living in and interacting with natural environments must monitor and respond to changing conditions and unpredictable situations. Using information from multiple sensory systems allows them to modify their behavior in response to their dynamic environment but also creates the challenge of integrating different, and potentially contradictory, sources of information for behavior control. Understanding how multiple information streams are integrated to produce flexible and reliable behavior is key to understanding how behavior is controlled in natural settings. Natural settings are rarely still, which challenges animals that require precise body position control, like hummingbirds, which hover while feeding from flowers. Tactile feedback, available only once the hummingbird is docked at the flower, could provide additional information to help maintain its position at the flower. To investigate the role of tactile information for hovering control during feeding, we first asked whether hummingbirds physically interact with a feeder once docked. We quantified physical interactions between docked hummingbirds and a feeder placed in front of a stationary background pattern. Force sensors on the feeder measured a complex time course of loading that reflects the wingbeat frequency and bill movement of feeding hummingbirds, and suggests that they sometimes push against the feeder with their bill. Next, we asked whether the measured tactile interactions were used by feeding hummingbirds to maintain position relative to the feeder. We created two experimental scenarios-one in which the feeder was stationary and the visual background moved and the other where the feeder moved laterally in front of a white background. When the visual background pattern moved, docked hummingbirds pushed significantly harder in the direction of horizontal visual motion. When the feeder moved, and the background was stationary, hummingbirds generated aerodynamic force in the opposite

  17. Broad substrate tolerance of tubulin tyrosine ligase enables one-step site-specific enzymatic protein labeling.

    Science.gov (United States)

    Schumacher, Dominik; Lemke, Oliver; Helma, Jonas; Gerszonowicz, Lena; Waller, Verena; Stoschek, Tina; Durkin, Patrick M; Budisa, Nediljko; Leonhardt, Heinrich; Keller, Bettina G; Hackenberger, Christian P R

    2017-05-01

    The broad substrate tolerance of tubulin tyrosine ligase is the basic rationale behind its wide applicability for chemoenzymatic protein functionalization. In this context, we report that the wild-type enzyme enables ligation of various unnatural amino acids that are substantially bigger than and structurally unrelated to the natural substrate, tyrosine, without the need for extensive protein engineering. This unusual substrate flexibility is due to the fact that the enzyme's catalytic pocket forms an extended cavity during ligation, as confirmed by docking experiments and all-atom molecular dynamics simulations. This feature enabled one-step C-terminal biotinylation and fluorescent coumarin labeling of various functional proteins as demonstrated with ubiquitin, an antigen binding nanobody, and the apoptosis marker Annexin V. Its broad substrate tolerance establishes tubulin tyrosine ligase as a powerful tool for in vitro enzyme-mediated protein modification with single functional amino acids in a specific structural context.

  18. An NMR-based scoring function improves the accuracy of binding pose predictions by docking by two orders of magnitude

    Energy Technology Data Exchange (ETDEWEB)

    Orts, Julien [EMBL, Structure and Computational Biology Unit (Germany); Bartoschek, Stefan [Industriepark Hoechst, Sanofi-Aventis Deutschland GmbH, R and D LGCR/Parallel Synthesis and Natural Products (Germany); Griesinger, Christian [Max Planck Institute for Biophysical Chemistry (Germany); Monecke, Peter [Industriepark Hoechst, Sanofi-Aventis Deutschland GmbH, R and D LGCR/Structure, Design and Informatics (Germany); Carlomagno, Teresa, E-mail: teresa.carlomagno@embl.de [EMBL, Structure and Computational Biology Unit (Germany)

    2012-01-15

    Low-affinity ligands can be efficiently optimized into high-affinity drug leads by structure based drug design when atomic-resolution structural information on the protein/ligand complexes is available. In this work we show that the use of a few, easily obtainable, experimental restraints improves the accuracy of the docking experiments by two orders of magnitude. The experimental data are measured in nuclear magnetic resonance spectra and consist of protein-mediated NOEs between two competitively binding ligands. The methodology can be widely applied as the data are readily obtained for low-affinity ligands in the presence of non-labelled receptor at low concentration. The experimental inter-ligand NOEs are efficiently used to filter and rank complex model structures that have been pre-selected by docking protocols. This approach dramatically reduces the degeneracy and inaccuracy of the chosen model in docking experiments, is robust with respect to inaccuracy of the structural model used to represent the free receptor and is suitable for high-throughput docking campaigns.

  19. Modeling and Proposed Molecular Mechanism of Hydroxyurea Through Docking and Molecular Dynamic Simulation to Curtail the Action of Ribonucleotide Reductase.

    Science.gov (United States)

    Iman, Maryam; Khansefid, Zeynab; Davood, Asghar

    2016-01-01

    Ribonucleotide Reductase (RNR) is an important anticancer chemotherapy target. It has main key role in DNA synthesis and cell growth. Therefore several RNR inhibitors, such as hydroxyurea, have entered the clinical trials. Based on our proposed mechanism, radical site of RNR protein reacts with hydroxyurea in which hydroxyurea is converted into its oxidized form compound III, and whereby the tyrosyl radical is converted into a normal tyrosine residue. In this study, docking and molecular dynamics simulations were used for proposed molecular mechanism of hydroxyurea in RNR inhibition as anticancer agent. The binding affinity of hydroxyurea and compound III to RNR was studied by docking method. The docking study was performed for the crystal structure of human RNR with the radical scavenger Hydroxyurea and its oxidized form to inhibit the human RNR. hydroxyurea and compound III bind at the active site with Tyr-176, which are essential for free radical formation. This helps to understand the functional aspects and also aids in the development of novel inhibitors for the human RNR2. To confirm the binding mode of inhibitors, the molecular dynamics (MD) simulations were performed using GROMACS 4.5.5, based upon the docked conformation of inhibitors. Both of the studied compounds stayed in the active site. The results of MD simulations confirmed the binding mode of ligands, accuracy of docking and the reliability of active conformations which were obtained by AutoDock. MD studies confirm our proposed mechanism in which compound III reacts with the active site residues specially Tyr-176, and inhibits the radical generation and subsequently inhibits the RNR enzyme.

  20. Balance and flexibility.

    Science.gov (United States)

    2003-12-01

    The 'work-life balance' and flexible working are currently key buzz terms in the NHS. Those looking for more information on these topics should visit Flexibility at www.flexibility.co.uk for a host of resources designed to support new ways of working, including information on flexible workers and flexible rostering, the legal balancing act for work-life balance and home working.

