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

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• 作者：Julian Garrec ; Chandan Patel ; Ursula Rothlisberger ; Elise Dumont
• 刊名：The Journal of the American Chemical Society
• 出版年：2012
• 出版时间：February 1, 2012
• 年：2012
• 卷：134
• 期：4
• 页码：2111-2119
• 全文大小：519K
• 年卷期：v.134,no.4(February 1, 2012)
• ISSN：1520-5126

文摘

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[8,5-Me]T, embedded in a solvated DNA dodecamer by means of quantum mechanics/molecular mechanics (QM/MM) Car鈥揚arrinello simulations. The free energy of activation required to bring the reactant close together and to form the C鈥揅 covalent-bond is estimated to be 10 kcal/mol. We observe that the G[8,5-Me]T tandem lesion is accommodated with almost no perturbation of the Watson鈥揅rick hydrogen-bond network and induces bend and unwinding angles of 20掳 and 8掳, 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.