Computing Rates and Understanding Unbinding Mechanisms in Host-Guest Systems

The long time scale associated with ligand residence times renders their computation challenging. Therefore, the influence of factors like solvation and steric hindrance on residence times is 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 an understanding of their unbinding mechanism. We observe that guest unbinding often proceeds via a series of intermediate states that can be labeled by the number of water molecules present in the binding cavity. In several cases the residence time is correlated to the water trapping times in the cavity.