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Title: The role of water in protein ligand binding.

Understanding the underlying physics of the binding of small-molecule ligands to protein active sites is a key objective of computational chemistry and biology. The displacement of water molecules from the active site by the ligand is a principal, and often dominant, source of binding free energy. Although continuum theories of hydration are routinely used to describe the contributions of the solvent to the binding affinity of the complex, it is still an unsettled question as to whether or not these continuum solvation theories describe the underlying molecular physics with sufficient accuracy to reliably rank the binding affinities of a set of ligands for a given protein. Here, we introduce a powerful solvation analysis tool that utilizes explicit molecular dynamics simulations and a rigorous statistical mechanical treatment to create an approximate 3-dimensional thermodynamic mapping of the solvation of protein active sites. This approach addresses two deficiencies common in many computational methods aimed at predicting ligand-binding affinity. First, while maintaining computational efficiency, it captures molecular length scale physics which many methodologies aimed at predicting ligand-protein binding affinities ignore. Second, it provides specific information and physical insight into how lead-drugs can be modified such as to produce derivatives that can bind both with greater affinity and specificity to given targets.