Open AccessOptimizing the Calculation of Free Energy Differences in Nonequilibrium Work SQM/MM Switching Simulations
Author(s) -
Andreas Schöller,
Fiona L. Kearns,
H. Lee Woodcock,
Stefan Boresch
Publication year - 2022
Publication title -
the journal of physical chemistry. b
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.864
H-Index - 392
eISSN - 1520-6106
pISSN - 1520-5207
DOI - 10.1021/acs.jpcb.2c00696
Subject(s) - work (physics) , non equilibrium thermodynamics , convergence (economics) , degrees of freedom (physics and chemistry) , energy (signal processing) , computer science , statistical physics , energy storage , mathematics , physics , thermodynamics , quantum mechanics , power (physics) , economics , economic growth
A key step during indirect alchemical free energy simulations using quantum mechanical/molecular mechanical (QM/MM) hybrid potential energy functions is the calculation of the free energy difference Δ A low→high between the low level (e.g., pure MM) and the high level of theory (QM/MM). A reliable approach uses nonequilibrium work (NEW) switching simulations in combination with Jarzynski's equation; however, it is computationally expensive. In this study, we investigate whether it is more efficient to use more shorter switches or fewer but longer switches. We compare results obtained with various protocols to reference free energy differences calculated with Crooks' equation. The central finding is that fewer longer switches give better converged results. As few as 200 sufficiently long switches lead to Δ A low→high values in good agreement with the reference results. This optimized protocol reduces the computational cost by a factor of 40 compared to earlier work. We also describe two tools/ways of analyzing the raw data to detect sources of poor convergence. Specifically, we find it helpful to analyze the raw data (work values from the NEW switching simulations) in a quasi-time series-like manner. Principal component analysis helps to detect cases where one or more conformational degrees of freedom are different at the low and high level of theory.