Department of Chemistry, University of Lethbridge, 4401 University Drive, Lethbridge, Alberta, Canada.
J Phys Chem B. 2010 Apr 1;114(12):4373-82. doi: 10.1021/jp911993f.
Previous computational work suggests that isolated C8-phenoxyl-2'-deoxyguanosine nucleoside adducts preferentially adopt a syn orientation about the glycosidic bond, which is the first step in the mechanism by which many bulky C8 adducts exert their mutagenic effects. Since it is not clear whether these results can be directly extrapolated to the preferred conformation in DNA helices, approaches that more accurately reflect the physiological environment were used in the present study to understand the anti/syn preference of the ortho and para C8-phenoxyl-2'-deoxyguanosine adducts. Using nucleoside models and methods (B3LYP) similar to those previously implemented, we determine that the syn conformer is less stable than previously predicted when geometries relevant to B-DNA are considered. This indicates that the conformational energy trend is model dependent and stresses the importance of considering models that better mimic the DNA environment when determining the conformational preference of damaged bases. Therefore, we expanded our computational model to include the 5'-monophosphate group. Since the correct anti/syn energy trend for 2'-deoxyguanosine (dG) 5'-monophosphate has only been found using very specific computational models and prior knowledge of the biologically relevant nucleotide conformation, which is unavailable for most damaged systems, we initially benchmark our computational approach by studying the natural nucleotide. Despite the wide use of gas-phase optimizations in the current literature, only through the implementation of solvation-phase optimizations, as well as the use of a counterion model for the phosphate backbone, is the correct anti/syn energy trend predicted. Indeed, this is the first time in the literature that a biologically relevant syn structure is characterized for dG using methods suitable for studying bulky DNA adducts. Subsequently, our newly identified approach for DNA lesions was used to study C8-phenoxyl DNA adducts. In contrast to previously published results, we predict that the ortho and para adducts may adopt both the anti and syn conformations in DNA helices. These results have implications for the base-pairing properties and mutagenicity of these adducts, which must be further considered in future work.
先前的计算工作表明，孤立的 C8-苯氧-2'-脱氧鸟苷核苷加合物优先在糖苷键处采取顺式取向，这是许多大体积 C8 加合物发挥其诱变作用的机制中的第一步。由于目前尚不清楚这些结果是否可以直接外推到 DNA 螺旋中的首选构象，因此本研究采用更能准确反映生理环境的方法来理解邻位和对位 C8-苯氧-2'-脱氧鸟苷加合物的反式/顺式偏好。使用与先前实施的核苷模型和方法（B3LYP）相似的方法，我们确定当考虑到 B-DNA 相关的几何形状时，顺式构象比以前预测的更不稳定。这表明构象能趋势取决于模型，并且强调了在确定受损碱基的构象偏好时考虑更能模拟 DNA 环境的模型的重要性。因此，我们扩展了我们的计算模型，包括 5'-单磷酸基团。由于只有在使用非常特定的计算模型和对生物相关核苷酸构象的先验知识的情况下，才能找到 2'-脱氧鸟苷（dG）5'-单磷酸的正确反式/顺式能趋势，而对于大多数受损系统来说，这些知识是不可用的，因此我们首先通过研究天然核苷酸来基准我们的计算方法。尽管在当前文献中广泛使用气相优化，但只有通过实施溶剂化相优化以及使用磷酸骨架的抗衡离子模型，才能预测正确的反式/顺式能趋势。事实上，这是文献中首次使用适合研究大体积 DNA 加合物的方法来描述 dG 的生物相关顺式结构。随后，我们新确定的用于 DNA 损伤的方法用于研究 C8-苯氧 DNA 加合物。与以前发表的结果相反，我们预测邻位和对位加合物在 DNA 螺旋中可能采取反式和顺式构象。这些结果对这些加合物的碱基配对性质和诱变活性有影响，这在未来的工作中必须进一步考虑。
