Incorporating replacement free energy of binding‐site waters in molecular docking

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. Proteins 2014; 82:1765–1776. © 2014 Wiley Periodicals, Inc.