Computational Biochemistry Laboratory, Department of Chemistry and Centre for Advanced Studies in Chemistry , Panjab University , Chandigarh 160014 , India.
Departments of Chemistry and Toxicology , University of Guelph , Guelph , Ontario N1G 2W1 , Canada.
Chem Res Toxicol. 2018 Aug 20;31(8):712-720. doi: 10.1021/acs.chemrestox.8b00064. Epub 2018 Jul 6.
Exposure to ochratoxin A (OTA) is associated with chronic renal diseases and carcinogenesis. The deleterious effects of OTA have been linked to its covalent binding at the C position of guanine (G) to form a DNA adduct (OT-G), which causes various mutations. To contribute toward understanding the complex mutagenic profile of OTA, the present work uses a robust computational approach to characterize postreplication DNA structures containing OT-G mismatched with canonical nucleobases. Our MD simulations provide insight into the effects of the opposing base, adduct ionization state, and flanking base on duplex structural features for the competing (major groove (B-type), wedge (W), and stacked (S)) conformers. For the B-type duplexes, our data suggest that significantly more stable lesion-site hydrogen bonding may lead to preferential insertion of an opposing cytosine (C) if the OT moiety is directed toward the major groove at the replication fork. Although the W conformation is consistently predicted to be less stable than the B conformer, a G mismatch is likely the most stable and least distorted replication outcome when the bulky moiety is directed into the DNA minor groove. These findings directly correlate with the limited contribution of substitution mutations to the overall mutagenic profile of OTA and suggest that the dominant mutations are G → C transversions. In contrast, stable S conformers that are known precursors to small (one- or two-base) deletion mutations are found when the lesion is opposite cytosine, adenine, or thymine, which directly correlates with the large number of deletion mutations previously reported for animals exposed to OTA. Nevertheless, the predicted sequence and ionization-dependent distortion of the S conformer points toward the dependence of the repair propensity on the cellular environment, which rationalizes the reported tissue specific OTA-induced toxicity.
OTA（赭曲霉毒素 A）暴露与慢性肾脏疾病和致癌作用有关。OTA 的有害影响与其在鸟嘌呤 (G) 的 C 位置形成 DNA 加合物（OT-G）的共价结合有关，这会导致各种突变。为了深入了解 OTA 的复杂诱变谱，本工作采用了一种强大的计算方法来描述含有与标准碱基错配的 OT-G 的复制后 DNA 结构。我们的 MD 模拟深入了解了相反碱基、加合物离子化状态和侧翼碱基对双螺旋结构特征的影响，对于竞争（大沟（B 型）、楔（W）和堆积（S））构象体。对于 B 型双螺旋，我们的数据表明，如果 OT 部分在复制叉处指向大沟，那么病变部位的氢键可能更稳定，从而导致优先插入相反的胞嘧啶 (C)。尽管 W 构象始终被预测为比 B 构象更不稳定，但当大块部分指向 DNA 小沟时，G 错配可能是最稳定和最小扭曲的复制结果。这些发现与 OTA 整体诱变谱中取代突变贡献有限直接相关，并表明主导突变是 G→C 颠换。相比之下，当病变位于胞嘧啶、腺嘌呤或胸腺嘧啶时，会发现稳定的 S 构象，这是小（一个或两个碱基）缺失突变的前体，这与先前报道的动物暴露于 OTA 时大量缺失突变直接相关。然而，预测的 S 构象的序列和电离依赖性扭曲指向修复倾向对细胞环境的依赖性，这合理化了报告的组织特异性 OTA 诱导毒性。
