Kinetics of Ligand–Protein Dissociation from All-Atom Simulations: Are We There Yet?

Large parallel gains in the development of both computational resources and sampling methods have now made it possible to simulate dissociation events in ligand–protein complexes with all-atom resolution. Such encouraging progress, together with the inherent spatiotemporal resolution associated with molecular simulations, has left their use for investigating dissociation processes brimming with potential, both in rational drug design, where it can be an invaluable tool for determining the mechanistic driving forces behind dissociation rate constants, and in force-field development, where it can provide a catalog of transient molecular structures with which to refine force fields. Although much progress has been made in making force fields more accurate, reducing their error for transient structures along a transition path could yet prove to be a critical development helping to make kinetic predictions much more accurate. In what follows, we will provide a state-of-the-art compilation of the enhanced sampl...