title: Evaluation of protein-protein docking model structures using all-atom molecular dynamics simulations combined with the solution theory in the energy representation.
abstract: We propose a method to evaluate binding free energy differences among distinct protein-protein complex model structures through all-atom molecular dynamics simulations in explicit water using the solution theory in the energy representation. Complex model structures are generated from a pair of monomeric structures using the rigid-body docking program ZDOCK. After structure refinement by side chain optimization and all-atom molecular dynamics simulations in explicit water, complex models are evaluated based on the sum of their conformational and solvation free energies, the latter calculated from the energy distribution functions obtained from relatively short molecular dynamics simulations of the complex in water and of pure water based on the solution theory in the energy representation. We examined protein-protein complex model structures of two protein-protein complex systems, bovine trypsin/CMTI-1 squash inhibitor (PDB ID: 1PPE) and RNase SA/barstar (PDB ID: 1AY7), for which both complex and monomer structures were determined experimentally. For each system, we calculated the energies for the crystal complex structure and twelve generated model structures including the model most similar to the crystal structure and very different from it. In both systems, the sum of the conformational and solvation free energies tended to be lower for the structure similar to the crystal. We concluded that our energy calculation method is useful for selecting low energy complex models similar to the crystal structure from among a set of generated models.
authors.affiliation: Institute of Molecular and Cellular Biosciences, University of Tokyo 1-1-1 Yayoi, Bunkyo, Tokyo 113-0032, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Takemura
authors.forename: Hao
authors.initials: H
authors.lastname: Guo
authors.forename: Shun
authors.initials: S
authors.lastname: Sakuraba
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Matubayasi
authors.forename: Akio
authors.initials: A
authors.lastname: Kitao
mesh_terms: D000818:Animals; D002417:Cattle; D006860:Hydrogen Bonding; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*; D012260:Ribonucleases / Q000737:chemistry / Q000378:metabolism; D012996:Solutions; D012997:Solvents / Q000737:chemistry; D055672:Static Electricity; D013816:Thermodynamics; D014357:Trypsin / Q000737:chemistry / Q000378:metabolism; D014867:Water / Q000737:chemistry
chemical_list: D011506:Proteins; D012996:Solutions; D012997:Solvents; D014867:Water; D012260:Ribonucleases; C077002:ribonuclease Sa3; D014357:Trypsin