ScMiles2: A Script to Conduct and Analyze Milestoning Trajectories for Long Time Dynamics

Abstract

Milestoning is a theory and an algorithm that computes kinetics and thermodynamics at long time scales. It is based on partitioning the (phase) space into cells and running a large number of short trajectories between the boundaries of the cells. The termination points of the trajectories are analyzed with the Milestoning theory to obtain kinetic and thermodynamic information. Managing the tens to hundreds of thousands of Milestoning trajectories is a challenge, which we handle with a python script, ScMiles. Here, we introduce a new version of the python script ScMiles2 to conduct Milestoning simulations. Major enhancements are: (i) post analysis of Milestoning trajectories to obtain the free energy, mean first passage time, the committor function, and exit times; (ii) similar to (i) but the post analysis is for a single long trajectory; (iii) we support the use of the GROMACS software in addition to NAMD; (iv) a restart option; (v) the automated finding, sampling, and launching trajectories from new milestones that are found on the fly; and (vi) support Milestoning calculations with several coarse variables and for complex reaction coordinates. We also evaluate the simulation parameters and suggest new algorithmic features to enhance the rate of convergence of observables. We propose the use of an iteration-averaged kinetic matrix for a rapid approach to asymptotic values. Illustrations are provided for small systems and one large example.

Approximating First Hitting Point Distribution in Milestoning for Rare Event Kinetics

“…We here summarize only the essential aspects of the Milestoning algorithm with the focus on illustrating how the FHPD affects the MFPT computation. Readers are referred to recent reviews for more detailed discussions of Milestoning algorithms , and software implementation …”

“…Readers are referred to recent reviews for more detailed discussions of Milestoning algorithms 26,27 and software implementation. 28 Consider a phase space of dimension N 6 with N denoting the number of atoms. We are interested in computing the MFPT from a metastable region A (the reactant state) to a disjoint metastable region B (the product state).…”

Exploring Biomolecular Conformational Dynamics with Polarizable Force Field AMOEBA and Enhanced Sampling Method Milestoning

“…Milestoning − is an enhanced sampling method that shows unique strength in handling complex systems, for which the energy landscape can involve many metastable states, numerous local minima, and a wide distribution of energy barriers. Generally, the main challenges of tackling an energy landscape are activation and diffusion problems.…”