Von Szentpaly L, Shamovsky I L
Chemistry Department, University of the West Indies, St. Andrew, Kingston 7, Jamaica.
Mol Pharmacol. 1995 Mar;47(3):624-9.
The equilibrium structures of 20 intercalated physical complexes of "bay-region" triol carbocations of polycyclic aromatic hydrocarbons (PAHs) with B-DNA are obtained by AMBER molecular modeling. The complexes with highly potent carcinogens are found (i) to undergo only minor conformational changes upon complexation, (ii) to be stabilized by hydrogen bonds between two hydroxyl groups of the triol carbocations and N3 atoms of the adjacent guanine residues, and (iii) to be "preorganized" for covalent bonding. A new explanation for the absolute stereochemical and shape dependence of carcinogenesis by PAHs is presented. The biologically active conformers of both carcinogenic stereoisomers (anti and syn) of triol carbocations are characterized by a quasi-diaxial orientation of the neighboring hydroxyl groups and fulfill the spatial requirements for hydrogen bonding to the adjacent guanine residues of B-DNA. The striking dependence of potency on the shape of the PAHs is largely caused by repulsion from the C2'-methylene groups of the deoxyribose residues of DNA. This interaction may shift the intercalated triol carbocation, thereby enhancing or reducing the preorganization for covalent bonding. The molecular modeling study is augmented by benchmark ab initio calculations on the bay-region triol carbocation of phenanthrene.
通过AMBER分子模拟获得了多环芳烃（PAHs）的“湾区”三醇碳正离子与B-DNA的20种插入物理复合物的平衡结构。发现与高活性致癌物形成的复合物：（i）在复合时仅发生微小的构象变化；（ii）通过三醇碳正离子的两个羟基与相邻鸟嘌呤残基的N3原子之间的氢键而稳定；（iii）为共价键合“预先组织”。提出了对PAHs致癌作用的绝对立体化学和形状依赖性的新解释。三醇碳正离子的两种致癌立体异构体（反式和顺式）的生物活性构象异构体的特征在于相邻羟基的准双轴取向，并满足与B-DNA相邻鸟嘌呤残基形成氢键的空间要求。PAHs活性对其形状的显著依赖性很大程度上是由DNA脱氧核糖残基的C2'-亚甲基的排斥引起的。这种相互作用可能会使插入的三醇碳正离子发生移动，从而增强或降低共价键合的预组织。对菲的湾区三醇碳正离子进行的基准从头算计算增强了分子模拟研究。
