Dewetting-controlled binding of ligands to hydrophobic pockets

TL;DR

This study combines molecular dynamics simulations and an implicit solvent model to investigate how wetting and dewetting transitions in hydrophobic pockets influence ligand binding, revealing complex solvent fluctuations that affect binding affinity.

Contribution

It introduces a semi-quantitative implicit water model that captures the wetting/dewetting transitions in hydrophobic pockets during ligand binding.

Findings

Wetting/dewetting transitions induce bimodal solvent fluctuations.

These fluctuations significantly influence the strength and range of ligand-pocket attraction.

The implicit water model effectively reproduces the solvent response in the system.

Abstract

We report on a combined atomistic molecular dynamics simulation and implicit solvent analysis of a generic hydrophobic pocket-ligand (host-guest) system. The approaching ligand induces complex wetting/dewetting transitions in the weakly solvated pocket. The transitions lead to bimodal solvent fluctuations which govern magnitude and range of the pocket-ligand attraction. A recently developed implicit water model, based on the minimization of a geometric functional, captures the sensitive aqueous interface response to the concave-convex pocket-ligand configuration semi-quantitatively.