Exploring hierarchical refinement techniques for induced fit docking with protein and ligand flexibility.

TitleExploring hierarchical refinement techniques for induced fit docking with protein and ligand flexibility.
Publication TypeJournal
AuthorsBorrelli, K, Cossins, BP, Guallar, V
Year of Publication2010
Date Published2010 Apr 30
PublicationJournal of computational chemistry
Volume31
Issue6
Pagination1224-35
Publication Languageeng
ISSN Number1096-987X
KeywordsComputer Simulation, Ligands, Models, Chemical, Protein Binding, Proteins, Substrate Specificity
Abstract

We present a series of molecular-mechanics-based protein refinement methods, including two novel ones, applied as part of an induced fit docking procedure. The methods used include minimization; protein and ligand sidechain prediction; a hierarchical ligand placement procedure similar to a-priori protein loop predictions; and a minimized Monte Carlo approach using normal mode analysis as a move step. The results clearly indicate the importance of a proper opening of the active site backbone, which might not be accomplished when the ligand degrees of freedom are prioritized. The most accurate method consisted of the minimized Monte Carlo procedure designed to open the active site followed by a hierarchical optimization of the sidechain packing around a mobile flexible ligand. The methods have been used on a series of 88 protein-ligand complexes including both cross-docking and apo-docking members resulting in complex conformations determined to within 2.0 A heavy-atom RMSD in 75% of cases where the protein backbone rearrangement upon binding is less than 1.0 A alpha-carbon RMSD. We also demonstrate that physics-based all-atom potentials can be more accurate than docking-style potentials when complexes are sufficiently refined.

 
 
DOI10.1002/jcc.21409

http://www.ncbi.nlm.nih.gov/pubmed/19885871?dopt=Abstract

 
 
Citation Key3638