  1. QuickVina: accelerating AutoDock Vina using gradient-based heuristics for global optimization.

    Science.gov (United States)

    Handoko, Stephanus Daniel; Ouyang, Xuchang; Su, Chinh Tran To; Kwoh, Chee Keong; Ong, Yew Soon

    2012-01-01

    Predicting binding between macromolecule and small molecule is a crucial phase in the field of rational drug design. AutoDock Vina, one of the most widely used docking software released in 2009, uses an empirical scoring function to evaluate the binding affinity between the molecules and employs the iterated local search global optimizer for global optimization, achieving a significantly improved speed and better accuracy of the binding mode prediction compared its predecessor, AutoDock 4. In this paper, we propose further improvement in the local search algorithm of Vina by heuristically preventing some intermediate points from undergoing local search. Our improved version of Vina-dubbed QVina-achieved a maximum acceleration of about 25 times with the average speed-up of 8.34 times compared to the original Vina when tested on a set of 231 protein-ligand complexes while maintaining the optimal scores mostly identical. Using our heuristics, larger number of different ligands can be quickly screened against a given receptor within the same time frame.

  2. Dual role for DOCK7 in tangential migration of interneuron precursors in the postnatal forebrain.

    Science.gov (United States)

    Nakamuta, Shinichi; Yang, Yu-Ting; Wang, Chia-Lin; Gallo, Nicholas B; Yu, Jia-Ray; Tai, Yilin; Van Aelst, Linda

    2017-12-04

    Throughout life, stem cells in the ventricular-subventricular zone generate neuroblasts that migrate via the rostral migratory stream (RMS) to the olfactory bulb, where they differentiate into local interneurons. Although progress has been made toward identifying extracellular factors that guide the migration of these cells, little is known about the intracellular mechanisms that govern the dynamic reshaping of the neuroblasts' morphology required for their migration along the RMS. In this study, we identify DOCK7, a member of the DOCK180-family, as a molecule essential for tangential neuroblast migration in the postnatal mouse forebrain. DOCK7 regulates the migration of these cells by controlling both leading process (LP) extension and somal translocation via distinct pathways. It controls LP stability/growth via a Rac-dependent pathway, likely by modulating microtubule networks while also regulating F-actin remodeling at the cell rear to promote somal translocation via a previously unrecognized myosin phosphatase-RhoA-interacting protein-dependent pathway. The coordinated action of both pathways is required to ensure efficient neuroblast migration along the RMS. © 2017 Nakamuta et al.

  3. Identification of bioflavonoid as fusion inhibitor of dengue virus using molecular docking approach

    Directory of Open Access Journals (Sweden)

    Asif Mir

    Full Text Available Dengue virus with four distinct serotypes belongs to Flavivirus, poses a significant threat to human health and becomes an emerging global problem. Membrane fusion is a central molecular event during viral entry into host cell. To prevent viral infection it is necessary to interrupt the virus replication at an early stage of attachment. Dengue Virus (DENV envelope protein experiences conformational changes and it causes the virus to fuse with host cell. Hinge region movement of domain I and II in envelope protein facilitates the fusion process. Small molecules that bind in this pocket may have the ability to interrupt the conformational changes that trigger fusion process. We chose different flavonoids (baicalein, fisetin, hesperetin, naringenin/ naringin, quercetin and rutin that possess anti dengue activity. Molecular docking analysis was done to examine the inhibitory effect of flavonoids against envelope protein of DENV-2. Results manifest quercetin (flavonoid found in Carica papaya, apple and even in lemon as the only flavone that can interrupt the fusion process of virus by inhibiting the hinge region movement and by blocking the conformational rearrangement in envelope protein. These novel findings using computational approach are worthwhile and will be a bridge to check the efficacy of compounds using appropriate animal model under In vivo studies. This information can be used by new techniques and provides a way to control dengue virus infection. Keywords: Dengue virus, Inhibitor identification, Molecular docking, Interaction analysis

  4. Using Molecular Docking Analysis to Discovery Dregea sinensis Hemsl. Potential Mechanism of Anticancer, Antidepression, and Immunoregulation.

    Science.gov (United States)

    Liu, Xiujie; Shi, Yu; Deng, Yulin; Dai, Rongji

    2017-01-01

    Dregea sinensis Hemsl. plant of the genus Dregea volubilis (Asclepiadaceae), plays a vital role in anticancer, antidepression, and immunoregulation. Steroidal glycosides are the main constituents of this herb, which were significant biological active ingredients. The objective of this study is to recognize the mechanism of anticancer, antidepression, and immunoregulation of D. sinensis Hemsl. Seventy-two steroidal glycosides of D. sinensis Hemsl. were evaluated on the docking behavior of tumor-associated proteins (PI3K, Akt, mTOR), depression-related proteins (MAO-A, MAO-B) and immune-related proteins (tumor necrosis factor-α [TNF-α], tumor necrosis factor receptor 2 [TNFR2], interleukin-2Rα [IL-2Rα]) using Discovery Studio version 3.1 (Accelrys, San Diego, USA). The molecular docking analysis revealed that mostly steroidal glycosides of D. sinensis Hemsl. exhibited powerful interaction with the depression-related protein (MAO-A) and the immune-related proteins (TNFR2, IL-2Rα). Some ligands exhibited high binding energy for the tumor-associated proteins (PI3K, Akt, mTOR) and the immune-related protein (TNF-α), but MAO-B showed none interaction with the ligands. This study has paved better understanding of steroidal glycosides from D. sinensis Hemsl. as potential constituents to the prevention of associated cancer, depression and disorders of immunoregulation. The ligand database was consist of 72 steroidal glycosides from Dregea sinensis HemslSteroidal glycosides had the potential to dock with the tumor-associated proteins (PI3K, Akt, mTOR)Steroidal glycosides were bounded with MAO-A rather than MAO-B, accorded with the inhibitor selectivity of MAOs, can be considered as potent candidate inhibitors of MAO-A72 ligands got high interaction with TNFR2 and IL-2Rα, regard the steroidal glycoside as powerful candidate inhibitors of TNFR2 and IL-2Rα. Abbreviations used: PI3K: Phosphatidyl inositol 3-kinase; Akt: Protein kinase B; mTOR: Mammalian target of

  5. Coarse-grained versus atomistic simulations : realistic interaction free energies for real proteins

    NARCIS (Netherlands)

    May, Ali; Pool, René; van Dijk, Erik; Bijlard, Jochem; Abeln, Sanne; Heringa, Jaap; Feenstra, K Anton

    2014-01-01

    MOTIVATION: To assess whether two proteins will interact under physiological conditions, information on the interaction free energy is needed. Statistical learning techniques and docking methods for predicting protein-protein interactions cannot quantitatively estimate binding free energies. Full

  6. Coarse-grained versus atomistic simulations: realistic interaction free energies for real proteins

    NARCIS (Netherlands)

    May, A.; Pool, R.; van Dijk, E.; Bijlard, J.; Abeln, S.; Heringa, J.; Feenstra, K.A.

