Catalytic Reaction Mechanism in Native and Mutant Catechol- O-methyltransferase from the Adaptive String Method and Mean Reaction Force Analysis

The Journal of Physical Chemistry. B
David Adrian SaezEsteban Vöhringer-Martinez

Abstract

Catechol- O-methyltransferase is an enzyme that catalyzes the methylation reaction of dopamine by S-adenosylmethionine, increasing the reaction rate by almost 16 orders of magnitude compared to the reaction in aqueous solution. Here, we combine the recently introduced adaptive string method and the mean reaction force method, in combination with the structural and electronic descriptors to characterize the reaction mechanism. The catalytic effect of the enzyme is addressed by the comparison of the reaction in the human wild-type enzyme, in the less effective Y68A mutant, and in aqueous solution. The influence of these different environments at different stages of the chemical process and the significance of the key collective variables describing the reaction were quantified. Our results show that the native enzyme limits the access of water molecules to the active site, enhancing the interaction between the reactants and providing a more favorable electrostatic environment to assist the SN2 methyl transfer reaction.

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Citations

May 7, 2020·Proceedings of the National Academy of Sciences of the United States of America·Jianyu ZhangJudith P Klinman
Jul 9, 2021·The Journal of Physical Chemistry. B·Zhongyue Yang, Heather J Kulik
Aug 7, 2021·Biophysical Journal·Thomas J SummersNathan J DeYonker
Jun 28, 2019·The Journal of Physical Chemistry Letters·Zhongyue YangHeather J Kulik
Nov 22, 2019·ACS Catalysis·Xi Chen, Steven D Schwartz

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