Accurate prediction of absolute molecular process rates on multisecond time scales

Fully atomistic simulations of processes with rates of seconds to hours is still far beyond the scope of current molecular dynamics (MD). To access such time scales, we have developed dissipation-corrected targeted MD simulations to coarse-grain fully atomistic dynamics based on a Markovian Langevin equation framework and the Jarzynski equality. We enforce a molecular process along a reaction coordinate x and use the resulting bias force to calculate free energies ΔF(x) and friction profiles Γ(x). With ΔF(x) and Γ(x) as input for the temperature-boosted integration of the Langevin equation, we readily simulate dynamics far beyond the limits of fully atomistic MD methods. Using the dissociation-association of a sodium chloride ion pair in water as simple two-body problem, and two protein-ligand complexes as challenging test systems, we reproduce rates from unbiased simulations and experiments up to a time scale of 0.5 minutes within a factor of 2–20, and dissociation constants within a factor of 1–4 in reasonable computational time. Analysis of Γ(x) allows insight into system dynamics orthogonal to ΔF(x), revealing changes of hydration shells to mediate dynamics in all investigated systems.
Details in: Wolf, S., Lickert, B., Bray, S., & Stock, G. (2020). Nat. Commun. 11, 2918.