Water-Mediated Three-Particle Interactions between Hydrophobic Solutes: Size, Pressure, and Salt Effects

We use molecular dynamics (MD) simulations of solutions of hydrophobic solutes in explicit water to study the many-body character of hydrophobic interactions at the level of solute−solute−solute three-particle correlations. Comparisons of the calculated three-particle potentials of mean force (PMF) with that obtained by adding solute−solute pair PMFs are used to quantify the many-body effect. Our results shed light on both the range and magnitude of many-body (i.e., nonadditivity) effects. We find that the nonadditivity effects depend on the specific configuration of the three interacting particles and are short-ranged, restricted primarily to locations of the third solute within the first two solvation shells of the primary solute pair. The contact and solvent-separated configurations show anticooperative behavior (i.e., the actual three-particle PMF is less favorable than the pairwise additive approximation), whereas cooperativity is observed at the desolvation barrier. Increasing the solute size makes the nonadditive effects uniformly more anticooperative. Nonadditivity behavior is also short-ranged at higher pressures and in NaCl solutions. Interestingly, increasing pressure changes the nonadditivity effects toward cooperativity, whereas the opposite is true upon the addition of salt to the solution. The implications of these results on more complex self-assembly processes are discussed.