Browse
Submit Data
Databases
API
Help

Dataset Information

13 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

POVME 3.0: Software for Mapping Binding Pocket Flexibility.

ABSTRACT: We present a substantial update to the open-source POVME binding pocket analysis software. New capabilities of POVME 3.0 include a flexible chemical coloring scheme for feature identification, postanalysis tools for comparing large ensembles of pockets (e.g., from molecular dynamics simulations), and the introduction of scripts and methods that facilitate binding pocket comparison and analysis. We envision the use of this software for visualization of binding pocket dynamics, selection of representative structures for ensemble docking, and incorporation of molecular dynamics results into ligand design efforts.

SUBMITTER: Wagner JR

PROVIDER: S-EPMC5751414 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

POVME 3.0: Software for Mapping Binding Pocket Flexibility.

Wagner Jeffrey R JR Sørensen Jesper J Hensley Nathan N Wong Celia C Zhu Clare C Perison Taylor T Amaro Rommie E RE

Journal of chemical theory and computation 20170830 9

We present a substantial update to the open-source POVME binding pocket analysis software. New capabilities of POVME 3.0 include a flexible chemical coloring scheme for feature identification, postanalysis tools for comparing large ensembles of pockets (e.g., from molecular dynamics simulations), and the introduction of scripts and methods that facilitate binding pocket comparison and analysis. We envision the use of this software for visualization of binding pocket dynamics, selection of repres ...[more]

PMID: 28800393

Similar Datasets

Multiscale Monte Carlo Sampling of Protein Sidechains: Application to Binding Pocket Flexibility.

Project description:We present a Monte Carlo sidechain sampling procedure and apply it to assessing the flexibility of protein binding pockets. We implemented a multiple "time step" Monte Carlo algorithm to optimize sidechain sampling with a surface generalized Born implicit solvent model. In this approach, certain forces (those due to long-range electrostatics and the implicit solvent model) are updated infrequently, in "outer steps", while short-range forces (covalent, local nonbonded interactions) are updated at every "inner step". Two multistep protocols were studied. The first protocol rigorously obeys detailed balance, and the second protocol introduces an approximation to the solvation term that increases the acceptance ratio. The first protocol gives a 10-fold improvement over a protocol that does not use multiple time steps, while the second protocol generates comparable ensembles and gives a 15-fold improvement. A range of 50-200 inner steps per outer step was found to give optimal performance for both protocols. The resultant method is a practical means to assess sidechain flexibility in ligand binding pockets, as we illustrate with proof-of-principle calculations on six proteins: DB3 antibody, thermolysin, estrogen receptor, PPAR-?, PI3 kinase, and CDK2. The resulting sidechain ensembles of the apo binding sites correlate well with known induced fit conformational changes and provide insights into binding pocket flexibility.

| S-EPMC2612633 | biostudies-literature

Pash 3.0: A versatile software package for read mapping and integrative analysis of genomic and epigenomic variation using massively parallel DNA sequencing.

Project description:Massively parallel sequencing readouts of epigenomic assays are enabling integrative genome-wide analyses of genomic and epigenomic variation. Pash 3.0 performs sequence comparison and read mapping and can be employed as a module within diverse configurable analysis pipelines, including ChIP-Seq and methylome mapping by whole-genome bisulfite sequencing.Pash 3.0 generally matches the accuracy and speed of niche programs for fast mapping of short reads, and exceeds their performance on longer reads generated by a new generation of massively parallel sequencing technologies. By exploiting longer read lengths, Pash 3.0 maps reads onto the large fraction of genomic DNA that contains repetitive elements and polymorphic sites, including indel polymorphisms.We demonstrate the versatility of Pash 3.0 by analyzing the interaction between CpG methylation, CpG SNPs, and imprinting based on publicly available whole-genome shotgun bisulfite sequencing data. Pash 3.0 makes use of gapped k-mer alignment, a non-seed based comparison method, which is implemented using multi-positional hash tables. This allows Pash 3.0 to run on diverse hardware platforms, including individual computers with standard RAM capacity, multi-core hardware architectures and large clusters.

| S-EPMC3001746 | biostudies-literature

ChemProt-3.0: a global chemical biology diseases mapping.

Project description:ChemProt is a publicly available compilation of chemical-protein-disease annotation resources that enables the study of systems pharmacology for a small molecule across multiple layers of complexity from molecular to clinical levels. In this third version, ChemProt has been updated to more than 1.7 million compounds with 7.8 million bioactivity measurements for 19,504 proteins. Here, we report the implementation of global pharmacological heatmap, supporting a user-friendly navigation of chemogenomics space. This facilitates the visualization and selection of chemicals that share similar structural properties. In addition, the user has the possibility to search by compound, target, pathway, disease and clinical effect. Genetic variations associated to target proteins were integrated, making it possible to plan pharmacogenetic studies and to suggest human response variability to drug. Finally, Quantitative Structure-Activity Relationship models for 850 proteins having sufficient data were implemented, enabling secondary pharmacological profiling predictions from molecular structure. Database URL: http://potentia.cbs.dtu.dk/ChemProt/.

| S-EPMC4752971 | biostudies-literature

Role of Subunit D in Ubiquinone-Binding Site of Vibrio cholerae NQR: Pocket Flexibility and Inhibitor Resistance.

