The structure and solution thermodynamic property of a protein is intimately tied to the structure of water around it, and an extant goal of experiments, theory, and simulation is to understand this inter-relation between the solvent water and the solute protein. We pursue this question by modeling the hydration contribution to the osmotic second virial coefficient, B₂, of protein solutions. We adopt a quasi-chemical description in which a protein with the water molecules associated with it is treated as a distinct solution component. These associated water molecules are identified through molecular dynamics simulations. We examine this quasi-chemical view of hydration by predicting B₂ and compare our results with those derived from light-scattering measurements of B₂ for staphylococcal nuclease, lysozyme, and chymotrypsinogen at 25°C as a function of solution pH and ionic strength. We find that short-range protein interactions are influenced by water molecules strongly associated with a relatively small fraction of the protein surface. We find that these water molecules reduce the surface complementarity of highly favorable short-range interactions, and therefore play an important role in mediating protein-protein interactions. Thus specific hydration effects need to be taken into account for an accurate description of B₂. We also observe remarkably similar hydration behavior for these small globular proteins despite substantial differences in their three-dimensional structures and spatial charge distributions, suggesting a general characterization of hydration for such globular proteins.