Dissociation Rate Calculation via Constant Force Molecular Simulation

Steered molecular dynamics (SMD) simulation has been applied to molecular dissociation events by adding harmonic forces to molecules, and within most SMDs, molecules are pulled at a constant velocity. Instead of the constant-velocity pulling, a constant force can also be utilized in SMD, which we call constant-force SMD (CF-SMD) simulation. CF-SMD employs a constant force that reduces activation barriers, enhancing a dissociation event. Here, we present the capability of CF- SMD simulation to estimate a dissociation rate in equilibrium. We performed all-atom CF-SMD simulations for an NaCl system and protein-ligand systems, producing dissociation rates under various forces. We extrapolated them to the dissociation rate in the absence of a constant force, using Dudko-Hummer-Szabo model. We demonstrated that CF-SMD simulations combined with the model predicted a dissociation rate in equilibrium. CF-SMD simulation would be a powerful tool to estimate dissociation rate in a direct and computationally efficient manner.