Departamento de Quı́mica Fı́sica, Universidad de Murcia , 30100 Murcia, Spain.
J Phys Chem B. 2013 Dec 27;117(51):16397-404. doi: 10.1021/jp408947u. Epub 2013 Dec 17.
Oxidative intrastrand cross-links where two nucleobases are covalently tethered form a particularly harmful class of DNA lesions. Their formation follows a radical pathway, as initiated by reactive oxygen species, which often ends with the departure of the hydrogen H8 of guanine to restore a closed-shell adduct. The ease of this abstraction step is investigated here for three systems of increasing complexity, C8-methyleguanine, the guanine-thymine dinucleoside monophosphate (GpT), and GpT embedded in a hexameric DNA sequence. First-principle calculations, combined with semiempirical approaches for the latter system, are performed to determine the energetics of the intermediates and to compare their respective exergonicities, which turned out to significantly depend on the environment. The hydrogen departure path is shown to be strongly favored compared to usual H-abstraction sites for normal guanine, while the impact of the biological environment is evidenced as the H8 departure becomes more difficult when larger structures are considered. A computational assessment of a plausible oxime intermediate is discussed as well.
氧化的链内交联，其中两个碱基通过共价键连接在一起，形成了一类特别有害的 DNA 损伤。它们的形成遵循自由基途径，由活性氧物种引发，通常以鸟嘌呤的 H8 氢的离去结束，以恢复闭壳加合物。本文研究了三种复杂程度不断增加的系统中这一离解步骤的容易程度，它们是 C8-甲基鸟嘌呤、鸟嘌呤-胸腺嘧啶二核苷酸单磷酸（GpT）和嵌入六聚体 DNA 序列中的 GpT。首先进行了基于第一性原理的计算，并结合对后一系统的半经验方法，以确定中间体的能量和比较它们各自的非能，结果表明，这显著取决于环境。与正常鸟嘌呤的通常 H 原子离解位点相比，氢的离去路径被证明是非常有利的，而生物环境的影响也得到了证明，当考虑更大的结构时，H8 的离去变得更加困难。还讨论了一种可能的肟中间体的计算评估。