Project description:The ion-pumping NADH: ubiquinone dehydrogenase (NQR) is a vital component of the respiratory chain of numerous species of marine and pathogenic bacteria, including Vibrio cholerae. This respiratory enzyme couples the transfer of electrons from NADH to ubiquinone (UQ) to the pumping of ions across the plasma membrane, producing a gradient that sustains multiple homeostatic processes. The binding site of UQ within the enzyme is an important functional and structural motif that could be used to design drugs against pathogenic bacteria. Our group recently located the UQ site in the interface between subunits B and D and identified the residues within subunit B that are important for UQ binding. In this study, we carried out alanine scanning mutagenesis of amino acid residues located in subunit D of V. cholerae NQR to understand their role in UQ binding and enzymatic catalysis. Moreover, molecular docking calculations were performed to characterize the structure of the site at the atomic level. The results show that mutations in these positions, in particular, in residues P185, L190, and F193, decrease the turnover rate and increase the Km for UQ. These mutants also showed an increase in the resistance against the inhibitor HQNO. The data indicate that residues in subunit D fulfill important structural roles, restricting and orienting UQ in a catalytically favorable position. In addition, mutations of these residues open the site and allow the simultaneous binding of substrate and inhibitors, producing partial inhibition, which appears to be a strategy used by Pseudomonas aeruginosa to avoid autopoisoning.

| S-EPMC6868883 | biostudies-literature

Mapping the ligand-binding pocket of integrin alpha5beta1 using a gain-of-function approach.

Project description:Integrin alpha5beta1 is a key receptor for the extracellular matrix protein fibronectin. Antagonists of human integrin alpha5beta1 have therapeutic potential as anti-angiogenic agents in cancer and diseases of the eye. However, the structure of the integrin is unsolved and the atomic basis of fibronectin and antagonist binding by integrin alpha5beta1 is poorly understood. In the present study, we demonstrate that zebrafish alpha5beta1 integrins do not interact with human fibronectin or the human alpha5beta1 antagonists JSM6427 and cyclic peptide CRRETAWAC. Zebrafish alpha5beta1 integrins do bind zebrafish fibronectin-1, and mutagenesis of residues on the upper surface and side of the zebrafish alpha5 subunit beta-propeller domain shows that these residues are important for the recognition of the Arg-Gly-Asp (RGD) motif and the synergy sequence [Pro-His-Ser-Arg-Asn (PHSRN)] in fibronectin. Using a gain-of-function analysis involving swapping regions of the zebrafish integrin alpha5 subunit with the corresponding regions of human alpha5 we show that blades 1-4 of the beta-propeller are required for human fibronectin recognition, suggesting that fibronectin binding involves a broad interface on the side and upper face of the beta-propeller domain. We find that the loop connecting blades 2 and 3 of the beta-propeller, the D3-A3 loop, contains residues critical for antagonist recognition, with a minor role played by residues in neighbouring loops. A new homology model of human integrin alpha5beta1 supports an important function for D3-A3 loop residues Trp157 and Ala158 in the binding of antagonists. These results will aid the development of reagents that block integrin alpha5beta1 functions in vivo.

| S-EPMC3329623 | biostudies-literature

Mapping allosteric connections from the receptor to the nucleotide-binding pocket of heterotrimeric G proteins.

Project description:Heterotrimeric G proteins function as molecular relays that mediate signal transduction from heptahelical receptors in the cell membrane to intracellular effector proteins. Crystallographic studies have demonstrated that guanine nucleotide exchange on the Galpha subunit causes specific conformational changes in three key "switch" regions of the protein, which regulate binding to Gbetagamma subunits, receptors, and effector proteins. In the present study, nitroxide side chains were introduced at sites within the switch I region of Galphai to explore the structure and dynamics of this region throughout the G protein cycle. EPR spectra obtained for each of the Galpha(GDP), Galpha(GDP)betagamma heterotrimer and Galpha(GTPgammaS) conformations are consistent with the local environment observed in the corresponding crystal structures. Binding of the heterotrimer to activated rhodopsin to form the nucleotide-free (empty) complex, for which there is no crystal structure, causes prominent changes relative to the heterotrimer in the structure of switch I and contiguous sequences. The data identify a putative pathway of allosteric changes triggered by receptor binding and, together with previously published data, suggest elements of a mechanism for receptor-catalyzed nucleotide exchange.

| S-EPMC1876549 | biostudies-literature

Binding to retinoblastoma pocket domain does not alter the inter-domain flexibility of the J domain of SV40 large T antigen.

