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Communication Dans Un Congrès Année : 2014

Multi-scale simulations of complex oxidatively-generated DNA lesions: reactivity and structure.

Elise Dumont
Julian Garrec

Résumé

The identification of complex oxidatively-generated DNA lesions involving not only a single-nucleobase but two proximal nucleotides has truly revolutionized the DNA damage/repair line of research since such lesions are formed with a very low occurrence (typically a few lesions per 10 9 nucleotides) but turn out to be highly mutagenic [1]. The structural elucidation of complex lesions is extremely challenging and many questions unanswered and modelling insights are sought to corroborate multistep mechanisms [2] that are currently only postulated. Static calculations, most often based on a DFT framework, have proved their relevance [2,3] yet beyond single-nucleotide lesions we will show that they can be associated to a spurious description due to the formation of hydrogen bonds between dinucleosides and a deviation from an acceptable and representative π-stacked structure [4]. We lift these limitations resorting to hybrid Car-Parrinello MD simulations [5]: the B-DNA environment is realistically taken into account and we prove in passing that the B-helix embedding can reverse the intrinsic electronic reactivity of hydrogen-abstracted pyrimidines [6]. We also rely on classical MD simulations to generate the structures of oligonucleotides featuring a given lesions (C4'-oxidized abasic site [7] or guanine-pyrimidine intrastrand cross-links). This enables to monitor the B-helix distortion and the outcome of the initial Watson-Crick pairing: this way, we palliate the absence of NMR or X-ray structures and shed light on the lack of repair of tandem lesions. The NCI method and energy decomposition analysis within the ADF software are employed to assist the interpretation of the MD trajectories.
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hal-02061507 , version 1 (29-04-2019)

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  • HAL Id : hal-02061507 , version 1

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Elise Dumont, Chandan Patel, Julian Garrec. Multi-scale simulations of complex oxidatively-generated DNA lesions: reactivity and structure.. 9th Congress on Electronic Structure: Principles and Applications (ESPA), Jul 2014, Badajoz, Spain. ⟨hal-02061507⟩
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