Computing rates and understanding unbinding mechanism in host-guest systems

TL;DR

This paper demonstrates how Gaussian Mixture Based Enhanced Sampling can compute ligand residence times and elucidate unbinding mechanisms in host-guest systems, highlighting the role of water molecules in the process.

Contribution

It introduces the application of Gaussian Mixture Based Enhanced Sampling to study residence times and unbinding pathways in host-guest systems, revealing the influence of water molecules.

Findings

Unbinding proceeds via intermediate states characterized by water molecules.

Residence times correlate with water trapping times in the cavity.

Enhanced sampling enables computation of long ligand residence times.

Abstract

The long timescale associated with ligand residence times renders their computation challenging. Therefore, the influence of factors like solvation and steric hindrance on residence times are not fully understood. Here, we demonstrate in a set of model host-guest systems that the recently developed Gaussian Mixture Based Enhanced Sampling allows residence times to be computed and enables understanding their unbinding mechanism. We observe that guest unbinding often proceeds via a series of intermediate states that can be labelled by the number of water molecules present in the binding cavity. And in several cases the residence time is correlated to the water trapping times in the cavity.