    2014-01-01

    MOTIVATION: To assess whether two proteins will interact under physiological conditions, information on the interaction free energy is needed. Statistical learning techniques and docking methods for predicting protein-protein interactions cannot quantitatively estimate binding free energies. Full

  7. GalaxyHomomer: a web server for protein homo-oligomer structure prediction from a monomer sequence or structure.

    Science.gov (United States)

    Baek, Minkyung; Park, Taeyong; Heo, Lim; Park, Chiwook; Seok, Chaok

    2017-07-03

    Homo-oligomerization of proteins is abundant in nature, and is often intimately related with the physiological functions of proteins, such as in metabolism, signal transduction or immunity. Information on the homo-oligomer structure is therefore important to obtain a molecular-level understanding of protein functions and their regulation. Currently available web servers predict protein homo-oligomer structures either by template-based modeling using homo-oligomer templates selected from the protein structure database or by ab initio docking of monomer structures resolved by experiment or predicted by computation. The GalaxyHomomer server, freely accessible at http://galaxy.seoklab.org/homomer, carries out template-based modeling, ab initio docking or both depending on the availability of proper oligomer templates. It also incorporates recently developed model refinement methods that can consistently improve model quality. Moreover, the server provides additional options that can be chosen by the user depending on the availability of information on the monomer structure, oligomeric state and locations of unreliable/flexible loops or termini. The performance of the server was better than or comparable to that of other available methods when tested on benchmark sets and in a recent CASP performed in a blind fashion. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

  8. Synthesis, docking and anticancer activity studies of D-proline ...

    Indian Academy of Sciences (India)

    D-proline-incorporated wainunuamide — a cyclic octapeptide was synthesized and characterized ... Cyclic octapeptide; molecular docking; solution phase synthesis; anticancer activity ..... dynamics and their binding affinities, using free energy.

  9. Passive, Failure-Tolerant Docking and Undocking with Articulated Magnets

    Data.gov (United States)

    National Aeronautics and Space Administration — Current spacecraft docking relies on active movement (e.g. thrusters) to close the gap between participants, and to separate them when undocking. I intend to develop...

  10. Synthesis, in vitro anti-inflammatory activity and molecular docking ...

    Indian Academy of Sciences (India)

    alkyl and heterocyclic alkyl moieties were synthesized, characterized and subsequently evaluated for ... Docking studies with these compounds against cyclooxygenase-2 receptor ...... thiadiazole derivatives as possible anti-tubercular agents.

  11. Optimal Rendezvous and Docking Simulator for Elliptical Orbits, Phase I

    Data.gov (United States)

    National Aeronautics and Space Administration — It is proposed to develop and implement a simulation of spacecraft rendezvous and docking guidance, navigation, and control in elliptical orbit. The foundation of...

  12. Molecular docking studies on rocaglamide, a traditional Chinese ...

    African Journals Online (AJOL)

    Keywords: Periodontitis, Inflammation, Rocaglamide, Molecular docking, Lamarckian ... Index Medicus, JournalSeek, Journal Citation Reports/Science Edition, ... chronic, bacterial infection-associated auto- .... The binding pocket in this case.

  13. Mother Centriole Distal Appendages Mediate Centrosome Docking at the Immunological Synapse and Reveal Mechanistic Parallels with Ciliogenesis.

    Science.gov (United States)

    Stinchcombe, Jane C; Randzavola, Lyra O; Angus, Karen L; Mantell, Judith M; Verkade, Paul; Griffiths, Gillian M

    2015-12-21

    Cytotoxic T lymphocytes (CTLs) are highly effective serial killers capable of destroying virally infected and cancerous targets by polarized release from secretory lysosomes. Upon target contact, the CTL centrosome rapidly moves to the immunological synapse, focusing microtubule-directed release at this point [1-3]. Striking similarities have been noted between centrosome polarization at the synapse and basal body docking during ciliogenesis [1, 4-8], suggesting that CTL centrosomes might dock with the plasma membrane during killing, in a manner analogous to primary cilia formation [1, 4]. However, questions remain regarding the extent and function of centrosome polarization at the synapse, and recent reports have challenged its role [9, 10]. Here, we use high-resolution transmission electron microscopy (TEM) tomography analysis to show that, as in ciliogenesis, the distal appendages of the CTL mother centriole contact the plasma membrane directly during synapse formation. This is functionally important as small interfering RNA (siRNA) targeting of the distal appendage protein, Cep83, required for membrane contact during ciliogenesis [11], impairs CTL secretion. Furthermore, the regulatory proteins CP110 and Cep97, which must dissociate from the mother centriole to allow cilia formation [12], remain associated with the mother centriole in CTLs, and neither axoneme nor transition zone ciliary structures form. Moreover, complete centrosome docking can occur in proliferating CTLs with multiple centriole pairs. Thus, in CTLs, centrosomes dock transiently with the membrane, within the cell cycle and without progression into ciliogenesis. We propose that this transient centrosome docking without cilia formation is important for CTLs to deliver rapid, repeated polarized secretion directed by the centrosome. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  14. Companies hone in on radar-docking technology

    Science.gov (United States)

    Howell, Elizabeth

    2009-11-01

    As NASA prepares to retire the Space Shuttle next year, two private space firms have tested docking technology that could be used on the next generation of US spacecraft. In September, Canadian firm Neptec tested a new radar system on the Space Shuttle Discovery that allows spacecraft to dock more easily. Meanwhile, Space Exploration Technologies (SpaceX) based in California has revealed that it tested out a new proximity sensor, dubbed "Dragoneye", on an earlier shuttle mission in July.

