A modeling analysis has been conducted to assess the determinants of binding strength and specificity for three crystal complexes; the anti-hen egg white lysozyme antibody D1.3 complexed with hen egg white lysozyme (HEL), the D1.3 antibody complexed with the anti-lysozyme antibody E5.2, and barnase complexed with barstar. The strengths of individual binding components within these interfaces are evaluated using a model of binding free energy that is based on pairwise surface preferences. In all cases the energetics of binding are dominated by a relatively small number of interfacial residues that define the binding epitope. A precise geometric arrangement of these residues was not found; they were either localized to one region, or distributed throughout the binding interface. Surprisingly, interfacial crystal water molecules were calculated to contribute around 25% of the total calculated binding strength. Theoretical alanine mutations were completed by atomic deletions of the wild-type complexes. Strong correlations were observed between the calculated changes in binding free energy (deltadeltaG(calculated)) and the experimental values (deltadeltaG(observed)) for all but three of the 30 single residue mutations in the D1.3-HEL, D1.3-E5.2 and barnase-barstar systems and for all of the double mutations in the barnase-barstar system. This analysis finds that the observed differences in binding strength are consistent with a model that accounts for the changes in binding energy from the direct contacts between each member of the complex and indirect changes due to released crystallographic water molecules that are near the mutation site. The observed energy changes for double mutations in the barnase-barstar system is fully accounted for by considering water molecules bound jointly by each member of the complex.