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


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


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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Publikacja w czasopiśmie
artykuł w czasopiśmie wyróżnionym w JCR
Opublikowano w:
Journal of Chemical Theory and Computation nr 13, wydanie 12, strony 6415 - 6423,
ISSN: 1549-9618
Rok wydania:
Opis bibliograficzny:
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
Cyfrowy identyfikator dokumentu elektronicznego (otwiera się w nowej karcie) 10.1021/acs.jctc.7b00978
Politechnika Gdańska

wyświetlono 22 razy

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