The calculation of protein interaction energetics is of fundamental interest, yet accurate quantities are difficult to obtain due to the complex and dynamic nature of protein interfaces. This is further complicated by the presence of water molecules, which can exhibit transient interactions of variable duration and strength with the protein surface. The T-cell receptor (TCR) and its staphylococcal enterotoxin 3 (SEC3) binding partner are well-characterized examples of a protein−protein interaction system exhibiting interfacial plasticity, cooperativity, and additivity among mutants. Specifically engineered mutants induce intercalating interfacial water molecules, which subsequently enhance protein−protein binding affinity. In this work, we perform a set of molecular mechanics (MM) Poisson−Boltzmann (PB) surface area (SA) calculations on the wild type and two mutant TCR-SEC3 systems and show that the method is able to discriminate between weak and strong binders only when key explicit water molecules are included in the analysis. The results presented here point to the promise of MM-PBSA toward rationalizing molecular recognition at protein−protein interfaces, while establishing a general approach to handle explicit interfacial water molecules in such calculations.