Correct Protonation States and Relevant Waters = Better Computational Simulations?

The unique physicochemical properties of water make it the most important molecule for life. Water molecules have many roles, direct and indirect, related to both biological structure and function. This paper: 1) reviews tools for the prediction of water conservation in and around protein active sites, by empirical (knowledge-based) algorithms and by methods based on thermodynamics principles; 2) reviews principles and approaches to predict pKa for both protein residue ensembles and for ligands; and 3) discusses the HINT biomolecular interaction model and forcefield – based on experimental measurements of LogPo/w, the 1-octanol/water partition coefficient, which implicitly incorporates all solution phenomena like these, and others like tautomerism and entropy. Lastly, it must be considered that the “real” biological environment is a continuum of nano-states and it may not be possible to represent it as a single discrete all-atom model.