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.