title: Binding mode prediction for a flexible ligand in a flexible pocket using multi-conformation simulated annealing pseudo crystallographic refinement.
abstract: We describe multi-conformation simulated annealing-pseudo-crystallographic refinement (MCSA-PCR), a technique developed for predicting the binding mode of a flexible ligand in a flexible binding pocket. To circumvent the local-minimum problem efficiently, this method performs multiple independent cycles of simulated annealing with explicit solvent, "growing" the ligand in the binding pocket each time. From the ensemble of structures, a pseudo-crystallographic electron density map is calculated, and then conventional crystallographic refinement methods are used to best fit a single, optimal structure into the density map. The advantage of the MCSA-PCR method is that it provides a direct means to evaluate the accuracy and uniqueness of the calculated solution, provides a measure of ligand and protein dynamics from the refined B-factors, and facilitates comparison with X-ray crystallographic data. Here, we show that our MCSA-PCR method succeeds in predicting the correct binding mode of the VSV8 peptide to the major histocompatibility complex (MHC) receptor. Importantly, there is a significant correlation between the experimentally determined crystallographic water molecules and water density observed in the pseudo map by MCSA-PCR. Furthermore, comparison of different approaches for extracting a single, most probable structure from the calculated ensemble reveals the power of the PCR method and provides insights into the nature of the energetic landscape.
authors.affiliation: Howard Hughes Medical Institute and the Department of Biochemistry and Biophysics, University of California at San Francisco, CA 94143-0448, USA.
authors.forename: N
authors.initials: N
authors.lastname: Ota
authors.forename: D A
authors.initials: DA
authors.lastname: Agard
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004583:Electrons; D006649:Histocompatibility Antigens / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism*; D018583:Pliability; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D011487:Protein Conformation; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013269:Stochastic Processes; D013816:Thermodynamics; D014867:Water / Q000737:chemistry / Q000378:metabolism
chemical_list: D006649:Histocompatibility Antigens; D008024:Ligands; D010455:Peptides; D014867:Water