Multi-Conformer Ensemble Docking to Difficult Protein Targets
Abstract
We investigate large-scale ensemble docking using five proteins from the Directory of Useful Decoys (DUD, dud.docking.org) for which docking to crystal structures has proven difficult. Molecular dynamics trajectories are produced for each protein and an ensemble of representative conformational structures extracted from the trajectories. Docking calculations are performed on these selected simulation structures and ensemble-based enrichment factors compared with those obtained using docking in crystal structures of the same protein targets or random selection of compounds. We also found simulation-derived snapshots with improved enrichment factors that increased the chemical diversity of docking hits for four of the five selected proteins. A combination of all the docking results obtained from molecular dynamics simulation followed by selection of top-ranking compounds appears to be an effective strategy for increasing the number and diversity of hits when using docking to screen large libraries of chemicals against difficult protein targets.
- Authors:
-
- Univ. of Tennessee, Knoxville, TN (United States); Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Univ. of Kentucky, Lexington, KY (United States)
- Univ. of Tennessee, Knoxville, TN (United States); Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
- Publication Date:
- Research Org.:
- Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States). Oak Ridge Leadership Computing Facility (OLCF)
- Sponsoring Org.:
- USDOE Office of Science (SC)
- OSTI Identifier:
- 1265909
- 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: 119; Journal Issue: 3; Journal ID: ISSN 1520-6106
- Publisher:
- American Chemical Society
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES
Citation Formats
Ellingson, Sally R., Miao, Yinglong, Baudry, Jerome, and Smith, Jeremy C. Multi-Conformer Ensemble Docking to Difficult Protein Targets. United States: N. p., 2014.
Web. doi:10.1021/jp506511p.
Ellingson, Sally R., Miao, Yinglong, Baudry, Jerome, & Smith, Jeremy C. Multi-Conformer Ensemble Docking to Difficult Protein Targets. United States. https://doi.org/10.1021/jp506511p
Ellingson, Sally R., Miao, Yinglong, Baudry, Jerome, and Smith, Jeremy C. Mon .
"Multi-Conformer Ensemble Docking to Difficult Protein Targets". United States. https://doi.org/10.1021/jp506511p. https://www.osti.gov/servlets/purl/1265909.
@article{osti_1265909,
title = {Multi-Conformer Ensemble Docking to Difficult Protein Targets},
author = {Ellingson, Sally R. and Miao, Yinglong and Baudry, Jerome and Smith, Jeremy C.},
abstractNote = {We investigate large-scale ensemble docking using five proteins from the Directory of Useful Decoys (DUD, dud.docking.org) for which docking to crystal structures has proven difficult. Molecular dynamics trajectories are produced for each protein and an ensemble of representative conformational structures extracted from the trajectories. Docking calculations are performed on these selected simulation structures and ensemble-based enrichment factors compared with those obtained using docking in crystal structures of the same protein targets or random selection of compounds. We also found simulation-derived snapshots with improved enrichment factors that increased the chemical diversity of docking hits for four of the five selected proteins. A combination of all the docking results obtained from molecular dynamics simulation followed by selection of top-ranking compounds appears to be an effective strategy for increasing the number and diversity of hits when using docking to screen large libraries of chemicals against difficult protein targets.},
doi = {10.1021/jp506511p},
journal = {Journal of Physical Chemistry. B, Condensed Matter, Materials, Surfaces, Interfaces and Biophysical Chemistry},
number = 3,
volume = 119,
place = {United States},
year = {Mon Sep 08 00:00:00 EDT 2014},
month = {Mon Sep 08 00:00:00 EDT 2014}
}
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