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Catalytic Reaction Mechanism in Native and Mutant COMT from the Adaptive String Method and Mean Reaction Force Analysis.

submitted on 09.05.2018, 15:39 and posted on 10.05.2018, 14:14 by David Adrian Saez, Kirill Zinovjev, Iñaki Tuñon, Esteban Vöhringer-Martinez
Catechol-O-Methyltransferase is an enzyme which 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 structural and electronic descriptors to characterize the reaction mechanism. The catalytic effect of the enzyme is addressed by comparison of the reaction mechanism 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 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.


Fodencyt 1160197, Max-Planck Society, Ministerio de Economia y Competitividad, España


Email Address of Submitting Author


Department of Physical Chemistry, Faculty of Chemistry, University of Concepción



ORCID For Submitting Author


Declaration of Conflict of Interest