title: Protein-ligand docking using hamiltonian replica exchange simulations with soft core potentials.
abstract: Molecular dynamics (MD) simulations in explicit solvent allow studying receptor-ligand binding processes including full flexibility of the binding partners and an explicit inclusion of solvation effects. However, in MD simulations, the search for an optimal ligand-receptor complex geometry is frequently trapped in locally stable non-native binding geometries. A Hamiltonian replica-exchange (H-REMD)-based protocol has been designed to enhance the sampling of putative ligand-receptor complexes. It is based on softening nonbonded ligand-receptor interactions along the replicas and one reference replica under the control of the original force field. The efficiency of the method has been evaluated on two receptor-ligand systems and one protein-peptide complex. Starting from misplaced initial docking geometries, the H-REMD method reached in each case the known binding geometry significantly faster than a standard MD simulation. The approach could also be useful to identify and evaluate alternative binding geometries in a given binding region with small relative differences in binding free energy.
authors.affiliation: Physik-Department T38, Technische Universität München , James Franck Str. 1, 85748 Garching, Germany.
authors.forename: Manuel P
authors.initials: MP
authors.lastname: Luitz
authors.forename: Martin
authors.initials: M
authors.lastname: Zacharias
mesh_terms: D000818:Animals; D006183:H-2 Antigens / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008024:Ligands; D051379:Mice; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D022061:Tacrolimus Binding Protein 1A / Q000737:chemistry / Q000378:metabolism; D022021:Tacrolimus Binding Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D008024:Ligands; D010455:Peptides; D011506:Proteins; D022061:Tacrolimus Binding Protein 1A; D022021:Tacrolimus Binding Proteins; C403485:tacrolimus binding protein 4