Multi-Conformer Ensemble Docking to Difficult Protein Targets

Ellingson, Sally R.; Miao, Yinglong; Baudry, Jerome; Smith, Jeremy C.

doi:10.1021/jp506511p

Title: Multi-Conformer Ensemble Docking to Difficult Protein Targets

Journal Article · Mon Sep 08 00:00:00 EDT 2014 · Journal of Physical Chemistry. B, Condensed Matter, Materials, Surfaces, Interfaces and Biophysical Chemistry

DOI: https://doi.org/10.1021/jp506511p · OSTI ID:1265909

Ellingson, Sally R. ^[1]; Miao, Yinglong ^[2]; Baudry, Jerome ^[2]; Smith, Jeremy C. ^[2]

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)

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.

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Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States). Oak Ridge Leadership Computing Facility (OLCF); Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)

Sponsoring Organization:: DOE Office of Science; USDOE

Grant/Contract Number:: AC05-00OR22725

OSTI ID:: 1265909

Journal Information:: Journal of Physical Chemistry. B, Condensed Matter, Materials, Surfaces, Interfaces and Biophysical Chemistry, Journal Name: Journal of Physical Chemistry. B, Condensed Matter, Materials, Surfaces, Interfaces and Biophysical Chemistry Journal Issue: 3 Vol. 119; ISSN 1520-6106

Publisher:: American Chemical SocietyCopyright Statement

Country of Publication:: United States

Language:: English

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