Contribution of ligand desolvation to binding thermodynamics in a ligand-protein interaction.

Introduction Despite enormous advances in the structure determination of protein complexes, our ability to predict binding affinity from structure remains severely limited. Affinities are governed by both structure and dynamics, including solvent rearrangement. While a number of studies have examined the contribution of water molecules in the protein binding pocket, ligand solvation has received little attention. Here, we examine the latter in the major urinary protein (MUP), an abundant pheromone-binding protein where subtle recognition of a series of related compounds is essential to its biological function. Our approach involves the experimental determination of solvation thermodynamics of relevant ligands using air/water partition coefficient measurements supported by free energy perturbation calculations. These are interpreted in the context of thermodynamic binding data, leading to a decomposition of interaction thermodynamics at a level of detail unreported for any system.