Ensemble Docking in Drug Discovery: How Many Protein Configurations from Molecular Dynamics Simulations are Needed To Reproduce Known Ligand Binding?

Evangelista Falcon, Wilfredo; Ellingson, Sally R.; Smith, Jeremy C.; Baudry, Jerome

doi:10.1021/acs.jpcb.8b11491

Title: Ensemble Docking in Drug Discovery: How Many Protein Configurations from Molecular Dynamics Simulations are Needed To Reproduce Known Ligand Binding?

Abstract

Ensemble docking in drug discovery or chemical biology uses dynamical simulations of target proteins to generate binding site conformations for docking campaigns. We demonstrate that 600 ns molecular dynamics simulations of four G-protein-coupled receptors in their membrane environments generate ensembles of protein configurations that, collectively, are selected by 70–99% of the known ligands of these proteins. Thus, the process of ligand recognition by conformational selection can be reproduced by combining molecular dynamics and docking calculations. Clustering of the molecular dynamics trajectories, however, does not necessarily identify the protein conformations that are most often selected by the ligands.

Authors:

Evangelista Falcon, Wilfredo ^[1]; Ellingson, Sally R. ^[2];

^[3];

^[4]

Univ. of Tennessee, Knoxville, TN (United States); Univ. of Kentucky, Lexington, KY (United States); Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Univ. of Tennessee, Knoxville, TN (United States); Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Univ. of Alabama, Huntsville, AL (United States)

Publication Date:: Tue Jan 29 00:00:00 EST 2019

Research Org.:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)

Sponsoring Org.:: USDOE; Univ. of Alabama; Univ. of Kentucky

OSTI Identifier:: 1523730

Grant/Contract Number:: AC05-00OR22725

Resource Type:: Accepted Manuscript

Journal Name:: Journal of Physical Chemistry. B, Condensed Matter, Materials, Surfaces, Interfaces and Biophysical Chemistry

Additional Journal Information:: Journal Volume: TBD; Journal Issue: TBD; Journal ID: ISSN 1520-6106

Publisher:: American Chemical Society

Country of Publication:: United States

Language:: English

Subject:: 60 APPLIED LIFE SCIENCES

Citation Formats


                    Evangelista Falcon, Wilfredo, Ellingson, Sally R., Smith, Jeremy C., and Baudry, Jerome. Ensemble Docking in Drug Discovery: How Many Protein Configurations from Molecular Dynamics Simulations are Needed To Reproduce Known Ligand Binding?.  United States: N. p., 2019. 
Web.  doi:10.1021/acs.jpcb.8b11491.

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                    Evangelista Falcon, Wilfredo, Ellingson, Sally R., Smith, Jeremy C., & Baudry, Jerome. Ensemble Docking in Drug Discovery: How Many Protein Configurations from Molecular Dynamics Simulations are Needed To Reproduce Known Ligand Binding?.  United States.  https://doi.org/10.1021/acs.jpcb.8b11491

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                    Evangelista Falcon, Wilfredo, Ellingson, Sally R., Smith, Jeremy C., and Baudry, Jerome. Tue .  
"Ensemble Docking in Drug Discovery: How Many Protein Configurations from Molecular Dynamics Simulations are Needed To Reproduce Known Ligand Binding?".  United States.  https://doi.org/10.1021/acs.jpcb.8b11491.  https://www.osti.gov/servlets/purl/1523730.

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@article{osti_1523730,

  title        = {Ensemble Docking in Drug Discovery: How Many Protein Configurations from Molecular Dynamics Simulations are Needed To Reproduce Known Ligand Binding?},

  author       = {Evangelista Falcon, Wilfredo and Ellingson, Sally R. and Smith, Jeremy C. and Baudry, Jerome},

  abstractNote = {Ensemble docking in drug discovery or chemical biology uses dynamical simulations of target proteins to generate binding site conformations for docking campaigns. We demonstrate that 600 ns molecular dynamics simulations of four G-protein-coupled receptors in their membrane environments generate ensembles of protein configurations that, collectively, are selected by 70–99% of the known ligands of these proteins. Thus, the process of ligand recognition by conformational selection can be reproduced by combining molecular dynamics and docking calculations. Clustering of the molecular dynamics trajectories, however, does not necessarily identify the protein conformations that are most often selected by the ligands.},

  doi          = {10.1021/acs.jpcb.8b11491},

  journal      = {Journal of Physical Chemistry. B, Condensed Matter, Materials, Surfaces, Interfaces and Biophysical Chemistry},

  number       = TBD,

  volume       = TBD,

  place        = {United States},

  year         = {Tue Jan 29 00:00:00 EST 2019},

  month        = {Tue Jan 29 00:00:00 EST 2019}

}

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Chemical-Shift Perturbations Reflect Bile Acid Binding to Norovirus Coat Protein: Recognition Comes in Different Flavors
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Title: Ensemble Docking in Drug Discovery: How Many Protein Configurations from Molecular Dynamics Simulations are Needed To Reproduce Known Ligand Binding?

Abstract

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