Weighted Ensemble Simulation: Advances in methods, software, and applications

Area of Science:

• Computational Chemistry
• Molecular Dynamics
• Biophysics

Background:

• Weighted ensemble (WE) path sampling is a powerful simulation technique for rare events.
• Conventional simulations struggle with the computational cost of barrier-crossing processes.
• WE methods offer a way to simulate these processes with rigorous kinetics and reduced cost.

Purpose of the Study:

• To review recent advancements in WE methods and software.
• To highlight tools for mechanistic analysis and rate estimation in path ensembles.
• To showcase diverse applications of WE in condensed-phase processes.

Main Methods:

• Review of weighted ensemble (WE) path sampling strategies.
• Analysis of WE software for mechanistic insights and rate calculations.
• Application of WE to hybrid quantum mechanics/molecular mechanics (QM/MM) and atomistic simulations.

Main Results:

• WE enables simulation of microsecond to millisecond/second timescale processes.
• Successful applications include drug membrane permeation, ligand unbinding, and protein dynamics (e.g., SARS-CoV-2 spike protein).
• New tools improve mechanistic analysis and rate estimation from path ensembles.

Conclusions:

• WE strategies have significantly advanced the simulation of rare events in condensed-phase systems.
• Current limitations and challenges for WE methods are identified.
• WE approaches show great promise for future molecular simulations.