Local Ion Densities can Influence Transition Paths of Molecular Binding.

Abstract

Improper reaction coordinates can pose significant problems for path-based binding free energy calculations. Particularly, omission of long timescale motions can lead to over-estimation of the energetic barriers between the bound and unbound states. Many methods exist to construct the optimal reaction coordinate using a pre-defined basis set of features. Although simulations are typically conducted in explicit solvent, the solvent atoms are often excluded by these feature sets—resulting in little being known about their role in reaction coordinates, and ultimately, their role in determining (un)binding rates and free energies. In this work, analysis is done on an extensive set of host-guest unbinding trajectories, working to characterize differences between high and low probability unbinding trajectories with a focus on solvent-based features, including host-ion interactions, guest-ion interactions and location-dependent ion densities. We find that differences in ion densities as well as guest-ion interactions strongly correlate with differences in the probabilities of reactive paths that are used to determine free energies of (un)binding and play a significant role in the unbinding process.