Improper reaction coordinates in simulations can lead to the generation of highly variable results for enhanced sampling simulations. For example, weighted ensemble simulations often present inconsistent, high variability results which may in part be due to the use of an insufficient reaction coordinate. Many methods currently exist that aim to predict optimal reaction coordinates; however, these methods generally select from an existing basis set of predefined features that dramatically reduce the complexity of the system. In particular, solvent is commonly excluded, resulting in little being known about its role in optimal ligand (un)binding reaction coordinates. Here, an ensemble of unbinding pathways are analyzed for the OA-G6 and OA-G3 host-guest systems from the SAMPL6 challenge. These continuous, unbiased transition paths were generated using weighted ensemble simulations and have associated probabilities ranging between 10<sup>-6</sup> and 10<sup>-12</sup>. Here we characterize physical differences between these high- and low-probability unbinding trajectories with a focus on solvent-based features. These features include location-dependent ion densities, host-ion interactions, guest-ion interactions, and differences in the final locations of guests in the solvent. We have found that differences in ion densities as well as guest-ion interactions correlate strongly to differences in the probabilities of reactive paths of host-guest unbinding and play a significant role in the unbinding process. Together these results motivate a significant role for water and ions in the binding transition path ensemble, which should be considered during construction of reaction coordinates.

Differences in ion densities play a significant role in the host-guest unbinding process

ACS Spring 2022

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