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

TL;DR

This paper introduces a theoretical framework for analyzing protein-ligand unbinding pathways using dissipation-corrected targeted molecular dynamics, enabling the calculation of pathway-specific kinetics and their integration into overall rates, with applications to complex biomolecular systems.

Contribution

It presents a novel method to compute and combine pathway-specific unbinding rates from biased molecular dynamics simulations, improving kinetic predictions.

Findings

The framework accurately predicts unbinding kinetics in test systems.

Path-specific rates can be effectively combined into global rates.

The method demonstrates robustness and practical applicability for complex systems.

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. 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.