Reducing Weighted Ensemble Variance With Optimal Trajectory Management

Abstract: Weighted ensemble (WE) is an enhanced path-sampling method that is conceptually simple, widely applicable, and statistically exact. In a WE simulation, an ensemble of trajectories is periodically pruned or replicated to enhance sampling of rare transitions and improve estimation of mean first passage times (MFPTs). However, poor choices of the parameters governing pruning and replication can lead to high-variance MFPT estimates. Our previous work [J. Chem. Phys. 158, 014108 (2023)] presented an optimal WE parameterization strategy and applied it in low-dimensional example systems. The strategy harnesses estimated local MFPTs from different initial configurations to a single target state. In the present work, we apply the optimal parameterization strategy to more challenging, high-dimensional molecular models, namely, synthetic molecular dynamics (MD) models of Trp-cage folding and unfolding, as well as atomistic MD models of NTL9 folding in high-friction and low-friction continuum solvents. In each system we use WE to estimate the MFPT for folding or unfolding events. We show that the optimal parameterization reduces the variance of MFPT estimates in three of four systems, with dramatic improvement in the most challenging atomistic system. Overall, the parameterization strategy improves the accuracy and reliability of WE estimates for the kinetics of biophysical processes.