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Photoinduced formation mechanism of the thymine–thymine (6–4) adduct in DNA; a QM(CASPT2//CASSCF):MM(AMBER) study
Faraday Discussions ( IF 3.4 ) Pub Date : 2017-10-24 , DOI: 10.1039/c7fd00202e
Angelo Giussani 1, 2, 3, 4 , Irene Conti 1, 2, 3, 4, 5 , Artur Nenov 1, 2, 3, 4, 5 , Marco Garavelli 1, 2, 3, 4, 5
Affiliation  

The UVB-induced photomechanism leading the carbonyl group of a thymine nucleobase to react with the carbon–carbon double bond of a consecutive thymine nucleobase in a DNA strand to form the thymine–thymine (6–4) photodamage adduct remains poorly understood. Key questions remain unanswered, concerning both the intrinsic features of the photoreaction (such as the contribution (or not) of triplet states, the nature of the involved states and the time-scale of the photoprocess) and the role played by the non-reactive surroundings of the two reactive pyrimidine nucleobases (such as the nature of the flanked nucleobases and the flexibility of the whole DNA molecule). A small number of theoretical studies have been carried out on the title photoreaction, most of which have used reduced model systems of DNA, consequently neglecting potential key parameters for the photoreaction such as the constraints due to the double strain structure and the presence of paired and stacked nucleobases. In the present contribution the photoactivation step of the title reaction has been studied in a DNA system, and in particular for a specific DNA hairpin for which the quantum yield of photodamage formation has been recently experimentally measured. The reaction has been characterized by carrying out high-level QM/MM computations, combining the CASPT2//CASSCF approach for the study of the reactive part (i.e. the two thymine molecules) with an MM-Amber treatment of the surrounding environment. The possibility of a reaction path along both the singlet and triplet manifolds has been characterized, the nature of the reactive states has been analyzed, and the role played by the flexibility of the whole system, which in turn determines the initial accessible geometrical conformations, has been evaluated, thus substantially contributing towards the elucidation of the photoreaction mechanism. On the basis of the obtained results, it can be observed that a charge-transfer state can decay from a pro-reactive initial structure towards a region of energy degeneracy with the ground state, from which the subsequent decay along the ground state hypersurface can lead to the photoreaction.

中文翻译:

胸腺嘧啶-胸腺嘧啶(6-4)加合物在DNA中的光诱导形成机理;QM(CASPT2 // CASSCF):MM(AMBER)研究

UVB诱导的光机制导致胸腺嘧啶核苷的羰基与DNA链中连续的胸腺嘧啶核苷的碳-碳双键反应,形成胸腺嘧啶-胸腺嘧啶(6-4)的光损伤加合物。关于光反应的内在特征(例如三重态的贡献(或不影响),所涉及的状态的性质和光反应过程的时间尺度)以及非反应性所起的作用,仍未解决关键问题。两个反应性嘧啶核碱基的周围环境(如侧翼核碱基的性质和整个DNA分子的柔韧性)。关于标题光反应的研究很少,其中大部分使用简化的DNA模型系统,因此,忽略了光反应的潜在关键参数,例如由于双重应变结构以及成对和堆叠的核碱基的存在所造成的限制。在本发明中,已经在DNA系统中研究了标题反应的光活化步骤,特别是对于特定的DNA发夹,最近已通过实验测量了该特定的DNA发夹的光损伤形成的量子产率。反应的特征是通过进行高级QM / MM计算,结合CASPT2 // CASSCF方法来研究反应性部分(尤其是对于特定的DNA发夹,最近已通过实验测量了该DNA发夹的光损伤形成的量子产率。反应的特征是通过进行高级QM / MM计算,结合CASPT2 // CASSCF方法来研究反应性部分(尤其是对于特定的DNA发夹,最近已通过实验测量了该DNA发夹的光损伤形成的量子产率。反应的特征是通过进行高级QM / MM计算,结合CASPT2 // CASSCF方法来研究反应性部分(两个胸腺嘧啶分子)对周围环境进行了MM-Amber处理。表征了沿着单重态和三重态歧管的反应路径的可能性,分析了反应态的性质,以及整个系统的灵活性所起的作用,而整个系统的灵活性又决定了初始可及的几何构象,进行了评价,因此对阐明光反应机理有实质性的贡献。根据获得的结果,可以观察到电荷转移态可以从前反应性初始结构向具有基态的能量简并区域衰减,随后沿基态超表面的衰减可以导致对光反应。
更新日期:2018-04-17
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