How hydrophobic drying forces impact the kinetics of molecular recognition

TL;DR

This paper presents a model for protein-ligand binding kinetics that incorporates slow solvent dynamics due to hydrophobic drying transitions, validated by molecular dynamics simulations and offering improved kinetic predictions.

Contribution

It introduces a Diffusive Surface Hopping Model capturing solvent fluctuations and their impact on binding kinetics, advancing understanding of hydrophobic effects in molecular recognition.

Findings

Model agrees with explicit solvent MD simulations

Improves description of hydrophobic assembly kinetics

Consistent with non-Markovian Brownian theory

Abstract

A model of protein-ligand binding kinetics in which slow solvent dynamics results from hydrophobic drying transitions is investigated. Molecular dynamics simulations show that solvent in the receptor pocket can fluctuate between wet and dry states with lifetimes in each state that are long enough for the extraction of a separable potential of mean force and wet-to-dry transitions. We introduce a Diffusive Surface Hopping Model that is represented by a two-dimensional Markovian master equation. One dimension is the standard reaction coordinate, the ligand-pocket separation, and the other is the solvent state in the region between ligand and binding pocket which specifies whether it is wet or dry. In our model, the ligand diffuses on a dynamic free energy surface which undergoes kinetic transitions between the wet and dry states. The model yields good agreement with results from explicit solvent molecular dynamics simulation and an improved description of the kinetics of hydrophobic assembly. Furthermore, it is consistent with a "non-Markovian Brownian theory" for the ligand-pocket separation coordinate alone.