Project description:Simian Virus 40 uses the large T antigen (Tag) to bind and inactivate retinoblastoma tumor suppressor proteins (Rb), which can result in cellular transformation. Tag is a modular protein with four domains connected by flexible linkers. The N-terminal J domain of Tag is necessary for Rb inactivation. Binding of Rb is mediated by an LXCXE consensus motif immediately C-terminal to the J domain. Nuclear magnetic resonance (NMR) and small angle X-ray scattering (SAXS) were used to study the structural dynamics and interaction of Rb with the LXCXE motif, the J domain and a construct (N(260)) extending from the J domain through the origin binding domain (OBD). NMR and SAXS data revealed substantial flexibility between the domains in N(260). Binding of pRb to a construct containing the LXCXE motif and the J domain revealed weak interactions between pRb and the J domain. Analysis of the complex of pRb and N(260) indicated that the OBD is not involved and retains its dynamic independence from the remainder of Tag. These results support a 'chaperone' model in which the J domain of Tag changes its orientation as it acts upon different protein complexes.

| S-EPMC3279518 | biostudies-literature

Chloroperoxidase-catalyzed epoxidation of cis-?-methylstyrene: distal pocket flexibility tunes catalytic reactivity.

Project description:Chloroperoxidase, the most versatile heme protein, has a hybrid active site pocket that shares structural features with peroxidases and cytochrome P450s. The simulation studies presented here show that the enzyme possesses a remarkable ability to efficiently utilize its hybrid structure, assuming structurally different peroxidase-like and P450-like distal pocket faces and thereby enhancing the inherent catalytic capability of the active center. We find that, during epoxidation of cis-?-methylstyrene (CBMS), the native peroxidase-like aspect of the distal pocket is diminished as the polar Glu183 side chain is displaced away from the active center and the distal pocket takes on a more hydrophobic, P450-like, aspect. The P450-like distal pocket provides a significant enthalpic stabilization of ?4 kcal/mol of the 14 kcal/mol reaction barrier for gas-phase epoxidation of CMBS by an oxyferryl heme-thiolate species. This stabilization comes from breathing of the distal pocket. As until recently the active site of chloroperoxidase was postulated to be inflexible, these results suggest a new conceptual understanding of the enzyme's versatility: catalytic reactivity is tuned by flexibility of the distal pocket.

| S-EPMC3726198 | biostudies-literature

The impact of curcumin derived polyphenols on the structure and flexibility COVID-19 main protease binding pocket: a molecular dynamics simulation study.

Project description:The newly occurred SARS-CoV-2 caused a leading pandemic of coronavirus disease (COVID-19). Up to now it has infected more than one hundred sixty million and killed more than three million people according to 14 May 2021 World Health Organization report. So far, different types of studies have been conducted to develop an anti-viral drug for COVID-19 with no success yet. As part of this, silico were studied to discover and introduce COVID-19 antiviral drugs and results showed that protease inhibitors could be very effective in controlling. This study aims to investigate the binding affinity of three curcumin derived polyphenols against COVID-19 the main protease (Mpro), binding pocket, and identification of important residues for interaction. In this study, molecular modeling, auto-dock coupled with molecular dynamics simulations were performed to analyze the conformational, and stability of COVID-19 binding pocket with diferuloylmethane, demethoxycurcumin, and bisdemethoxycurcumin. All three compounds have shown binding affinity -39, -89 and -169.7, respectively. Demethoxycurcumin and bisdemethoxycurcumin showed an optimum binding affinity with target molecule and these could be one of potential ligands for COVID-19 therapy. And also, COVID-19 main protease binding pocket binds with the interface region by one hydrogen bond. Moreover, the MD simulation parameters indicated that demethoxycurcumin and bisdemethoxycurcumin were stable during the simulation run. These findings can be used as a baseline to develop therapeutics with curcumin derived polyphenols against COVID-19.

| S-EPMC8297469 | biostudies-literature

HLA-DM Focuses on Conformational Flexibility Around P1 Pocket to Catalyze Peptide Exchange.

Project description:Peptides presented by major histocompatibility complex class II (MHCII) molecules to CD4+ T cells play a central role in the initiation of adaptive immunity. This antigen presentation process is characterized by the proteolytic cleavage of foreign and self proteins, and loading of the resultant peptides onto MHCII molecules. Loading and exchange of antigenic peptides is catalyzed by a non-classical MHCII molecule, HLA-DM. The impact of HLA-DM on epitope selection has been appreciated for a long time. However, the molecular mechanism by which HLA-DM mediates peptide exchange remains elusive. Here, we review recent efforts in elucidating how HLA-DM works, highlighted by two recently solved co-structures of HLA-DM bound to HLA-DO (a natural inhibitor of HLA-DM), or to HLA-DR1 (a common MHCII). In light of these efforts, a model for HLA-DM action in which HLA-DM utilizes conformational flexibility around the P1 pocket of the MHCII-peptide complex to catalyze peptide exchange is proposed.

| S-EPMC3797982 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data