Protein-Ligand Dissociation Rate Constant from All-Atom Simulation

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.