受损和未受损 DNA 的碱基翻转自由能曲线。
Base flipping free energy profiles for damaged and undamaged DNA.
机构信息
Department of Biology, New York University, New York, New York 10003, USA.
出版信息
Chem Res Toxicol. 2010 Dec 20;23(12):1868-70. doi: 10.1021/tx1003613.
Abstract
Lesion-induced thermodynamic destabilization is believed to facilitate β-hairpin intrusion by the human XPC/hHR23B nucleotide excision repair (NER) recognition factor, accompanied by partner-base flipping, as suggested by the crystal structure of the yeast orthologue (Min, J. H., and Pavletich, N. P. (2007) Nature 449, 570-575). To investigate this proposed mechanism, we employed the umbrella sampling method to compute partner base flipping free energies for the repair susceptible 14R (+)-trans-anti-DB[a,l]P-N(2)-dG modified duplex 11-mer, derived from the fjord region polycyclic aromatic hydrocarbon dibenzo[a,l]pyrene, and for the undamaged duplex. Our flipping free energy profiles show that the adduct has a lower flipping barrier by ∼7.7 kcal/mol, consistent with its thermally destabilizing impact on the damaged DNA duplex and its susceptibility to NER.
摘要
据信，损伤诱导的热力学不稳定性有助于人类 XPC/hHR23B 核苷酸切除修复（NER）识别因子的β发夹侵入，同时伴有碱基对翻转，这是酵母同源物晶体结构所提示的（Min，J.H.和 Pavletich，N.P.（2007）自然 449，570-575）。为了研究这一拟议的机制，我们采用伞状采样方法计算了修复敏感的 14R（+）-反式-抗-DB[a，l]P-N（2）-dG 修饰的双链 11 -mer 的碱基对翻转自由能，该 11-mer 来自多环芳烃二苯并[a，l]芘的峡湾区域，以及未受损的双链。我们的翻转自由能曲线表明，加合物的翻转势垒降低了约 7.7 kcal/mol，这与它对损伤 DNA 双链的热不稳定性及其对 NER 的易感性一致。
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