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

Abstract

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 costeffectiveness 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.

An Investigation of the YidC-Mediated Membrane Insertion of Pf3 Coat Protein Using Molecular Dynamics Simulations

“…The combination of equilibrium and non-equilibrium MD simulations has proven effective for investigating biological challenges. 12,[56][57][58][59][60][61][62][63][64] In this work, the YidC independent insertion mechanism was studied using non-equilibrium targeted MD (TMD) as implemented within the colvars module of NAMD. 65 TMD simulation was performed on the final conformation of the pose 1 system obtained from the 550 ns equilibrium trajectory in order to transfer the Pf3 peptide to the periplasmic side of the membrane, as seen in pose 2.…”

“…They can be found in all aspects of life and are necessary for cell viability . [9][10][11][12] They are adaptable proteins and can function along with the SecYEG pathway to insert peptides into the membrane through the Signal Recognition Particle (SRP) mechanism. They can fold and insert proteins independently of the Sec pathway.…”

Deciphering the Inter-domain Decoupling in the Gram-negative Bacterial Membrane Insertase

“…In the NPT ensemble at 310 K, 1 µ s of equilibrium MD simulations were performed under periodic boundary conditions for each system. In the simulations, a Langevin integrator with a damping coefficient of γ =0.5 ps − 1 and 1 atm pressure was maintained using the Nose-Hoover Langevin piston method 56,57 18,58–67 .…”

“…YidC catalyzes the transmembrane insertion of freshly produced membrane proteins in the absence of an energy supply domain, such as an ATPase 15 . It also plays a vital role in insertion in the insertion and positioning of membrane proteins in bacteria 16–18 . Insertase proteins, such as YidC, have been exhaustively investigated to determine their importance for the insertion of proteins into membranes 19 .…”

“…It also plays a vital role in insertion in the insertion and positioning of membrane proteins in bacteria [16][17][18] . Insertase proteins, such as YidC, have been exhaustively investigated to determine their importance for the insertion of proteins into membranes 19 .…”