Methylated DNA bases can be damaging and can trigger diseases such as cancer and genetic disorders. ALKBH2 is a non-heme iron enzyme that uses a mononuclear Fe(II) site and cofactors 2-oxoglutarate (2OG) and dioxygen molecule to perform oxidative demethylation of damaged DNA bases. It displays robust repair activity against lesioned N3-methylcytosine (m3C) and N1-methyladenine (m1A) substrates in double-stranded DNA (dsDNA). This work aimed at using MD and combined QM/MM to study the conformation dynamics and catalytic mechanism of ALKBH2 in the reparation of damaged DNA using m3C substrate in dsDNA. The MD simulations and QM/MM calculations were performed using Amber16 and ChemShell, respectively. ChemShell combines Turbomole and DL_POLY. The former was used for QM region while MM region was treated with the latter. The MM region was described with Amber force field and the QM region was accounted for using DFT and unrestricted B3LYP functional. The catalytic mechanism involves three (3) basic steps: oxygen activation, hydrogen atom abstraction (HAT) and rebound hydroxylation steps.

Exploring the mechanism of DNA repair by ALKBH2 enzyme: Multilevel modeling study

2019 Fall National Meeting

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