Water: How to evaluate its contribution in protein-ligand interactions

Water can be considered the most important molecule in living systems. It can play a variety of roles: (a) the solvent of most biological molecules, (b) substrate and product of enzyme catalysis, (c) a building block of macromolecules, or (d) functioning as a “lubricant” via the formation of networks linking distant residues. In particular, protein–protein, protein–nucleic acid, and protein–ligand recognition are water dependent via both enthalpic and entropic contributions. We present a computational approach based on the natural force field Hydropathic INTeractions (HINT) that incorporates atomic LogPoctanol/water data, to evaluate the strength of the interaction between water molecules and protein, as well as the contribution of water molecules bridging protein and ligand to the free energy of binding. We describe the rules for characterizing the binding/energetic roles of water molecules located at ligand binding sites. As an example, results from a set of 23 HIV‐1 protease ligand complexes are described. © 2005 Wiley Periodicals, Inc. Int J Quantum Chem, 2006