title: Molecular docking to ensembles of protein structures.
abstract: Until recently, applications of molecular docking assumed that the macromolecular receptor exists in a single, rigid conformation. However, structural studies involving different ligands bound to the same target biomolecule frequently reveal modest but significant conformational changes in the target. In this paper, two related methods for molecular docking are described that utilize information on conformational variability from ensembles of experimental receptor structures. One method combines the information into an "energy-weighted average" of the interaction energy between a ligand and each receptor structure. The other method performs the averaging on a structural level, producing a "geometry-weighted average" of the inter-molecular force field score used in DOCK 3.5. Both methods have been applied in docking small molecules to ensembles of crystal and solution structures, and we show that experimentally determined binding orientations and computed energies of known ligands can be reproduced accurately. The use of composite grids, when conformationally different protein structures are available, yields an improvement in computational speed for database searches in proportion to the number of structures.
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco 94143-0446, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Knegtel
authors.forename: I D
authors.initials: ID
authors.lastname: Kuntz
authors.forename: C M
authors.initials: CM
authors.lastname: Oshiro
mesh_terms: D003198:Computer Simulation; D016208:Databases, Factual; D015195:Drug Design; D006153:Guanosine Diphosphate / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D016333:HIV Protease / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D008958:Models, Molecular; D015689:Oncogene Protein p21(ras) / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry*; D012177:Retinol-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D012680:Sensitivity and Specificity; D012984:Software; D014598:Uteroglobin / Q000737:chemistry / Q000378:metabolism
chemical_list: D008024:Ligands; D011506:Proteins; D012177:Retinol-Binding Proteins; D006153:Guanosine Diphosphate; D006160:Guanosine Triphosphate; D014598:Uteroglobin; D016333:HIV Protease; D015689:Oncogene Protein p21(ras)