Computing rates and understanding unbinding mechanism in host-guest systems

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.