title: Accounting for global protein deformability during protein-protein and protein-ligand docking.
abstract: Computational docking methods are valuable tools aimed to simplify the costly process of drug development and improvement. Most current approaches assume a rigid receptor structure to allow virtual screening of large numbers of possible ligands and putative binding sites on a receptor molecule. However, inclusion of receptor flexibility can be of critical importance since binding of a ligand can lead to changes in the receptor protein conformation that are sterically necessary to accommodate a ligand. Recent approaches to efficiently account for receptor flexibility during docking simulations are reviewed. In particular, accounting efficiently for global conformational changes of the protein backbone during docking is a still challenging unsolved problem. An approximate method has recently been suggested that is based on relaxing the receptor conformation during docking in pre-calculated soft collective degrees of freedom (M. Zacharias, Rapid protein-ligand docking using soft modes from molecular dynamics simulations to account for protein deformability: binding of FK506 to FKBP, Proteins: Struct., Funct., Genet. 54 (2004) 759-767). Test applications on protein-protein docking and on docking the inhibitor staurosporine to the apo-form of cAMP-dependent protein kinase A catalytic domain indicate significant improvement of docking results compared to rigid docking at a very modest computational demand. Accounting for receptor conformational changes in pre-calculated global degrees of freedom might offer a promising route to improve systematic docking screening simulations.
authors.affiliation: Computational Biology, School of Engineering and Science, International University Bremen, Campus Ring 6, D-28759 Bremen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: May
authors.forename: Martin
authors.initials: M
authors.lastname: Zacharias
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D017868:Cyclic AMP-Dependent Protein Kinases / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary / Q000187:drug effects; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D019311:Staurosporine / Q000737:chemistry / Q000378:metabolism
chemical_list: D008024:Ligands; D011506:Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D019311:Staurosporine