  15. A primer on wood as dock construction material

    Science.gov (United States)

    Stan Lebow

    2007-01-01

    To be a successful marina owner and operator, it’s important to understand all the facets of one’s facility, including the intricacies of one part of the marina that most boaters take for granted: the docks. When it comes to dock construction, marinas have a wide-range of materials to choose from, with one of the most commonly used materials being preservative-treated...

  16. Demonstration of automated proximity and docking technologies

    Science.gov (United States)

    Anderson, Robert L.; Tsugawa, Roy K.; Bryan, Thomas C.

    An autodock was demonstrated using straightforward techniques and real sensor hardware. A simulation testbed was established and validated. The sensor design was refined with improved optical performance and image processing noise mitigation techniques, and the sensor is ready for production from off-the-shelf components. The autonomous spacecraft architecture is defined. The areas of sensors, docking hardware, propulsion, and avionics are included in the design. The Guidance Navigation and Control architecture and requirements are developed. Modular structures suitable for automated control are used. The spacecraft system manager functions including configuration, resource, and redundancy management are defined. The requirements for autonomous spacecraft executive are defined. High level decisionmaking, mission planning, and mission contingency recovery are a part of this. The next step is to do flight demonstrations. After the presentation the following question was asked. How do you define validation? There are two components to validation definition: software simulation with formal and vigorous validation, and hardware and facility performance validated with respect to software already validated against analytical profile.

  17. Reactive Path Planning Approach for Docking Robots in Unknown Environment

    Directory of Open Access Journals (Sweden)

    Peng Cui

    2017-01-01

    Full Text Available Autonomous robots need to be recharged and exchange information with the host through docking in the long-distance tasks. Therefore, feasible path is required in the docking process to guide the robot and adjust its pose. However, when there are unknown obstacles in the work area, it becomes difficult to determine the feasible path for docking. This paper presents a reactive path planning approach named Dubins-APF (DAPF to solve the path planning problem for docking in unknown environment with obstacles. In this proposed approach the Dubins curves are combined with the designed obstacle avoidance potential field to plan the feasible path. Firstly, an initial path is planned and followed according to the configurations of the robot and the docking station. Then when the followed path is evaluated to be infeasible, the intermediate configuration is calculated as well as the replanned path based on the obstacle avoidance potential field. The robot will be navigated to the docking station with proper pose eventually via the DAPF approach. The proposed DAPF approach is efficient and does not require the prior knowledge about the environment. Simulation results are given to validate the effectiveness and feasibility of the proposed approach.

  18. In silico molecular modeling of neuraminidase enzyme H1N1 avian influenza virus and docking with zanamivir ligands

    Directory of Open Access Journals (Sweden)

    Muthiyan Ramachandran

    2012-12-01

    Full Text Available Objective: Neuraminidase is an enzyme aspartic protease that is essential for the life cycle of H1N1. Methods: Constructed a model of Neuraminidase enzyme the 3D structure as template using with Modeller software. The Neuraminidase enzyme model was predicted and validated by Procheck, What check, Errat, Verify-3D and AutoDock web server for reliability. Results: The Modeller homology-modeling algorithm was demonstrated excellent accuracy in blind predictions. The Neuraminidase enzyme model built with little, 35% identity could be accurate enough to be successfully used in receptor based rational drug design. The closest homologue with the highest sequence identity 100% was selected. Zanamivir drug and analogues were retrieved from PubChem database, as well as subjected to docking interaction with Neuraminidase enzyme used AutoDock programme. Based on the root mean square deviation and lowest binding energy values the best docking orientation was selected. The better lowest binding energy value -6.91 was selected of CID_25209232. Conclusions: This study will be used in broad screening of inhibitors of the protein. However, further implemented experimental and clinical verification is needed to establishment these analogues as drug.

  19. Flexible magnetoimpedance sensor

    KAUST Repository

    Li, Bodong; Kavaldzhiev, Mincho; Kosel, Jü rgen

    2015-01-01

    Flexible magnetoimpedance (MI) sensors fabricated using a NiFe/Cu/NiFe tri-layer on Kapton substrate have been studied. A customized flexible microstrip transmission line was employed to investigate the MI sensors's magnetic field and frequency

  20. ARF1 and ARF6 regulate recycling of GRASP/Tamalin and the Rac1-GEF Dock180 during HGF-induced Rac1 activation.

    Science.gov (United States)

    Koubek, Emily J; Santy, Lorraine C

    2018-05-04

    Hepatocyte growth factor (HGF) is a potent signaling factor that acts on epithelial cells, causing them to dissociate and scatter. This migration is coordinated by a number of small GTPases, such as ARF6 and Rac1. Active ARF6 is required for HGF-stimulated migration and intracellular levels of ARF6-GTP and Rac1-GTP increase following HGF treatment. During migration, cross talk between ARF6 and Rac1 occurs through formation of a multi-protein complex containing the ARF-GEF cytohesin-2, the scaffolding protein GRASP/Tamalin, and the Rac1-GEF Dock180. Previously, the role of ARF6 in this process was unclear. We have now found that ARF6 and ARF1 regulate trafficking of GRASP and Dock180 to the plasma membrane following HGF treatment. Trafficking of GRASP and Dock180 is impaired by blocking ARF6-mediated recycling pathways and is required for HGF-stimulated Rac1 activation. Finally, HGF treatment stimulates association of GRASP and Dock180. Inhibition of ARF6 trafficking pathways traps GRASP and Dock180 as a complex in the cell.

  1. Fluorometric and molecular docking investigation on the binding characteristics of SB202190 to human serum albumin

    International Nuclear Information System (INIS)

    Nasruddin, Ahmad N.; Feroz, Shevin R.; Mukarram, Abdul K.; Mohamad, Saharuddin B.; Tayyab, Saad

    2016-01-01

    The interaction of SB202190, a p38 mitogen-activated protein kinase inhibitor with the main drug transporter in human circulation, human serum albumin (HSA) was studied using fluorescence spectroscopy and in silico docking methods. The association constant, K a of the binding reaction was determined to be 3.24±0.07×10 4 M −1 at 25 °C based on fluorescence quenching titration results. The values of enthalpy change and entropy change for the interaction were found as −8.54 kJ mol −1 and 58.01 J mol −1 K −1 , respectively. Both thermodynamic data and docking results suggested the involvement of hydrophobic and van der Waals forces in the complex formation. Three-dimensional fluorescence data of SB202190–HSA complex demonstrated significant changes in the microenvironment around the protein fluorophores upon drug binding. Comparison of HSA thermograms obtained in the absence and the presence of SB202190 suggested improved protein thermal stability upon complexation with the drug. Competitive drug displacement results as well as modeling data concluded the preferred binding site of SB202190 on HSA as Sudlow's site I. - Highlights: • SB202190 interacts with HSA with moderate affinity. • Involvement of hydrophobic and van der Waals forces in SB202190 binding. • SB202190 binding results in microenvironmental changes around fluorophores. • Sudlow's site I is the preferred binding site of SB202190.

