AlkB catalyzes the dealkylation of alkylated DNA by a non-heme iron, O2 and a-ketoglutarate. The activation of the terminal methyl C-H bond in the alkylated DNA base is proposed to be the rate determining step. QM/MM calculations with five different functionals have been performed to study the reaction mechanism associated with this step. Triplet and quintet surfaces have been explored. Our results suggest that the Fe can be in an intermediate- or high-spin state. The lowest calculated barrier at the ?B97XD/6-31G(d,p) level is 22.4 kcal/mol (experimental = 19.8 kcal/mol) and corresponds to the quintet state (intermediate-spin reactant, high-spin transition state). Energy Decomposition Analysis (EDA) results reveal that thirteen residues (de)stabilize the TS via Coulomb or Van der Waals interactions. Effects of the amount of exact exchange on the calculated barriers, cluster model calculations and an alternative reaction mechanism will also be presented.

Insights on the rate limiting step in the dealkylation catalyzed by AlkB from QM/MM simulations

244th National Meeting (2012)

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