Kinetic rate calculation via non-equilibrium dynamics

Abstract

This study introduces a novel computational approach based on ratchet-and-pawl molecular dynamics (rMD) for accurately estimating ligand dissociation kinetics in protein–ligand complexes. By integrating Kramers’s theory with Bell’s equation, our method systematically investigates the relationship between the effective biasing force applied during simulations and the ligand residence times. The proposed technique is demonstrated through extensive simulations of the benzamidine–trypsin complex, employing first an implicit solvent model (multi-eGO) to set up the approach parameters and then an explicit solvent model. Our results illustrate the method’s reliability, accuracy, and computational efficiency, with calculated kinetic rates closely matching experimental values. Overall, this study highlights rMD as a versatile and efficient non-equilibrium methodology, broadly applicable to kinetic analyses in chemical and biological systems.