Role of structural dynamics in selectivity and mechanism of non-heme Fe(II) and 2-Oxoglutarate-dependent Oxygenases involved in DNA repair

Authors

Sodiq Waheed, Michigan Technological UniversityFollow
Rajeev Ramanan, Michigan Technological UniversityFollow
Shobhit Chaturvedi, Michigan Technological UniversityFollow
Nicolai Lehnert, The University Of Michigan
Christopher J. Schofield, University of Oxford
Christo Z. Christov, Michigan Technological UniversityFollow
Tatyana Karabencheva-Christova, Michigan Technological UniversityFollow

Document Type

Article

Publication Date

5-8-2020

Department

Department of Chemistry

Abstract

AlkB and its human homologue AlkBH2 are Fe(II)- and 2-oxoglutarate (2OG)-dependent oxygenases that repair alkylated DNA bases occurring as a consequence of reactions with mutagenic agents. We used molecular dynamics (MD) and combined quantum mechanics/molecular mechanics (QM/MM) methods to investigate how structural dynamics influences the selectivity and mechanisms of the AlkB- and AlkBH2-catalyzed demethylation of 3-methylcytosine (m₃C) in single (ssDNA) and double (dsDNA) stranded DNA. Dynamics studies reveal the importance of the flexibility in both the protein and DNA components in determining the preferences of AlkB for ssDNA and of AlkBH2 for dsDNA. Correlated motions, including of a hydrophobic β-hairpin, are involved in substrate binding in AlkBH2–dsDNA. The calculations reveal that 2OG rearrangement prior to binding of dioxygen to the active site Fe is preferred over a ferryl rearrangement to form a catalytically productive Fe(IV)═O intermediate. Hydrogen atom transfer proceeds via a σ-channel in AlkBH2–dsDNA and AlkB–dsDNA; in AlkB–ssDNA, there is a competition between σ- and π-channels, implying that the nature of the complexed DNA has potential to alter molecular orbital interactions during the substrate oxidation. Our results reveal the importance of the overall protein–DNA complex in determining selectivity and how the nature of the substrate impacts the mechanism.

Publisher's Statement

© 2020 American Chemical SocietyArticle deposited here in compliance with publisher policy. Publisher's version of record: https://doi.org/10.1021/acscentsci.0c00312

Publication Title

ACS Central Science

Recommended Citation

Waheed, S., Ramanan, R., Chaturvedi, S., Lehnert, N., Schofield, C. J., Christov, C. Z., & Karabencheva-Christova, T. (2020). Role of structural dynamics in selectivity and mechanism of non-heme Fe(II) and 2-Oxoglutarate-dependent Oxygenases involved in DNA repair. ACS Central Science, 6(5), 795-814. http://doi.org/10.1021/acscentsci.0c00312
Retrieved from: https://digitalcommons.mtu.edu/michigantech-p/1894

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Version

Publisher's PDF