Free Energy Profile Decomposition Analysis for QM/MM Simulations of Enzymatic Reactions

25 August 2023, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


In enzyme mechanistic studies and mutant design, it is highly desirable to know the individual residue contributions to the reaction free energy barrier. In this work, we show that such free energy contributions from each residue can be readily obtained by post-processing ab initio quantum mechanical molecular mechanical (ai-QM/MM) free energy simulation trajectories. Specifically, through a mean force integration along the minimum free energy pathway, one can obtain the electrostatic, polarization, and van der Waals contributions from each residue to the free energy barrier. Separately, a similar analysis procedure allows us to assess the contribution from different collective variables along the reaction coordinate. The chorismate mutase reaction is used to demonstrate the utilization of these two trajectory analysis tools.


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