Efficient consideration of coordinated water molecules improves computational protein-protein and protein-ligand docking discrimination

Highly coordinated water molecules are frequently an integral part of protein-protein and protein-ligand interfaces. We introduce an updated energy model that efficiently captures the energetic effects of these ordered water molecules on the surfaces of proteins. A two-stage method is developed in which polar groups arranged in geometries suitable for water placement are first identified, then a modified Monte Carlo simulation allows highly coordinated waters to be placed on the surface of a protein while simultaneously sampling amino acid side chain orientations. This “semi-explicit” water model is implemented in Rosetta and is suitable for both structure prediction and protein design. We show that our new approach and energy model yield significant improvements in native structure recovery of protein-protein and protein-ligand docking discrimination tests.