Despite the increasing number of high-quality co-crystal structures and corresponding binding data, the origin of protein specificity is still poorly understood. This is not surprising since most scoring functions ignore crystallographic water molecules even though they provide snapshots of optimal solutions for the role of solvent in protein interactions. Here, we will show how molecular waters distort the binding free energy in ways that are not possible to be addressed by a solute-solute code alone. Motivated by high-resolution crystal structures of protein and DNA, we describe a simple quantitative approach to explicitly incorporate the role of molecular water in protein interactions. Our empirical energies are fully consistent with mobile water molecules having a strong polarization effect in direct intermolecular interactions. Finally, we relate the tuning of protein-DNA interactions by a few (kcal/mol) waters molecules to the low affinity high complementarity required by transcription factors binding to DNA.

Quantifying desolvation free energies one water at a time

248th National Meeting (2014)

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