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research article

Insights into Intrastrand Cross-Link Lesions of DNA from QM/MM Molecular Dynamics Simulations

Garrec, Julian  
•
Patel, Chandan
•
Rothlisberger, Ursula  
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2012
Journal of the American Chemical Society

DNA damages induced by oxidative intrastrand cross-links have been the subject of intense research during the past decade. Yet, the currently available experimental protocols used to isolate such lesions only allow to get structural information about linked dinucleotides. The detailed structure of the damaged DNA macromolecule has remained elusive. In this study we generated in silico the most frequent oxidative intrastrand cross-link adduct, G[8,S-Me]T, embedded in a solvated DNA dodecamer by means of quantum mechanics/molecular mechanics (QM/MM) Car-Parrinello simulations. The free energy of activation required to bring the reactant close together and to form the C-C covalent-bond is estimated to be similar to 40 kcal/mol. We observe that the G[8,5-Me]T tandem lesion is accommodated with almost no perturbation of the Watson-Crick hydrogen-bond network and induces bend and unwinding angles of similar to 20 degrees and 8 degrees, respectively. This rather small structural distortion of the DNA macromolecule compared to other well characterized intrastrand cross-links, such as cyclobutane pyrimidines dimers or cisplatin-DNA complex adduct, is a probable rationale for the known lack of efficient repair of oxidative damages.

  • Details
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Type
research article
DOI
10.1021/ja2084042
Web of Science ID

WOS:000301084600047

Author(s)
Garrec, Julian  
Patel, Chandan
Rothlisberger, Ursula  
Dumont, Elise
Date Issued

2012

Published in
Journal of the American Chemical Society
Volume

134

Start page

2111

End page

2119

Subjects

Density-Functional Theory

•

Duplex Dna

•

Dependent Formation

•

Spore Photoproduct

•

Tandem Lesions

•

Thymine Dimer

•

Repair

•

Oxidation

•

Mechanism

•

Energy

Editorial or Peer reviewed

REVIEWED

Written at

EPFL

EPFL units
LCBC  
Available on Infoscience
April 19, 2012
Use this identifier to reference this record
https://infoscience.epfl.ch/handle/20.500.14299/79512
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