Path separation of dissipation-corrected targeted molecular dynamics simulations of protein-ligand unbinding.

Abstract

Protein-ligand (un)binding simulations are a recent focus of biased molecular dynamics simulations. Such binding and unbinding can occur via different pathways in and out of a binding site. Here, we present a theoretical framework on how to compute kinetics along separate paths and on how to combine the path-specific rates into global binding and unbinding rates for comparison with experimental results. Using dissipation-corrected targeted molecular dynamics in combination with temperature-boosted Langevin equation simulations [S. Wolf et al., Nat. Commun. 11, 2918 (2020)] applied to a two-dimensional model and the trypsin-benzamidine complex as test systems, we assess the robustness of the procedure and discuss the aspects of its practical applicability to predict multisecond kinetics of complex biomolecular systems.