AquaMMapS: an alternative tool to monitor the role of water molecules during protein-ligand association

Unquestionably water appears to be an active player in noncovalent protein-ligand association processes, as it can either bridge interactions between protein and ligand or can be replaced by the bound ligand. Accordingly, in the last decade, alternative computational methodologies have been sought, that guess the position and thermodynamic profile of water molecules (i.e., hydration sites) in the binding site using either the ligand-bound or ligand-free protein conformation. Herein, we present an alternative approach, named AquaMMapS, that provides a three-dimensional sampling of putative hydration sites. Interestingly, AquaMMapS can post-inspect molecular dynamics trajectories obtained from different molecular dynamics engines and using indifferently crystallographic or docking-driven structures as a starting point. Moreover, AquaMMapS is naturally integrated to supervised molecular dynamics (SuMD) simulations Finally, a penalty scoring method, named AquaMMapScoring,(AMS), has been developed to evaluate, during the binding event, the number and the nature of the water molecules displaced by a ligand approaching its binding site, guiding a medicinal chemist to explore the most suitable regions of a ligand that can be decorated either with or without interfering with the interaction networks mediated by water molecules with specific recognition regions of the protein.