Dumont Elise, Grüber Raymond, Bignon Emmanuelle, Morell Christophe, Aranda Juan, Ravanat Jean-Luc, Tuñón Iñaki
Univ.Lyon, Ens de Lyon, CNRS UMR 5182, Université Claude Bernard Lyon 1, Laboratoire de Chimie, 69342, Lyon, France.
Univ. Lyon, CNRS, Université Claude Bernard Lyon 1, Ens de Lyon, Institut des sciences analytiques, UMR 5280, 5 rue de la Doua, 69100, Villeurbanne, France.
Chemistry. 2016 Aug 22;22(35):12358-62. doi: 10.1002/chem.201601287. Epub 2016 Jul 21.
Oxidatively generated DNA lesions are numerous and versatile, and have been the subject of intensive research since the discovery of 8-oxoguanine in 1984. Even for this prototypical lesion, the precise mechanism of formation remains elusive due to the inherent difficulties in characterizing high-energy intermediates. We have probed the stability of the guanine endoperoxide in B-DNA as a key intermediate and determined a unique activation free energy of around 6 kcal mol(-1) for the formation of the first C-O covalent bond upon the attack of singlet molecular oxygen ((1) O2 ) on the central guanine of a solvated 13 base-pair poly(dG-dC), described by means of quantum mechanics/molecular mechanics (QM/MM) simulations. The B-helix remains stable upon oxidation in spite of the bulky character of the guanine endoperoxide. Our modeling study has revealed the nature of the versatile (1) O2 attack in terms of free energy and shows a sensitivity to electrostatics and solvation as it involves a charge-separated intermediate.
氧化产生的DNA损伤种类繁多且具有多样性，自1984年发现8-氧代鸟嘌呤以来，一直是深入研究的对象。即使对于这种典型的损伤，由于表征高能中间体存在固有的困难，其精确的形成机制仍然难以捉摸。我们探究了B-DNA中鸟嘌呤内过氧化物作为关键中间体的稳定性，并通过量子力学/分子力学（QM/MM）模拟确定了单重态分子氧（¹O₂）攻击溶剂化的13碱基对聚（dG-dC）中心鸟嘌呤时形成第一个C-O共价键的独特活化自由能约为6 kcal·mol⁻¹。尽管鸟嘌呤内过氧化物体积较大，但B-螺旋在氧化后仍保持稳定。我们的建模研究揭示了¹O₂攻击在自由能方面的多样性，并表明由于涉及电荷分离中间体，其对静电和溶剂化敏感。