  2. Flexible Carpooling: Exploratory Study

    OpenAIRE

    Dorinson, Diana; Gay, Deanna; Minett, Paul; Shaheen, Susan

    2009-01-01

    Energy consumption could be reduced if more people shared rides rather than driving alone yet carpooling represents a small proportion of all potential carpoolers. Prior research has found that many who might carpool were concerned about reduced flexibility with carpooling. If flexibility is one of the barriers how could carpooling be organized to be more flexible? In Northern Virginia a flexible system has evolved where there are 3,500 single-use carpools per day. In another example there ...

  3. Study of Interactions of an Anticancer Drug Neratinib With Bovine Serum Albumin: Spectroscopic and Molecular Docking Approach

    OpenAIRE

    Tanveer A. Wani; Ahmed H. Bakheit; Ahmed H. Bakheit; M. A. Abounassif; Seema Zargar

    2018-01-01

    Binding of therapeutic agents to plasma proteins, particularly to serum albumin, provides valuable information in the drug development. This study was designed to evaluate the binding interaction of neratinib with bovine serum albumin (BSA). Neratinib blocks HER2 signaling and is effective in trastuzumab-resistant breast cancer treatment. Spectrofluorometric, UV spectrophotometric, and fourier transform infrared (FT-IR) and molecular docking experiments were performed to study this interactio...

  4. Orion Handling Qualities During ISS Rendezvous and Docking

    Science.gov (United States)

    Hart, Jeremy J.; Stephens, J. P.; Spehar, P.; Bilimoria, K.; Foster, C.; Gonzalex, R.; Sullivan, K.; Jackson, B.; Brazzel, J.; Hart, J.

    2011-01-01

    The Orion spacecraft was designed to rendezvous with multiple vehicles in low earth orbit (LEO) and beyond. To perform the required rendezvous and docking task, Orion must provide enough control authority to perform coarse translational maneuvers while maintaining precision to perform the delicate docking corrections. While Orion has autonomous docking capabilities, it is expected that final approach and docking operations with the International Space Station (ISS) will initially be performed in a manual mode. A series of evaluations was conducted by NASA and Lockheed Martin at the Johnson Space Center to determine the handling qualities (HQ) of the Orion spacecraft during different docking and rendezvous conditions using the Cooper-Harper scale. This paper will address the specifics of the handling qualities methodology, vehicle configuration, scenarios flown, data collection tools, and subject ratings and comments. The initial Orion HQ assessment examined Orion docking to the ISS. This scenario demonstrates the Translational Hand Controller (THC) handling qualities of Orion. During this initial assessment, two different scenarios were evaluated. The first was a nominal docking approach to a stable ISS, with Orion initializing with relative position dispersions and a closing rate of approximately 0.1 ft/sec. The second docking scenario was identical to the first, except the attitude motion of the ISS was modeled to simulate a stress case ( 1 degree deadband per axis and 0.01 deg/sec rate deadband per axis). For both scenarios, subjects started each run on final approach at a docking port-to-port range of 20 ft. Subjects used the THC in pulse mode with cues from the docking camera image, window views, and range and range rate data displayed on the Orion display units. As in the actual design, the attitude of the Orion vehicle was held by the automated flight control system at 0.5 degree deadband per axis. Several error sources were modeled including Reaction

  5. The Performance of Several Docking Programs at Reproducing Protein–Macrolide-Like Crystal Structures

    Directory of Open Access Journals (Sweden)

    Alejandro Castro-Alvarez

    2017-01-01

    Full Text Available The accuracy of five docking programs at reproducing crystallographic structures of complexes of 8 macrolides and 12 related macrocyclic structures, all with their corresponding receptors, was evaluated. Self-docking calculations indicated excellent performance in all cases (mean RMSD values ≤ 1.0 and confirmed the speed of AutoDock Vina. Afterwards, the lowest-energy conformer of each molecule and all the conformers lying 0–10 kcal/mol above it (as given by Macrocycle, from MacroModel 10.0 were subjected to standard docking calculations. While each docking method has its own merits, the observed speed of the programs was as follows: Glide 6.6 > AutoDock Vina 1.1.2 > DOCK 6.5 >> AutoDock 4.2.6 > AutoDock 3.0.5. For most of the complexes, the five methods predicted quite correct poses of ligands at the binding sites, but the lower RMSD values for the poses of highest affinity were in the order: Glide 6.6 ≈ AutoDock Vina ≈ DOCK 6.5 > AutoDock 4.2.6 >> AutoDock 3.0.5. By choosing the poses closest to the crystal structure the order was: AutoDock Vina > Glide 6.6 ≈ DOCK 6.5 ≥ AutoDock 4.2.6 >> AutoDock 3.0.5. Re-scoring (AutoDock 4.2.6//AutoDock Vina, Amber Score and MM-GBSA improved the agreement between the calculated and experimental data. For all intents and purposes, these three methods are equally reliable.

  6. ARCADE small-scale docking mechanism for micro-satellites

    Science.gov (United States)

    Boesso, A.; Francesconi, A.

    2013-05-01

    The development of on-orbit autonomous rendezvous and docking (ARD) capabilities represents a key point for a number of appealing mission scenarios that include activities of on-orbit servicing, automated assembly of modular structures and active debris removal. As of today, especially in the field of micro-satellites ARD, many fundamental technologies are still missing or require further developments and micro-gravity testing. In this framework, the University of Padova, Centre of Studies and Activities for Space (CISAS), developed the Autonomous Rendezvous Control and Docking Experiment (ARCADE), a technology demonstrator intended to fly aboard a BEXUS stratospheric balloon. The goal was to design, build and test, in critical environment conditions, a proximity relative navigation system, a custom-made reaction wheel and a small-size docking mechanism. The ARCADE docking mechanism was designed against a comprehensive set of requirements and it can be classified as small-scale, central, gender mating and unpressurized. The large use of commercial components makes it low-cost and simple to be manufactured. Last, it features a good tolerance to off-nominal docking conditions and a by-design soft docking capability. The final design was extensively verified to be compliant with its requirements by means of numerical simulations and physical testing. In detail, the dynamic behaviour of the mechanism in both nominal and off-nominal conditions was assessed with the multibody dynamics analysis software MD ADAMS 2010 and functional tests were carried out within the fully integrated ARCADE experiment to ensure the docking system efficacy and to highlight possible issues. The most relevant results of the study will be presented and discussed in conclusion to this paper.

