title: Two-dimensional replica-exchange method for predicting protein-ligand binding structures.
abstract: We have developed a two-dimensional replica-exchange method for the prediction of protein-ligand binding structures. The first dimension is the umbrella sampling along the reaction coordinate, which is the distance between a protein binding pocket and a ligand. The second dimension is the solute tempering, in which the interaction between a ligand and a protein and water is weakened. The second dimension is introduced to make a ligand follow the umbrella potential more easily and enhance the binding events, which should improve the sampling efficiency. As test cases, we applied our method to two protein-ligand complex systems (MDM2 and HSP 90-alpha). Starting from the configuration in which the protein and the ligand are far away from each other in each system, our method predicted the ligand binding structures in excellent agreement with the experimental data from Protein Data Bank much faster with the improved sampling efficiency than the replica-exchange umbrella sampling method that we have previously developed.
authors.affiliation: Pharmaceutical Research Division, Medicinal Chemistry Research Laboratories, Takeda Pharmaceutical Co., Ltd., 26-1 Muraoka-Higashi 2-chome, Fujisawa, Kanagawa, 251-8585, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Kokubo
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Tanaka
authors.forename: Yuko
authors.initials: Y
authors.lastname: Okamoto
mesh_terms: D001569:Benzodiazepines / Q000737:chemistry*; D001665:Binding Sites; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry*; D008024:Ligands; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry*; D011743:Pyrimidines / Q000737:chemistry*
chemical_list: D018841:HSP90 Heat-Shock Proteins; D008024:Ligands; D011743:Pyrimidines; D001569:Benzodiazepines; D051736:Proto-Oncogene Proteins c-mdm2
keywords: computer-aided drug design; molecular dynamics; protein-ligand binding; replica exchange with solute tempering; replica-exchange umbrella sampling; structure prediction