Comparison of Accuracy and Efficiency of Milestoning Variants: Introducing Buffer Milestoning

• Published in: The journal of physical chemistry. B 2024-02, Vol.128 (6), p.1438-1447
• Main Authors: Narayan, Brajesh, Elber, Ron
• Format: Article
• Language: English
• Subjects: B: Biophysical and Biochemical Systems and Processes
• ISSN: 1520-6106; 1520-5207
• DOI: 10.1021/acs.jpcb.3c07933

The Milestoning algorithm is a method for long-time molecular dynamics simulations. It enables the sampling of rare events. The precise calculations of observables depend on accurately determining the first hitting point distribution (FHPD) for each milestone. There is no analytical expression for FHPD, which is estimated numerically. Several variants of Milestoning offer approximations to the FHPD. Here, we examine in detail the FHPD of an exact calculation and Milestoning variants. We also introduce a new version of the Milestoning algorithm, buffer Milestoning, with a comparable cost to conventional Milestoning but higher accuracy. We use the mean first passage time and the free energy to assess the simulation quality, and we compare the accuracy and efficiency of buffer Milestoning to exact calculations, conventional Milestoning, local-passage-time-weighted Milestoning, Markovian Milestoning with Voronoi tessellation, and exact Milestoning. Conventional Milestoning requires milestone decorrelation. If this condition is not satisfied, it is the least accurate approach of all the techniques we examined. We conclude that for a small increase in cost compared to conventional Milestoning, buffer Milestoning provides accurate results for a range of problems, including more correlated milestones and is, therefore, versatile compared to other variants. Local-passage-time-weighted Milestoning provides accuracy similar to that of buffer Milestoning but at an increased simulation cost. Markovian Milestoning with Voronoi tessellation is the most accurate compared with other approximations, but it is less stable for high barriers and more expensive.