  7. Molecular dynamics of CYP2D6 polymorphisms in the absence and presence of a mechanism-based inactivator reveals changes in local flexibility and dominant substrate access channels.

    Directory of Open Access Journals (Sweden)

    Parker W de Waal

    Full Text Available Cytochrome P450 enzymes (CYPs represent an important enzyme superfamily involved in metabolism of many endogenous and exogenous small molecules. CYP2D6 is responsible for ∼ 15% of CYP-mediated drug metabolism and exhibits large phenotypic diversity within CYPs with over 100 different allelic variants. Many of these variants lead to functional changes in enzyme activity and substrate selectivity. Herein, a molecular dynamics comparative analysis of four different variants of CYP2D6 was performed. The comparative analysis included simulations with and without SCH 66712, a ligand that is also a mechanism-based inactivator, in order to investigate the possible structural basis of CYP2D6 inactivation. Analysis of protein stability highlighted significantly altered flexibility in both proximal and distal residues from the variant residues. In the absence of SCH 66712, *34, *17-2, and *17-3 displayed more flexibility than *1, and *53 displayed more rigidity. SCH 66712 binding reversed flexibility in *17-2 and *17-3, through *53 remained largely rigid. Throughout simulations with docked SCH 66712, ligand orientation within the heme-binding pocket was consistent with previously identified sites of metabolism and measured binding energies. Subsequent tunnel analysis of substrate access, egress, and solvent channels displayed varied bottle-neck radii. Taken together, our results indicate that SCH 66712 should inactivate these allelic variants, although varied flexibility and substrate binding-pocket accessibility may alter its interaction abilities.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2016-01-15

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

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

    International Nuclear Information System (INIS)

    Barb, Adam W.; Subedi, Ganesh P.

    2016-01-01

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

  10. Flexible Electrostatic Technologies for Capture and Handling, Phase 1

    Science.gov (United States)

    Bryan, Thomas

    2015-01-01

    Fundamental to many of NASA's in-space transportation missions is the capture and handling of various objects and vehicles in various orbits for servicing, debris disposal, sample retrieval, and assembly without the benefit of sufficient grapple fixtures and docking ports. To perform similar material handling tasks on Earth, pincher grippers, suction grippers, or magnetic chucks are used, but are unable to reliably grip aluminum and composite spacecraft, insulation, radiators, solar arrays, or extra-terrestrial objects in the vacuum of outer space without dedicated handles in the right places. The electronic Flexible Electrostatic Technologies for space Capture and Handling (FETCH) will enable reliable and compliant gripping (soft dock) of practically any object in various orbits or surfaces without dedicated mechanical features, very low impact capture, and built-in proximity sensing without any conventional actuators. Originally developed to handle semiconductor and glass wafers during vacuum chamber processing without contamination, the normal rigid wafer handling chucks are replaced with thin metal foil segments laminated in flexible insulation driven by commercial off-the-shelf solid state, high-voltage power supplies. Preliminary testing in NASA Marshall Space Flight Center's (MSFC's) Flat Floor Robotics Lab demonstrated compliant alignment and gripping with a full-sized, 150-lb microsat mockup and translation before a clean release with a flip of a switch. The flexible electrostatic gripper pads can be adapted to various space applications with different sizes, shapes, and foil electrode layouts even with openings through the gripper pads for addition of guidance sensors or injection of permanent adhesives. With gripping forces estimated between 0.5 and 2.5 lb/in2 or 70-300 lb/ft2 of surface contact, the FETCH can turn on and off rapidly and repeatedly to enable sample handling, soft docking, in-space assembly, precision relocation, and surface translation

  11. Virtual screening approach to identifying influenza virus neuraminidase inhibitors using molecular docking combined with machine-learning-based scoring function.

    Science.gov (United States)

    Zhang, Li; Ai, Hai-Xin; Li, Shi-Meng; Qi, Meng-Yuan; Zhao, Jian; Zhao, Qi; Liu, Hong-Sheng

    2017-10-10

    In recent years, an epidemic of the highly pathogenic avian influenza H7N9 virus has persisted in China, with a high mortality rate. To develop novel anti-influenza therapies, we have constructed a machine-learning-based scoring function (RF-NA-Score) for the effective virtual screening of lead compounds targeting the viral neuraminidase (NA) protein. RF-NA-Score is more accurate than RF-Score, with a root-mean-square error of 1.46, Pearson's correlation coefficient of 0.707, and Spearman's rank correlation coefficient of 0.707 in a 5-fold cross-validation study. The performance of RF-NA-Score in a docking-based virtual screening of NA inhibitors was evaluated with a dataset containing 281 NA inhibitors and 322 noninhibitors. Compared with other docking-rescoring virtual screening strategies, rescoring with RF-NA-Score significantly improved the efficiency of virtual screening, and a strategy that averaged the scores given by RF-NA-Score, based on the binding conformations predicted with AutoDock, AutoDock Vina, and LeDock, was shown to be the best strategy. This strategy was then applied to the virtual screening of NA inhibitors in the SPECS database. The 100 selected compounds were tested in an in vitro H7N9 NA inhibition assay, and two compounds with novel scaffolds showed moderate inhibitory activities. These results indicate that RF-NA-Score improves the efficiency of virtual screening for NA inhibitors, and can be used successfully to identify new NA inhibitor scaffolds. Scoring functions specific for other drug targets could also be established with the same method.

  12. Discover binding pathways using the sliding binding-box docking approach: application to binding pathways of oseltamivir to avian influenza H5N1 neuraminidase

    Science.gov (United States)

    Tran, Diem-Trang T.; Le, Ly T.; Truong, Thanh N.

