Multi-Resolution Wire-Fencing for Efficient Path Sampling

Abstract

Path sampling methods enable the computation of thermodynamic and kinetic properties through Monte Carlo (MC) moves that generate trajectories from short forward and backward molecular dynamics (MD) segments. Recently, the wire-fencing move was developed to achieve near-unity acceptance while also rapidly decorrelating successive paths, two properties that are usually in conflict in conventional MC schemes. However, in large systems, such as biomolecular simulations, the frame-saving frequency is often kept low to reduce storage requirements. Likewise, when evaluating the order parameter is expensive, frames are saved less frequently to reduce the associated cost. In either situation, this can severely limit the number of available shooting points, in extreme situations leaving only a single point, typically the one with the highest order parameter value, accessible for shooting. Repeated shootings may then originate from the same configuration, reducing sampling efficiency. Here, we introduce a multi-resolution variant of the wire-fencing move in which selected subtrajectories are propagated at higher temporal resolution than the stored trajectories. This refinement affects only the MC move and does not alter the structure or storage of the generated paths, but enhances the diffusion of shooting points along the trajectory and thereby improves sampling efficiency. The approach is demonstrated on two model systems and a realistic protein--ligand unbinding process, with the latter showing an estimated efficiency improvement of more than an order of magnitude.