Weighted Ensemble Milestoning (WEM): A Combined Approach for Rare Event Simulations

Abstract

To directly simulate rare events using atomistic molecular dynamics is a significant challenge in computational biophysics. Well-established enhanced-sampling techniques do exist to obtain the thermodynamic functions for such systems. But developing methods for obtaining the kinetics of long timescale processes from simulation at atomic detail is comparatively less developed an area. Milestoning and the weighted ensemble (WE) method are two different stratification strategies; both have shown promise for computing long timescales of complex biomolecular processes. Nevertheless, both require a significant investment of computational resources. We have combined WE and milestoning to calculate observables in orders of magnitude less CPU and wall-clock time. Our weighted ensemble milestoning method (WEM) uses WE simulation to converge the transition probability and first passage times between milestones, followed by the utilization of the theoretical framework of milestoning to extract thermodynamic and kinetic properties of the entire process. We tested our method for a simple one-dimensional double well potential, an eleven-dimensional potential energy surface with energy barrier, and on the biomolecular model system alanine dipeptide. We were able to recover the free energy profiles, time correlation functions, and mean first passage times for barrier crossing events at a significantly small computational cost. WEM promises to extend the applicability of molecular dynamics simulation to slow dynamics of large systems which are well beyond the scope of present day brute-force computations.

References in corpus (9)

• Escaping free-energy minima
• Identification of slow molecular order parameters for Markov model construction
• A Novel Path Sampling Method for the Calculation of Rate Constants
• From Metadynamics to Dynamics
• Forward Flux Sampling for rare event simulations
• Forward Flux Sampling-type schemes for simulating rare events: Efficiency analysis
• Steady-state simulations using weighted ensemble path sampling
• Frequency adaptive metadynamics for the calculation of rare-event kinetics
• Efficient Dynamic Importance Sampling of Rare Events in One Dimension

Cited by in corpus (7)

• Rare Event Kinetics from Adaptive Bias Enhanced Sampling
• Weighted ensemble: Recent mathematical developments
• Kinetics and Free Energy of Ligand Dissociation Using Weighted Ensemble Milestoning
• Approximating First Hitting Point Distribution in Milestoning for Rare Event Kinetics
• WeTICA: A directed search weighted ensemble based enhanced sampling method to estimate rare event kinetics in a reduced dimensional space
• Kinetic network in Milestoning: Clustering, reduction, and transition path analysis
• Compound Mutations in the Abl1 Kinase Cause Inhibitor Resistance by Shifting DFG Flip Mechanisms and Relative State Populations