Indrajit Deb, and Aaron T Frank (2019).
Journal of chemical theory and computation, 15, 5817-5828.   (PubMed)

Molecular dynamics (MD) simulations can be a powerful tool for modeling complex dissociative processes such as ligand unbinding. However, many biologically relevant dissociative processes occur on timescales that far exceed the timescales of typical MD simulations. Here, we implement and apply an enhanced sampling method in which specific energy terms in the potential energy function are selectively "scaled" to accelerate dissociative events during simulations. Using ligand unbinding as an example of a complex dissociative process, we selectively scaled up ligand-water interactions in an attempt to increase the rate of ligand unbinding. After applying our selectively scaled MD (ssMD) approach to several cyclin-dependent kinase-inhibitor complexes, we discovered that we could accelerate ligand unbinding, thereby allowing, in some cases, unbinding events to occur within as little as 2 ns. Moreover, we found that we could make realistic estimates of the initial unbinding times (τunbindsim) as well as the accompanying change in free energy (ΔGsim) of the inhibitors from our ssMD simulation data. To accomplish this, we employed a previously described Kramers'-based rate extrapolation method and a newly described free energy extrapolation method. Because our ssMD approach is general, it should find utility as an easy-to-deploy, enhanced sampling method for modeling other dissociative processes.

This work describes an example of using Selectively Scaled MD in kinetic calculations.