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. Author manuscript; available in PMC: 2022 Jan 28.
Published in final edited form as: J Phys Chem B. 2021 Jan 6;125(3):689–702. doi: 10.1021/acs.jpcb.0c09898

Figure 3:

Figure 3:

Results from an automated reinforcement learning driven free energy simulation of methyl phosphate hydrolysis in solution. The three coordinates are the nucleophilic attack P-O distance, the leaving group P-O distance and the antisymmetric O-H-O stretch that describes the proton transfer from the nucleophile (water) to the phosphate oxygen. (a) The three-dimensional PMF converges after 42 iterations of automated restrained MD-reinforcement learning cycles; the results indicate that with the current DFTB3/MM model, the solvent-assisted pathway120 is not the dominant mechanism. (b) The two-dimensional PMF cut after the proton transfer is complete indicates a dissociative pathway that involves a loosely bound metaphosphate species. Further refinement of the QM/MM energetics will provide insights into this prototypical phosphoryl transfer reaction at an unprecedented level of detail.