Finding Multiple Reaction Pathways of Ligand Unbinding

Abstract: Searching for reaction pathways describing rare events in large systems presents a long-standing challenge in chemistry and physics. Incorrectly computed reaction pathways result in the degeneracy of microscopic configurations and inability to sample hidden energy barriers. To this aim, we present a general enhanced sampling method to find multiple diverse reaction pathways of ligand unbinding through non-convex optimization of a loss function describing ligand-protein interactions. The method successfully overcomes large energy barriers using an adaptive bias potential, and constructs possible reaction pathways along transient tunnels without the initial guesses of intermediate or final states, requiring crystallographic information only. We examine the method on the T4 lysozyme L99A mutant which is often used as a model system to study ligand binding to proteins, provide a previously unknown reaction pathway, and show that using the bias potential and the tunnel widths it is possible to capture heterogeneity of the unbinding mechanisms between the found transient protein tunnels.