Noncovalent interactions of a benzo[a]pyrene diol epoxide with DNA base pairs: insight into the formation of adducts of (+)-BaP DE-2 with DNA.
Noncovalent interactions of a benzo[a]pyrene diol epoxide with DNA base pairs: insight into the formation of adducts of (+)-BaP DE-2 with DNA.
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DOI：
10.1021/jp911376p
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发表时间：
2010-02-04
期刊：
影响因子：
--
通讯作者：
Wheeler SE
中科院分区：
文献类型：
--
作者：
Hargis JC;Schaefer HF 3rd;Houk KN;Wheeler SE
致瘤苯并[a]芘二醇环氧化物与鸟嘌呤-胞嘧啶和腺嘌呤-胸腺嘧啶碱基对的非共价复合物已通过计算进行了检查。 (+)-BaP DE-2 通过对 (+)-BaP DE-2 环氧化物的亲核攻击与 DNA 形成共价加合物。计算结果预测 AT 与 (+)-BaP DE-2 的五种热力学可接近的复合物与完整 DNA 相容。其中，有两种预计会产生腺嘌呤加合物。在能量最低的 AT...(+)-BaP DE-2 络合物中，其气相相互作用能为 -20.9 kcal mol−1，腺嘌呤的环外 NH2 被定位用于背面环氧化物攻击并形成反式加合物。导致形成顺式开环加合物的能量最有利的配合物的能量仅高 0.6 kcal mol−1。对于 GC...(+)-BaP DE-2，只有两种热力学可接近的配合物。相对于分离的 GC 和 (+)-BaP DE-2，较高位置的复合物在气相中以 24.4 kcal mol−1 结合，将导致反式开环 N2-鸟嘌呤加合物。在全局最小能量 GC...(+)-BaP DE-2 复合物中，由 27.3 kcal mol−1 结合，胞嘧啶的环外 NH2 基团定位用于顺式环氧化物加成。然而，(+)-BaP DE-2 与胞嘧啶的加合物很少在实验中观察到。尽管该 GC...(+)-BaP DE-2 复合物具有预测的热力学稳定性，但胞嘧啶加合物的缺乏归因于被认为在顺式加成之前的苄型阳离子中间体的静电不稳定。
Non-covalent complexes of a tumorigenic benzo[a]pyrene diol epoxide with the guanine-cytosine and adenine-thymine base pairs have been examined computationally. (+)-BaP DE-2 forms covalent adducts with DNA via nucleophilic attack on the (+)-BaP DE-2 epoxide. Computational results predict five thermodynamically accessible complexes of AT with (+)-BaP DE-2 that are compatible with intact DNA. Among these, two are expected to lead to adenine adducts. In the lowest energy AT...(+)-BaP DE-2 complex, which has a gas-phase interaction energy of −20.9 kcal mol−1, the exocyclic NH2 of adenine is positioned for backside epoxide attack and formation of a trans adduct. The most energetically favorable complex leading to formation of a cis ring-opened adduct lies only 0.6 kcal mol−1 higher in energy. For GC...(+)-BaP DE-2, there are only two thermodynamically accessible complexes. The higher-lying complex, bound in the gas phase by 24.4 kcal mol−1 relative to separated GC and (+)-BaP DE-2, would lead to a trans ring opened N2-guanine adduct. In the global minimum energy GC...(+)-BaP DE-2 complex, bound by 27.3 kcal mol−1, the exocyclic NH2 group of cytosine is positioned for cis epoxide addition. However, adducts of (+)-BaP DE-2 with cytosine are rarely observed experimentally. The paucity of cytosine adducts, despite the predicted thermodynamic stability of this GC...(+)-BaP DE-2 complex, is attributed to the electrostatic destabilization of the benzylic cation intermediate thought to precede cis addition.
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