A Companion Guide to the String Method with Swarms of Trajectories: Characterization, Performance, and Pitfalls

• Published in: Journal of chemical theory and computation Vol. 18; no. 3; pp. 1406 - 1422
• Main Authors: Chen, Haochuan, Ogden, Dylan, Pant, Shashank, Cai, Wensheng, Tajkhorshid, Emad, Moradi, Mahmoud, Roux, Benoît, Chipot, Christophe
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 08.03.2022
• Subjects: Algorithms; Free energy; Molecular dynamics; Optimization; Polypeptides; Statistical Mechanics; Strings; Trajectories
• ISSN: 1549-9618; 1549-9626; 1549-9626
• DOI: 10.1021/acs.jctc.1c01049

The string method with swarms of trajectories (SMwST) is an algorithm that identifies a physically meaningful transition pathwaya one-dimensional curve, embedded within a high-dimensional space of selected collective variables. The SMwST algorithm leans on a series of short, unbiased molecular dynamics simulations spawned at different locations of the discretized path, from whence an average dynamic drift is determined to evolve the string toward an optimal pathway. However conceptually simple in both its theoretical formulation and practical implementation, the SMwST algorithm is computationally intensive and requires a careful choice of parameters for optimal cost-effectiveness in applications to challenging problems in chemistry and biology. In this contribution, the SMwST algorithm is presented in a self-contained manner, discussing with a critical eye its theoretical underpinnings, applicability, inherent limitations, and use in the context of path-following free-energy calculations and their possible extension to kinetics modeling. Through multiple simulations of a prototypical polypeptide, combining the search of the transition pathway and the computation of the potential of mean force along it, several practical aspects of the methodology are examined with the objective of optimizing the computational effort, yet without sacrificing accuracy. In light of the results reported here, we propose some general guidelines aimed at improving the efficiency and reliability of the computed pathways and free-energy profiles underlying the conformational transitions at hand.