Role of base sequence context in conformational equilibria and nucleotide excision repair of benzo[a]pyrene diol epoxide-adenine adducts.
Role of base sequence context in conformational equilibria and nucleotide excision repair of benzo[a]pyrene diol epoxide-adenine adducts.
复制标题
碱基序列背景在苯并[a]芘二醇环氧化物-腺嘌呤加合物的构象平衡和核苷酸切除修复中的作用。
DOI：
10.1021/bi0270081
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发表时间：
2003
期刊：
影响因子：
--
通讯作者：
Broyde,Suse
中科院分区：
文献类型：
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作者：
Yan,Shixiang;Wu,Min;Buterin,Tonko;Naegeli,Hanspeter;Geacintov,NicholasE;Broyde,Suse
我们通过分子动力学（MD）模拟和自由能计算研究了碱基序列背景对10S(+)-和10R(−)-反式-[BP]- n6 - da加合物构象的影响，并将结构发现与人类细胞提取物中的核苷酸切除修复（NER）测定结果联系起来。在以前的研究中，这些加合物是在CA*A序列背景下研究的，在这里我们报告了CA*C序列的结果。我们的模拟表明，碱基序列背景通过调节这些态在能面上的势垒高度来影响10S（+）加合物的合成-反构象平衡，其中CA*C的势垒较高。我们的核苷酸切除修复实验发现，CA*C序列背景下10S（+）加合物对NER的敏感性更高。一个结构原理将这些结果联系在一起。在对CA*C序列的模拟中，我们发现了一个序列特异性氢键，伴随着10S（+）加合物显著增加的滚动和弯曲，这可能解释了我们在该异构体和序列中观察到的核苷酸切除修复增强以及synn -反平衡差异。这种序列特异性差异修复可能导致突变热点的存在，从而导致癌症发生的复杂性。
We investigate the influence of base sequence context on the conformations of the 10S(+)- and 10R(−)-trans-anti-[BP]-N6-dA adducts through molecular dynamics (MD) simulations with free energy calculations, and relate the structural findings to results of nucleotide excision repair (NER) assays in human cell extracts. In previous studies, these adducts were studied in the CA*A sequence context, and here we report results for the CA*C sequence. Our simulations indicate that the base sequence context affects thesyn−anticonformational equilibrium in the 10S(+) adduct by modulating the barrier heights between these states on the energy surface, with a higher barrier in the CA*C case. Our nucleotide excision repair assay finds greater NER susceptibilities in the 10S(+) adduct for the CA*C sequence context. A structural rationale ties together these results. A sequence specific hydrogen bond, accompanied by a significantly increased roll and consequent bending in the 10S(+) adduct, has been found in our simulations for the CA*C sequence, which could account for the enhanced nucleotide excision repair as well as thesyn−antiequilibrium difference we observe in this isomer and sequence. Such sequence specific differential repair could contribute to the existence of mutational hotspots and thereby contribute to the complexity of cancer initiation.