Dominant Pathways of Adenosyl Radical-Induced DNA Damage Revealed by QM/MM Metadynamics

Paweł Wityk; Miłosz Wieczór; Samanta Makurat; Lidia Chomicz-Mańka; Jacek Czub; Janusz Rak

doi:10.1021/acs.jctc.7b00978

Dominant Pathways of Adenosyl Radical-Induced DNA Damage Revealed by QM/MM Metadynamics

Abstract

Brominated nucleobases sensitize double stranded DNA to hydrated electrons, one of the dominant genotoxic species produced in hypoxic cancer cells during radiotherapy. Such radiosensitizers can therefore be administered locally to enhance treatment efficiency within the solid tumor while protecting the neighboring tissue. When a solvated electron attaches to 8-bromoadenosine, a potential sensitizer, the dissociation of bromide leads to a reactive C8 adenosyl radical known to generate a range of DNA lesions. In the current work, we propose a multiscale computational approach to elucidate the mechanism by which this unstable radical causes further damage in genomic DNA. We employed a combination of classical molecular dynamics conformational sampling and QM/MM metadynamics to study the thermodynamics and kinetics of plausible reaction pathways in a realistic model, bridging between different time scales of the key processes and accounting for the spatial constraints in DNA. The obtained data allowed us to build a kinetic model that correctly predicts the products predominantly observed in experimental settings—cyclopurine and β-elimination (single strand break) lesions—with their ratio and yield dependent on the effective lifetime of the radical species. To date, our study provides the most complete description of purine radical reactivity in double stranded DNA, explaining the radiosensitizing action of electrophilic purines in molecular detail as well as providing a conceptual framework for the computational modeling of competing reaction pathways in biomolecules.

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Authors (6)

Paweł Wityk dr inż.
- Uniwersytet Gdański/Wydział Chemii Katedra Chemii Fizycznej
Miłosz Wieczór dr inż.
Samanta Makurat Mgr.
- Uniwersytet Gdański/Wydział Chemii Katedra Chemii Fizycznej
Lidia Chomicz-Mańka
- Uniwersytet Gdański/Wydział Chemii Katedra Chemii Fizycznej
Jacek Czub prof. dr hab. inż.
Janusz Rak Prof.
- Uniwersytet Gdański/Wydział Chemii Katedra Chemii Fizycznej

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Category:: Articles
Type:: artykuł w czasopiśmie wyróżnionym w JCR
Published in:: Journal of Chemical Theory and Computation no. 13, edition 12, pages 6415 - 6423,
ISSN: 1549-9618
Language:: English
Publication year:: 2017
Bibliographic description:: Wityk P., Wieczór M., Makurat S., Chomicz-Mańka L., Czub J., Rak J.: Dominant Pathways of Adenosyl Radical-Induced DNA Damage Revealed by QM/MM Metadynamics// Journal of Chemical Theory and Computation. -Vol. 13, iss. 12 (2017), s.6415-6423
DOI:: Digital Object Identifier (open in new tab) 10.1021/acs.jctc.7b00978
Verified by:: Gdańsk University of Technology