    2013-08-01

    Drug binding and unbinding are transient processes which are hardly observed by experiment and difficult to analyze by computational techniques. In this paper, we employed a cost-effective method called "pathway docking" in which molecular docking was used to screen ligand-receptor binding free energy surface to reveal possible paths of ligand approaching protein binding pocket. A case study was applied on oseltamivir, the key drug against influenza a virus. The equilibrium pathways identified by this method are found to be similar to those identified in prior studies using highly expensive computational approaches.

  13. Inspection by docking of nuclear-powered ship 'Mutsu'

    International Nuclear Information System (INIS)

    1989-01-01

    Japan Atomic Energy Research Institute carried out the docking and inspection of the nuclear-powered ship 'Mutsu' at Sekinehama Port, Mutsu City, Aomori Prefecture, from the middle of June to late in July, 1989. In this inspection, the Mutsu was mounted on a floating dock off the coast, the dock was towed by tugboats into the port and moored at the pier, and after completing the works in the dock, the dock was towed to the outside of the port, and the Mutsu was launched. The Mutsu was built as a nuclear power experiment ship, and length 130 m, breadth 19 m, depth 13.2 m, design draft at full load 6.9 m, 8242 GT. One PWR of 36 MWt and one steam turbine of 10000 ps are installed, and velocity is 16.5 knots. In September, 1974, after the first criticality, the leak of radioactivity occurred. The repair of shield and general inspection on safety were carried out in Sasebo Shipyard from August, 1980 to August, 1982. Thereafter, the Mutsu stayed in Ominato, but in January, 1988, after the completion of Sekinehama Port, the Mutsu was brought there. The Sekinehama Port, the test and inspection of the Mutsu carried out so far and the plan of hereafter are reported. (K.I.)

  14. GPU acceleration of Dock6's Amber scoring computation.

    Science.gov (United States)

    Yang, Hailong; Zhou, Qiongqiong; Li, Bo; Wang, Yongjian; Luan, Zhongzhi; Qian, Depei; Li, Hanlu

    2010-01-01

    Dressing the problem of virtual screening is a long-term goal in the drug discovery field, which if properly solved, can significantly shorten new drugs' R&D cycle. The scoring functionality that evaluates the fitness of the docking result is one of the major challenges in virtual screening. In general, scoring functionality in docking requires a large amount of floating-point calculations, which usually takes several weeks or even months to be finished. This time-consuming procedure is unacceptable, especially when highly fatal and infectious virus arises such as SARS and H1N1, which forces the scoring task to be done in a limited time. This paper presents how to leverage the computational power of GPU to accelerate Dock6's (http://dock.compbio.ucsf.edu/DOCK_6/) Amber (J. Comput. Chem. 25: 1157-1174, 2004) scoring with NVIDIA CUDA (NVIDIA Corporation Technical Staff, Compute Unified Device Architecture - Programming Guide, NVIDIA Corporation, 2008) (Compute Unified Device Architecture) platform. We also discuss many factors that will greatly influence the performance after porting the Amber scoring to GPU, including thread management, data transfer, and divergence hidden. Our experiments show that the GPU-accelerated Amber scoring achieves a 6.5× speedup with respect to the original version running on AMD dual-core CPU for the same problem size. This acceleration makes the Amber scoring more competitive and efficient for large-scale virtual screening problems.

  15. Involvement of complexin 2 in docking, locking and unlocking of different SNARE complexes during sperm capacitation and induced acrosomal exocytosis.

    Directory of Open Access Journals (Sweden)

    Pei-Shiue J Tsai

    Full Text Available Acrosomal exocytosis (AE is an intracellular multipoint fusion reaction of the sperm plasma membrane (PM with the outer acrosomal membrane (OAM. This unique exocytotic event enables the penetration of the sperm through the zona pellucida of the oocyte. We previously observed a stable docking of OAM to the PM brought about by the formation of the trans-SNARE complex (syntaxin 1B, SNAP 23 and VAMP 3. By using electron microscopy, immunochemistry and immunofluorescence techniques in combination with functional studies and proteomic approaches, we here demonstrate that calcium ionophore-induced AE results in the formation of unilamellar hybrid membrane vesicles containing a mixture of components originating from the two fused membranes. These mixed vesicles (MV do not contain the earlier reported trimeric SNARE complex but instead possess a novel trimeric SNARE complex that contained syntaxin 3, SNAP 23 and VAMP 2, with an additional SNARE interacting protein, complexin 2. Our data indicate that the earlier reported raft and capacitation-dependent docking phenomenon between the PM and OAM allows a specific rearrangement of molecules between the two docked membranes and is involved in (1 recruiting SNAREs and complexin 2 in the newly formed lipid-ordered microdomains, (2 the assembly of a fusion-driving SNARE complex which executes Ca(2+-dependent AE, (3 the disassembly of the earlier reported docking SNARE complex, (4 the recruitment of secondary zona binding proteins at the zona interacting sperm surface. The possibility to study separate and dynamic interactions between SNARE proteins, complexin and Ca(2+ which are all involved in AE make sperm an ideal model for studying exocytosis.

  16. Molecular docking as a popular tool in drug design, an in silico travel

    Directory of Open Access Journals (Sweden)

    de Ruyck J

    2016-06-01

    Full Text Available Jerome de Ruyck, Guillaume Brysbaert, Ralf Blossey, Marc F Lensink University Lille, CNRS UMR8576 UGSF, Lille, FranceAbstract: New molecular modeling approaches, driven by rapidly improving computational platforms, have allowed many success stories for the use of computer-assisted drug design in the discovery of new mechanism- or structure-based drugs. In this overview, we highlight three aspects of the use of molecular docking. First, we discuss the combination of molecular and quantum mechanics to investigate an unusual enzymatic mechanism of a flavoprotein. Second, we present recent advances in anti-infectious agents' synthesis driven by structural insights. At the end, we focus on larger biological complexes made by protein–protein interactions and discuss their relevance in drug design. This review provides information on how these large systems, even in the presence of the solvent, can be investigated with the outlook of drug discovery.Keywords: structure-based drug design, protein–protein docking, quaternary structure prediction, residue interaction networks, RINs, water position

  17. Effects of administration of a local anaesthetic and/or an NSAID and of docking length on the behaviour of piglets during 5 h after tail docking

    DEFF Research Database (Denmark)

    Herskin, Mette S.; Di Giminiani, Pierpaolo; Thodberg, Karen

    2016-01-01

    cautery 2–4 days after birth and based on behaviour during docking as well as the following 5 h. The study involved three main factors: local anaesthetic (Lidocain), NSAID (Meloxicam) and docking length. Either 100%, 75%, 50% or 25% of the tails were left on the body of the piglets. Irrespective...... that effects of this management routine are more persistent than earlier suggested, and suggesting that docking length may influence the post-surgical behaviour of piglets. By use of the present sites of injection and dosages, neither local anaesthetic nor NSAID had marked effects on post-surgical behavioural......In many countries, piglets are tail docked to prevent tail biting. The aim of this study was 1) to evaluate the efficacy of a local anaesthetic and/or NSAID to reduce pain caused by tail docking; and 2) to examine interactions with docking length. This was examined in 295 piglets docked by hot iron...

