Boxed Molecular Dynamics: A Simple and General Technique for Accelerating Rare Event Kinetics and Mapping Free Energy in Large Molecular Systems

We present a simple, comprehensive technique for accelerating simulation of rare events and calculating free energy profiles in molecular dynamics (MD) simulations. The technique is based on two related and complementary methods (AXD and BXD), which provide both thermodynamic and kinetic information along some reaction coordinate. The idea is to slice the reaction coordinate into several “boxes”, and then run trajectories, locking them consecutively within each box to generate kinetic rate coefficients for exchange between neighboring boxes. In this way, a reaction coordinate may be efficiently explored, including those regions that would otherwise be visited only rarely. Combined with a simple and exact method for renormalizing the statistics obtained within each box, the box-to-box rate coefficients permit efficient free energy mapping. Tests carried out on model peptides demonstrate the utility of the method as well as the validity of the detailed balance assumption that underpins the derivations.