Intercalative Conformations of the 14R (+)- and 14S (-)-trans-anti-DB[a,l]P-N6-dA Adducts: Molecular Modeling and MD Simulations
Intercalative Conformations of the 14R (+)- and 14S (-)-trans-anti-DB[a,l]P-N6-dA Adducts: Molecular Modeling and MD Simulations
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DOI：
10.1021/tx1004002
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发表时间：
2011-04-01
影响因子：
4.1
通讯作者：
Broyde, Suse
中科院分区：
文献类型：
--
作者：
Cai, Yuqin;Ding, Shuang;Broyde, Suse
在多环芳烃类化学致癌物中，二苯并[a,l]芘（DB[a,l]P）是迄今为止已确定的最有效的致瘤原。从结构上看，它体积庞大，有六个芳香环，并且包含非平面峡湾区域。 DB [a,l]P 衍生的 DNA 加合物的构象特性因其非凡的致癌性而引起了人们的极大兴趣。我们对 DB [a,l]P 二醇环氧化物与双链 DNA 中腺嘌呤反应衍生的 14R (+)- 和 14S (-)-trans-anti-DB[a,l]P-N-6-dA 加合物进行了分子建模和 MD 模拟。该结构基于类似峡湾区苯并[c]菲衍生的-N-6-dA加合物的经典插层NMR溶液结构。一;目的是深入了解体积较大的 DB [a,l] P 环系统对插入加合物构象的结构特征的影响。进一步的目标是阐明与峡湾区空间位阻芳环相关的柔性扭曲对插层构象的影响，以与插层但平面的湾区苯并[a]芘衍生的-N-6-dA加合物进行比较。对于 DB [a,l]P-N-6-dA 加合物，我们的结果表明 14R (+)-加合物比插在其 3'-侧的立体异构 14S (-)-加合物更有利地插在修饰腺嘌呤的 5'-侧。与 14S (-)-加合物相比，14R (+)-加合物表现出更好的与侧翼碱基对的范德华堆积相互作用、更少扰动的 Watson Crick 氢键、更少的局部凹槽扩大、更少的解旋以及更低的溶剂暴露。这些结构发现与观察到的热力学熔化数据、紫外线吸收特性和荧光猝灭研究一致。相比之下，类似但体积较小的 B[c]Ph 衍生加合物的 NMR 溶液结构没有显示出这种立体异构效应，而平面湾区苯并[a]芘衍生的 -N-6-dA 加合物则显示出这种立体异构效应。峡湾和海湾地区加合物的核苷酸切除修复敏感性的差异源于其插入构象的差异，这是由其多环芳环系统的内在拓扑变化产生的。
Among the polycyclic aromatic hydrocarbon class of chemical carcinogens, dibenzo[a,l]pyrene (DB[a,l]P) is the most potent tumorigen that has been identified to date. Structurally, it is bulky with six aromatic rings, and it contains the nonplanar fjord-region. The conformational properties of DB [a,l]P-derived DNA adducts responsible for its extraordinary carcinogenicity are hence of great interest. We have carried out molecular modeling and MD simulations for the 14R (+)- and 14S (-)-trans-anti-DB[a,l]P-N-6-dA adducts derived from the reactions of the DB [a,l] P diol epoxides with adenine in double-stranded DNA. The structures are based on the classically intercalated NMR solution structures of the analogous fjord-region benzo[c]phenanthrene-derived-N-6-dA adducts. One; objective was to gain insight on the impact of the more bulky DB [a,l] P ring system on the structural characteristics of the intercalative adduct conformations. A further objective was to elucidate the effect of the flexible twist associated with the sterically hindered aromatic ring in the fjord-region on the intercalated conformations, for comparison with the intercalated but planar bay-region benzo[a]pyrene-derived-N-6-dA adducts. For the DB [a,l]P-N-6-dA adducts, our results show that the 14R (+)-adduct is more favorably intercalated on the 5'-side of the modified adenine than the stereoisomeric 14S (-)-adduct, intercalated on its 3'-side. The 14R (+)-adduct manifests better van der Waals stacking interactions with flanking base pairs, less perturbed Watson Crick hydrogen bonding, less local groove enlargement, less unwinding, and a lower solvent exposure than the 14S (-)-adduct. These structural findings are consistent with observed thermodynamic melting data, UV absorption properties, and fluorescence quenching studies. By contrast, the NMR solution structures for the analogous but less bulky B[c]Ph-derived adducts reveal no such stereoisomeric effect, while the planar bay-region benzo[a]pyrene-derived-N-6-dA adducts do. Differences in nucleotide excision repair susceptibilities of the fjord and bay region adducts stem from distinctions in their intercalative conformations, produced by the intrinsic topological variations in their polycyclic aromatic ring systems.