  18. A non-docking intraoperative electron beam applicator system

    International Nuclear Information System (INIS)

    Palta, J.R.; Suntharalingam, N.

    1989-01-01

    A non-docking intraoperative radiation therapy electron beam applicator system for a linear accelerator has been designed to minimize the mechanical, electrical, and tumor visualization problems associated with a docking system. A number of technical innovations have been used in the design of this system. These include: (a) a new intraoperative radiation therapy cone design that gives a better dose uniformity in the treatment volume at all depths; (b) a collimation system which reduces the leakage radiation dose to tissues outside the intraoperative radiation therapy cone; (c) a non-docking system with a translational accuracy of 2 mm and a rotational accuracy of 0.5 degrees; and (d) a rigid clamping system for the cones. A comprehensive set of dosimetric characteristics of the intraoperative radiation therapy applicator system is presented

  19. Structural and dynamical aspects of Streptococcus gordonii FabH through molecular docking and MD simulations.

    Science.gov (United States)

    Shamim, Amen; Abbasi, Sumra Wajid; Azam, Syed Sikander

    2015-07-01

    β-Ketoacyl-ACP-synthase III (FabH or KAS III) has become an attractive target for the development of new antibacterial agents which can overcome the multidrug resistance. Unraveling the fatty acid biosynthesis (FAB) metabolic pathway and understanding structural coordinates of FabH will provide valuable insights to target Streptococcus gordonii for curing oral infection. In this study, we designed inhibitors against therapeutic target FabH, in order to block the FAB pathway. As compared to other targets, FabH has more interactions with other proteins, located on the leading strand with higher codon adaptation index value and associated with lipid metabolism category of COG. Current study aims to gain in silico insights into the structural and dynamical aspect of S. gordonii FabH via molecular docking and molecular dynamics (MD) simulations. The FabH protein is catalytically active in dimerization while it can lock in monomeric state. Current study highlights two residues Pro88 and Leu315 that are close to each other by dimerization. The active site of FabH is composed of the catalytic triad formed by residues Cys112, His249, and Asn279 in which Cys112 is involved in acetyl transfer, while His249 and Asn279 play an active role in decarboxylation. Docking analysis revealed that among the studied compounds, methyl-CoA disulfide has highest GOLD score (82.75), binding affinity (-11 kcal/mol) and exhibited consistently better interactions. During MD simulations, the FabH structure remained stable with the average RMSD value of 1.7 Å and 1.6 Å for undocked protein and docked complex, respectively. Further, crucial hydrogen bonding of the conserved catalytic triad for exhibiting high affinity between the FabH protein and ligand is observed by RDF analysis. The MD simulation results clearly demonstrated that binding of the inhibitor with S. gordonii FabH enhanced the structure and stabilized the dimeric FabH protein. Therefore, the inhibitor has the potential to become

  20. Damped-dynamics flexible fitting.

    Science.gov (United States)

    Kovacs, Julio A; Yeager, Mark; Abagyan, Ruben

    2008-10-01

    In fitting atomic structures into EM maps, it often happens that the map corresponds to a different conformation of the structure. We have developed a new methodology to handle these situations that preserves the covalent geometry of the structure and allows the modeling of large deformations. The first goal is achieved by working in generalized coordinates (positional and internal coordinates), and the second by avoiding harmonic potentials. Instead, we use dampers (shock absorbers) between every pair of atoms, combined with a force field that attracts the atomic structure toward incompletely occupied regions of the EM map. The trajectory obtained by integrating the resulting equations of motion converges to a conformation that, in our validation cases, was very close to the target atomic structure. Compared to current methods, our approach is more efficient and robust against wrong solutions and to overfitting, and does not require user intervention or subjective decisions. Applications to the computation of transition pathways between known conformers, homology and loop modeling, as well as protein docking, are also discussed.

  1. Combining NMR and small angle X-ray and neutron scattering in the structural analysis of a ternary protein-RNA complex

    International Nuclear Information System (INIS)

    Hennig, Janosch; Wang, Iren; Sonntag, Miriam; Gabel, Frank; Sattler, Michael

    2013-01-01

    Many processes in the regulation of gene expression and signaling involve the formation of protein complexes involving multi-domain proteins. Individual domains that mediate protein-protein and protein-nucleic acid interactions are typically connected by flexible linkers, which contribute to conformational dynamics and enable the formation of complexes with distinct binding partners. Solution techniques are therefore required for structural analysis and to characterize potential conformational dynamics. Nuclear magnetic resonance spectroscopy (NMR) provides such information but often only sparse data are obtained with increasing molecular weight of the complexes. It is therefore beneficial to combine NMR data with additional structural restraints from complementary solution techniques. Small angle X-ray/neutron scattering (SAXS/SANS) data can be efficiently combined with NMR-derived information, either for validation or by providing additional restraints for structural analysis. Here, we show that the combination of SAXS and SANS data can help to refine structural models obtained from data-driven docking using HADDOCK based on sparse NMR data. The approach is demonstrated with the ternary protein-protein-RNA complex involving two RNA recognition motif (RRM) domains of Sex-lethal, the N-terminal cold shock domain of Upstream-to-N-Ras, and msl-2 mRNA. Based on chemical shift perturbations we have mapped protein-protein and protein-RNA interfaces and complemented this NMR-derived information with SAXS data, as well as SANS measurements on subunit-selectively deuterated samples of the ternary complex. Our results show that, while the use of SAXS data is beneficial, the additional combination with contrast variation in SANS data resolves remaining ambiguities and improves the docking based on chemical shift perturbations of the ternary protein-RNA complex.

  2. Combining NMR and small angle X-ray and neutron scatte