Effect of Size and Shape of Nitrogen-Containing Aromatics on Conformational Preferences of DNA Containing Damaged Guanine,Journal of Chemical Information and Modeling

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Effect of Size and Shape of Nitrogen-Containing Aromatics on Conformational Preferences of DNA Containing Damaged Guanine
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2018-06-20 00:00:00 , DOI: 10.1021/acs.jcim.8b00238
Ryan W. Kung ₁ , Purshotam Sharma ₁ , Stacey D. Wetmore ₁

Affiliation

The present work investigates the effects of the size and shape of the nitrogen-containing aromatic (NCA) skeleton on the structure of DNA damaged through adduct formation at C⁸ of 2′-deoxyguanosine (dG), a common DNA lesion associated with chemical carcinogenesis. Specifically, density functional theory (DFT) calculations (B3LYP-D3) and molecular dynamics (MD) simulations (AMBER) are performed on seven model adducts with systematic expansion of the NCA moiety. DFT calculations reveal that the NCA moiety shape affects the structure at the nucleobase–carcinogen linkage. Approximately 4.5 μs of MD simulations on damaged oligonucleotides adopting three established conformational themes (namely, B, W, and S) illustrate that the structure and lesion-site stabilization strongly depend on the NCA moiety shape and size, which provides insight into the repair propensity of C⁸-dG adducted DNA. Our results add bulky moiety shape to the growing list of previously established effects on the conformational and repair outcomes of damaged DNA (i.e., size, ionization state, substitution, linker type, and DNA sequence). Furthermore, this work illustrates the utility of a systematic set of model DNA lesions for understanding the structure–activity relationship for DNA damaged by carcinogens of different sizes and shapes, which should be used in future studies of the cellular processing of damaged DNA.

中文翻译：

含氮芳香族化合物的大小和形状对受损鸟嘌呤DNA构象偏好的影响

本工作研究了含氮芳香族化合物（NCA）骨架的大小和形状对在C ⁸处形成加合物而破坏的DNA结构的影响。2'-脱氧鸟苷（dG）的发现，这是一种与化学致癌作用有关的常见DNA损伤。具体来说，在NCA部分进行系统扩展的情况下，对七个模型加合物进行了密度泛函理论（DFT）计算（B3LYP-D3）和分子动力学（MD）模拟（AMBER）。DFT计算表明，NCA部分的形状会影响核碱基与致癌物连接处的结构。采用三个已确立的构象主题（即B，W和S）对受损寡核苷酸进行的大约4.5μs的MD模拟表明，结构和病变部位的稳定性在很大程度上取决于NCA部分的形状和大小，从而提供了修复倾向的见解的C ⁸-dG加成的DNA。我们的结果为先前建立的对受损DNA的构象和修复结果（即大小，电离状态，取代，接头类型和DNA序列）建立的影响不断增加的列表中增加了庞大的部分形状。此外，这项工作说明了一套系统的DNA损伤模型在了解被不同大小和形状的致癌物损伤的DNA的结构-活性关系中的作用，应将其用于将来对损伤的DNA进行细胞加工的研究中。

更新日期：2018-06-20

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