We explore the relationship between the complex electrostatic and van der Waals surfaces of proteins and the structure and thermodynamics of the water solvating these surfaces. We present a method for estimating the entropy and enthalpy of solvating these surfaces and demonstrate how this can be used to predict difference in binding affinities between congeneric pairs of ligands. This methodology gives a great deal of physical insight into the interplay of protein surface structure and the thermodynamics of solvation which plays an essential role in molecular recognition.