Principles for Tuning Hydrophobic Ligand-Receptor Binding Kinetics.

We investigate how to tune the rate of hydrophobic ligand-receptor association due to the role of solvent in adjustable receptor pockets by explicit-water molecular dynamics (MD) simulations. Our model considers the binding of a spherical ligand (key/guest) to a concave surface recess in a nonpolar wall as receptor (lock/host). We systematically modify the receptor's physicochemical properties in terms of geometry and dispersion attraction which, in turn, alter the water occupancy and fluctuations within the pocket. We demonstrate that even minor pocket modifications can lead to a significant acceleration of the water-mediated association. For example, the binding switches from comparably slow to fast if the binding pocket becomes only slightly deeper. We find that the degree of hydrophobicity, characterized by hydration occupancy and its fluctuations, clearly correlates with the binding times and, for instance, links the sudden acceleration to an abrupt increase in hydrophobicity. For a deeper analysis based on passage time theory, we quantify the intimate coupling between solvent fluctuations and the ligand's local dynamics and friction. The coupling exhibits substantial nonequilibrium effects and maximizes shortly before binding, which slows down the binding kinetics in all cases. In summary, we rationalize how the physicochemical properties of a nonpolar, concave binding site tune key-lock binding kinetics due to water-mediated forces and fluctuations. Our study thus complements the profound understanding of the solvent's influence in host-guest binding, which is essential for tailored solutions in catalysis and pharmaceutical applications.