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

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. We here present a theoretical framework how to compute kinetics along separate paths and to combine the path-specific rates into global binding and unbinding rates for comparison with experiment. Using dissipation-corrected targeted molecular dynamics in combination with temperature-boosted Langevin equation simulations [Nat. Commun. \textbf{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 aspects of its practical applicability to predict multisecond kinetics of complex biomolecular systems.

Steffen Wolf, Matthias Post, Gerhard Stock · 2022