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

Abstract

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 highly-coordinated water molecules on the surfaces of proteins. A two-stage protocol 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.