Sharma Purshotam, Majdi Yazdi Mohadeseh, Merriman Ashlyn, Manderville Richard A, Wetmore Stacey D
†Department of Chemistry and Biochemistry, University of Lethbridge, Lethbridge, Alberta, Canada T1K 3M4.
‡Departments of Chemistry and Toxicology, University of Guelph, Guelph, Ontario, Canada N1G2W1.
Chem Res Toxicol. 2015 Apr 20;28(4):782-96. doi: 10.1021/tx500527p. Epub 2015 Feb 20.
Computational (DFT, MD, and free energy) methods are used to systematically compare the structural and energetic properties of C(8)-bonded 2'-deoxyguanosine (dG) adducts derived from phenolic toxins, namely, the oxygen-linked (unsubstituted) adduct ((PhO)dG) and carbon-linked adducts ((ortho-PhOH)dG or (para-PhOH)dG) that contain a hydroxyl group in the bulky moiety. Despite restricted rotation at the C(8)-X bond due to the presence of the oxygen linker, the (PhO)dG adduct likely possesses the greatest glycosidic (anti/syn) conformational flexibility at the 5'-terminus of DNA. However, the anti/syn energy difference is the smallest for the (para-PhOH)dG nucleotide at other helical positions, which correlates with the greatest conformational heterogeneity for the corresponding (NarI) adducted DNA. Most importantly, the total number of accessible conformations of adducted DNA depend on the phenolic adduct considered. Specifically, although the only conformations accessible to (PhO)dG adducted DNA correspond to the anti adduct glycosidic orientation, the C-linked adducts can also adopt the syn orientation in the double helix. Moreover, the number of accessible conformations for DNA containing the C-linked adducts depends on the nature of discrete interactions involving the hydroxyl group in the C(8)-moiety. In fact, such interactions lead to a novel (intercalated) conformational theme in the case of the (para-PhOH)dG adduct. Together, these results indicate that the type of C(8)-linkage, and the presence and location of additional functional groups in the bulky moiety affect the conformational outcomes, which adds to the list of previously established effects including the size of the carcinogenic moiety, adduct ionization state, and sequence context on the conformational preferences of damaged DNA. Most importantly, our study provides valuable structural information that explains the experimentally observed mutagenic potential of DNA phenolic adducts and predicts the relative repair propensity of the three phenolic lesions.
计算（密度泛函理论、分子动力学和自由能）方法被用于系统地比较源自酚类毒素的C(8)键合的2'-脱氧鸟苷（dG）加合物的结构和能量性质，即氧连接（未取代）加合物（(PhO)dG）以及在庞大基团中含有羟基的碳连接加合物（(邻位-PhOH)dG或(对位-PhOH)dG）。尽管由于氧连接基的存在，C(8)-X键处的旋转受限，但(PhO)dG加合物在DNA的5'-末端可能具有最大的糖苷（反式/顺式）构象灵活性。然而，对于(对位-PhOH)dG核苷酸在其他螺旋位置，反式/顺式能量差最小，这与相应的（NarI）加合DNA的最大构象异质性相关。最重要的是，加合DNA可及构象的总数取决于所考虑的酚类加合物。具体而言，虽然(PhO)dG加合DNA唯一可及的构象对应于反式加合物糖苷取向，但碳连接加合物在双螺旋中也可采用顺式取向。此外，含有碳连接加合物的DNA的可及构象数量取决于涉及C(8)基团中羟基的离散相互作用的性质。事实上，在(对位-PhOH)dG加合物的情况下，这种相互作用导致了一种新的（插入）构象模式。总之，这些结果表明C(8)连接的类型以及庞大基团中其他官能团的存在和位置会影响构象结果，这增加了先前已确定的影响列表，包括致癌基团的大小、加合物电离状态以及序列背景对受损DNA构象偏好的影响。最重要的是，我们的研究提供了有价值的结构信息，解释了实验观察到的DNA酚类加合物的诱变潜力，并预测了三种酚类损伤的相对修复倾向。
