Department of Chemistry, Vanderbilt University, College of Arts and Science, Nashville, Tennessee 37235, United States.
Department of Biochemistry, Vanderbilt University, School of Medicine, Nashville, Tennessee 37232, United States.
Chem Res Toxicol. 2022 Oct 17;35(10):1903-1913. doi: 10.1021/acs.chemrestox.2c00165. Epub 2022 Aug 16.
-Methyl-2'-deoxyguanosine (-MeG) is one of the most common DNA lesions and arises as a consequence of both xenobiotic carcinogens and endogenous methylation by -adenosylmethionine. -MeG frequently causes G-to-A mutations during DNA replication due to the misincorporation of dTTP and continued DNA synthesis. Efforts to detect DNA adducts such as -MeG, and to understand their impacts on DNA structure and function, have motivated the creation of nucleoside analogs with altered base moieties to afford a more favorable interaction with the adduct as compared to the unmodified nucleotide. Such analogs directed at -MeG include benzimidazolinone and benzimidazole nucleotides, as well as their extended π surface analogs naphthimidazolinone and napthimidazole derivatives. These analogs form a more stable pair with -MeG than with G, most likely due to a combination of H-bonding and stacking. While extending the π surface of the analogs enhances their performance as adduct-directed probes, the precise origins of the increased affinity between the synthetic analogs and -MeG remain unclear. To better understand relevant conformational and pairing properties, we used X-ray crystallography and analyzed the structures of the DNA duplexes with naphthimidazolinone inserted opposite G or -MeG. The structures reveal a complex interaction of the analog found either in an anti orientation and stacked inside the duplex, either above or below G or -MeG, or in a syn orientation and paired opposite G with formation of a single H-bond. The experimental structural data are consistent with the stabilizing effect of the synthetic analog observed in UV melting experiments and calculations and moreover reveal that the origin of these observations appears to be superior stacking between -MeG and the extended π system of the synthetic probe.
-甲基-2'-脱氧鸟苷（-MeG）是最常见的 DNA 损伤之一，它是由外源性致癌剂和 - 腺苷甲硫氨酸的内源性甲基化引起的。-MeG 在 DNA 复制过程中经常导致 G 到 A 的突变，因为 dTTP 的错误掺入和持续的 DNA 合成。为了检测 DNA 加合物，如 -MeG，并了解它们对 DNA 结构和功能的影响，人们创造了改变碱基部分的核苷类似物，以便与加合物相比，与未修饰的核苷酸具有更有利的相互作用。针对 -MeG 的此类类似物包括苯并咪唑啉酮和苯并咪唑核苷酸，以及它们的扩展 π 表面类似物萘并咪唑啉酮和萘并咪唑衍生物。这些类似物与 -MeG 形成比 G 更稳定的配对，这很可能是由于氢键和堆积的结合。虽然扩展类似物的 π 表面增强了它们作为加合物导向探针的性能，但合成类似物与 -MeG 之间增加的亲和力的确切来源仍不清楚。为了更好地理解相关的构象和配对特性，我们使用 X 射线晶体学分析了插入 G 或 -MeG 对面的萘并咪唑啉酮的 DNA 双链体的结构。这些结构揭示了类似物的复杂相互作用，该类似物处于反式取向并堆积在双链体内部，位于 G 或 -MeG 上方或下方，或处于顺式取向并与 G 配对形成单个氢键。实验结构数据与 UV 融解实验和计算中观察到的合成类似物的稳定作用一致，而且还表明，这些观察结果的起源似乎是 -MeG 与合成探针的扩展 π 系统之间的优越堆积。
