Interfaces and hydrophobic interactions in receptor-ligand systems: A level-set variational implicit solvent approach.

A model nanometer-sized hydrophobic receptor-ligand system in aqueous solution is studied by the recently developed level-set variational implicit solvent model (VISM). This approach is compared to all-atom computer simulations. The simulations reveal complex hydration effects within the (concave) receptor pocket, sensitive to the distance of the (convex) approaching ligand. The ligand induces and controls an intermittent switching between dry and wet states of the hosting pocket, which determines the range and magnitude of the pocket-ligand attraction. In the level-set VISM, a geometric free-energy functional of all possible solute-solvent interfaces coupled to the local dispersion potential is minimized numerically. This approach captures the distinct metastable states that correspond to topologically different solute-solvent interfaces, and thereby reproduces the bimodal hydration behavior observed in the all-atom simulation. Geometrical singularities formed during the interface relaxation are found to contribute significantly to the energy barrier between different metastable states. While the hydration phenomena can thus be explained by capillary effects, the explicit inclusion of dispersion and curvature corrections seems to be essential for a quantitative description of hydrophobically confined systems on nanoscales. This study may shed more light onto the tight connection between geometric and energetic aspects of biomolecular hydration and may represent a valuable step toward the proper interpretation of experimental receptor-ligand binding rates.