Dominant Pathways of Adenosyl Radical-Induced DNA Damage Revealed by QM/MM Metadynamics
PBN-AR
Instytucja
Wydział Chemiczny (Politechnika Gdańska)
Źródłowe zdarzenia ewaluacyjne
Informacje podstawowe
Główny język publikacji
en
Czasopismo
Journal of Chemical Theory and Computation (40pkt w roku publikacji)
ISSN
1549-9618
EISSN
Wydawca
DOI
URL
Rok publikacji
2017
Numer zeszytu
12
Strony od-do
6415-6423
Numer tomu
13
Identyfikator DOI
Liczba arkuszy
Słowa kluczowe
DNA
MOLECULAR DYNAMICS
QM/MM
RADIOTHERAPY
Streszczenia
Język
Treść
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.
Inne
System-identifier
143420
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