Energetics of Hydrophilic Protein–Protein Association and the Role of Water

Hydrophilic protein–protein interfaces constitute a major part of all protein–protein interfaces and are thus of great importance. However, the quantitative characterization of their association is still an ongoing challenge and the driving force behind their association remains poorly characterized. Here, we have addressed the association of hydrophilic proteins and the role of water by means of extensive molecular dynamics simulations in explicit water using three well studied protein complexes; Barnase–Barstar, cytochrome c–cytochrome c peroxidase, and the N-terminal domain of enzyme I-histidine-containing phosphocarrier. The one-dimensional free energy profiles obtained from umbrella sampling simulations are downhill or, in other words, barrierless. Using these one-dimensional free energy profiles, the computed standard free energies of binding are −12.7 ± 1.1 kcal/mol, −9.4 ± 0.7 kcal/mol, and −8.4 ± 1.9 kcal/mol that are in reasonable to very good agreement with the experimental values of −19.6 kcal/mol, −8.8 kcal/mol, and −7.8 kcal/mol. As expected, analysis of the confined water between the hydrophilic complex partners shows that the density and the orientational order parameter deviate noticeably from the bulk values, especially at close separations of the confining proteins