Surface-Accelerated String Method for Locating Minimum Free Energy Paths

Timothy J. Giese

doi:10.1021/acs.jctc.3c01401

Surface-Accelerated String Method for Locating Minimum Free Energy Paths

2024-02-17

7

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AI

DOI：10.1021/acs.jctc.3c01401

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We present a surface-accelerated string method (SASM) to efficiently optimize low-dimensional reaction pathways from the sampling performed with expensive quantum mechanical/molecular mechanical (QM/MM) Hamiltonians. The SASM accelerates the convergence of the path using the aggregate sampling obtained from the current and previous string iterations, whereas approaches like the string method in collective variables (SMCV) or the modified string method in collective variables (MSMCV) update the path only from the sampling obtained from the current iteration. Furthermore, the SASM decouples the number of images used to perform sampling from the number of synthetic images used to represent the path. The path is optimized on the current best estimate of the free energy surface obtained from all available sampling, and the proposed set of new simulations is not restricted to being located along the optimized path. Instead, the umbrella potential placement is chosen to extend the range of the free energy surface and improve the quality of the free energy estimates near the path. In this manner, the SASM is shown to improve the exploration for a minimum free energy pathway in regions where the free energy surface is relatively flat. Furthermore, it improves the quality of the free energy profile when the string is discretized with too few images. We compare the SASM, SMCV, and MSMCV using 3 QM/MM applications: a ribozyme methyltransferase reaction using 2 reaction coordinates, the 2 '-O-transphosphorylation reaction of Hammerhead ribozyme using 3 reaction coordinates, and a tautomeric reaction in B-DNA using 5 reaction coordinates. We show that SASM converges the paths using roughly 3 times less sampling than the SMCV and MSMCV methods. All three algorithms have been implemented in the FE-ToolKit package made freely available.

Keyword:

PARTICLE MESH EWALD

HAMMERHEAD RIBOZYME CATALYSIS

COUPLED ELECTRON-TRANSFER

MOLECULAR-DYNAMICS

THERMODYNAMIC INTEGRATION

ENZYMATIC-REACTIONS

LAMBDA-DYNAMICS

ACID CATALYSIS

ACTIVE-SITE

RNA

Surface-Accelerated String Method for Locating Minimum Free Energy Paths

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