title: Incorporating replacement free energy of binding-site waters in molecular docking.
abstract: Binding-site water molecules play a crucial role in protein-ligand recognition, either being displaced upon ligand binding or forming water bridges to stabilize the complex. However, rigorously treating explicit binding-site waters is challenging in molecular docking, which requires to fully sample ensembles of waters and to consider the free energy cost of replacing waters. Here, we describe a method to incorporate structural and energetic properties of binding-site waters into molecular docking. We first developed a solvent property analysis (SPA) program to compute the replacement free energies of binding-site water molecules by post-processing molecular dynamics trajectories obtained from ligand-free protein structure simulation in explicit water. Next, we implemented a distance-dependent scoring term into DOCK scoring function to take account of the water replacement free energy cost upon ligand binding. We assessed this approach in protein targets containing important binding-site waters, and we demonstrated that our approach is reliable in reproducing the crystal binding geometries of protein-ligand-water complexes, as well as moderately improving the ligand docking enrichment performance. In addition, SPA program (free available to academic users upon request) may be applied in identifying hot-spot binding-site residues and structure-based lead optimization.
authors.affiliation: College of Life Sciences, Beijing Normal University, Beijing, 100875, China; National Institute of Biological Sciences, Beijing, Zhongguancun Life Science Park, Beijing, 102206, China.
authors.forename: Hanzi
authors.initials: H
authors.lastname: Sun
authors.forename: Lifeng
authors.initials: L
authors.lastname: Zhao
authors.forename: Shiming
authors.initials: S
authors.lastname: Peng
authors.forename: Niu
authors.initials: N
authors.lastname: Huang
mesh_terms: D000465:Algorithms; D001665:Binding Sites; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry*; D013816:Thermodynamics; D014867:Water / Q000737:chemistry*
chemical_list: D008024:Ligands; D011506:Proteins; D014867:Water
keywords: binding pose; binding-site water; docking enrichment; molecular docking; molecular dynamics; receptor desolvation energy