Protein-Ligand Dissociation Rate Constant from All-Atom Simulation.

Ekaterina Maximova,Vladimir Farafonov,Anastasia I Lavrova,Dmitry Nerukh,Eugene B Postnikov

doi:10.1021/acs.jpclett.1c02952

Abstract

Dissociation of a ligand isoniazid from a protein catalase was investigated using all-atom molecular dynamics (MD) simulations. Random acceleration MD (τ-RAMD) was used, in which a random artificial force applied to the ligand facilitates its dissociation. We have suggested a novel approach to extrapolate such obtained dissociation times to the zero-force limit assuming never before attempted universal exponential dependence of the bond strength on the applied force, allowing direct comparison with experimentally measured values. We have found that our calculated dissociation time was equal to 36.1 s with statistically significant values distributed in the interval of 0.2-72.0 s, which quantitatively matches the experimental value of 50 ± 8 s despite the extrapolation over 9 orders of magnitude in time.

Highlights

We have found that our calculated dissociation time was equal to 36.1 seconds with statistically significant values distributed in the interval 0.2-72.0 s, that quantitatively matches the experimental value of 50±8 seconds despite the extrapolation over nine orders of magnitude in time
All-atom Molecular Dynamics (MD) simulations can not in most cases calculate the kinetics of protein-ligand association and dissociation directly because experimental values are in the range of seconds, many orders of magnitude larger than currently accessible for straightforward MD
Using recent results from the stochastic theory of reaction rates, we show that the simulated data can be used for estimating dissociation times that quantitatively match the exp experimental value of τoff

Summary

Introduction

We have suggested an approach to extrapolate such obtained dissociation times to the zero-force limit that was never attempted before, allowing direct comparison with experimentally measured values. All-atom Molecular Dynamics (MD) simulations can not in most cases calculate the kinetics of protein-ligand association and dissociation directly because experimental values are in the range of seconds, many orders of magnitude larger than currently accessible for straightforward MD.

Results

Conclusion