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. 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.

This preprint is the unedited version of a manuscript that has been published in J. Chen. Phys. and can be downloaded for private use only. Copyright with AIP and and the authors

References in corpus (6)

• Array Programming with NumPy
• Enhanced sampling methods for molecular dynamics simulations
• Principal component analysis of nonequilibrium molecular dynamics simulations
• Correlation-based feature selection to identify functional dynamics in proteins
• Ligand unbinding pathway and mechanism analysis assisted by machine learning and graph methods
• Molecular origin of driving-dependent friction in fluids

Cited by in corpus (3)

• Learning protein-ligand unbinding pathways via single-parameter community detection
• Nonequilibrium friction and free energy estimates for kinetic coarse-graining -- Driven particles in responsive media
• More sophisticated is not always better: comparison of similarity measures for unsupervised learning of pathways in biomolecular simulations