In this work, we advance the previously developed Through‐Space/Through‐Bond (TS/TB) orbital interaction analysis and extend it to a new Through‐Space/Through‐Bond Energy Decomposition Analysis (TS/TB‐EDA). These methods are applied to investigate the mechanism behind the transition mutation from guanine:cytosine (G:C) to adenine:thymine (A:T) in DNA containing O6‐methylguanine (O6‐MeG) lesions. The mutagenicity of O6‐MeG has long been debated, with various geometric and energetic factors proposed. Using TS/TB and TS/TB‐EDA, we compare the electronic structures of damaged and undamaged base pairs at the mutation site during DNA replication, emphasizing the energetic components that influence base pair binding. Our analysis explores the strengths of individual orbital interactions, such as ‐bonds and hydrogen bonds, as well as decomposes the total binding energy between DNA bases into the physical components. We find that the electronic structure of the O6‐MeG lesion closely resembles that of A rather than G, while the O6‐MeG:T pair exhibits energetic and geometric characteristics similar to A:T. This similarity suggests the explanation for the polymerase's preference for pairing O6‐MeG with T. The obtained results are consistent with experimental data and provide insights into the high O6‐MeG:T mismatch rate observed in O6‐MeG damaged DNA sequences.

中文翻译：

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通过空间/通过键能量分解分析阐明了含有 O6-甲基鸟嘌呤损伤的 DNA 中转换突变的机制


在这项工作中，我们推进了先前开发的穿越空间/穿透键 （TS/TB） 轨道相互作用分析，并将其扩展到新的穿透空间/穿透键能量分解分析 （TS/TB‐EDA）。这些方法用于研究含有 O6-甲基鸟嘌呤 （O6-MeG） 损伤的 DNA 中从鸟嘌呤：胞嘧啶 （G：C） 到腺嘌呤：胸腺嘧啶 （A：T） 的转变突变背后的机制。O6-MeG 的致突变性长期以来一直存在争议，提出了各种几何和能量因子。使用 TS/TB 和 TS/TB‐EDA，我们比较了 DNA 复制过程中突变位点受损和未受损碱基对的电子结构，强调了影响碱基对结合的能量成分。我们的分析探讨了单个轨道相互作用的优势，例如 ‐ 键和氢键，并将 DNA 碱基之间的总结合能分解为物理成分。我们发现 O6-MeG 损伤的电子结构与 A 而不是 G 非常相似，而 O6-MeG：T 对表现出类似于 A：T 的能量和几何特征。这种相似性解释了聚合酶偏爱将 O6-MeG 与 T 配对的原因。获得的结果与实验数据一致，并有助于了解在 O6-MeG 受损 DNA 序列中观察到的高 O6-MeG：T 错配率。