ALKB family enzymes catalyze the direct dealkylation of various alkylated bases. The family consists of nine human homologues, including ALKBH2 and ALKBH3, which act on double and single stranded DNA respectively. The reaction proceeds via an oxidative pathway and is catalyzed by a non-heme iron and two co-factors: 2-oxo glutarate and molecular oxygen. We have previously used QM/MM calculations to study this step in the title enzyme, ALKB(<i>J. Phys. Chem. B </i>2013, 117, 21, 6410-6420)  on a methylated adenine (1-meA) substrate, and found that the limiting step for this reaction is the abstraction of an H atom from the methyl group by a Fe<sup>IV</sup>-oxo species in the active site. This work will present the use of QM/MM path energy optimizations of the hydrogen abstraction step of 1-mA by ALKBH2 and ALKBH3 using the nudged elastic band (NEB) method and the quadratic string method (QSM) to study the limiting step dealkylation reaction of alkylated DNA bases catalyzed by ALKBH2 and ALKBH3. The calculated structures along the path will be compared and results of topological QM analyses with ELF/NCI and Mossbauer** shifts will be discussed.

QM/MM simulations of the rate limiting step in the dealkylation reaction catalyzed by ALKBH2 and ALKBH3

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.