Consistent improvement of cross-docking results using binding site ensembles generated with elastic network normal modes

Manuel Rueda, Giovanni Bottegoni, Ruben Abagyan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

83 Citations (Scopus)

Abstract

The representation of protein flexibility is still a challenge for the state-of-the-art flexible ligand docking protocols. In this article, we use a large and diverse benchmark to prove that is possible to improve consistently the cross-docking performance against a single receptor conformation, using an equilibrium ensemble of binding site conformers. The benchmark contained 28 proteins, and our method predicted the top-ranked near native ligand poses 20% more efficiently than using a single receptor. The multiple conformations were derived from the collective variable space defined by all heavy-atom elastic network normal modes, including backbone and side chains. We have found that the binding site displacements for best positioning of the ligand seem rather independent from the global collective motions of the protein. We also found that the number of binding site conformations needed to represent nonredundant flexibility was <100. The ensemble of receptor conformations can be generated at our Web site at http://abagyan.scripps.edu/MRC.

Original languageEnglish
Pages (from-to)716-725
Number of pages10
JournalJournal of Chemical Information and Modeling
Volume49
Issue number3
DOIs
Publication statusPublished - 23 Mar 2009
Externally publishedYes

ASJC Scopus subject areas

  • General Chemistry
  • General Chemical Engineering
  • Computer Science Applications
  • Library and Information Sciences

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