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首页> 外文期刊>Biochemistry >Spectroscopic and theoretical insights into sequence effects of aminofluorene-induced conformational heterogeneity and nucleotide excision repair
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Spectroscopic and theoretical insights into sequence effects of aminofluorene-induced conformational heterogeneity and nucleotide excision repair

机译：对氨氟诱导的构象异质性和核苷酸切除修复的光谱和理论洞察序列效应

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A systematic spectroscopic and computational study was conducted in order to probe the influence of base sequences on stacked (S) versus B-type (13) conformational heterogeneity induced by the major dG adduct derived from the model carcinogen 7-fluoro-2-antinofluorene (FAF). We prepared and characterized eight 12-mer DNA duplexes (-AG*N-series, d[CTTCTAG*NCCTC]; -CG*N-series, d[CTTCTCG*NCCTC]), in which the central guanines (G*) were site-specifically modified with FAF with varying flanking bases (N = G, A, C, T). S/B heterogeneity was examined by CD, UV, and dynamic F-19 NMR spectroscopy. All the modified duplexes studied followed a typical dynamic exchange between the S and B conformers in a sequence dependent manner. Specifically, purine bases at the 3'-flanking site promoted the S conformation (G > A > C > T). Simulation analysis showed that the S/B energy barriers were in the 14-16 kcal/mol range. The correlation time's (iota = l/k) were found to be in the millisecond range at 20 degrees C. The van der Waals energy force field calculations indicated the importance of the stacking interaction between the carcinogen and neighboring base pairs. Quantum mechanics calculations showed the existence of correlations between the total interaction energies (including electrostatic and solvation effects) and the S/B population ratios. The S/B equilibrium seems to modulate the efficiency of Escherichia coli UvrABC-based nucleotide excision repair in a conformation-specific manner: i.e., greater repair susceptibility for the S over B conformation and for the -AG*N- over the -CG*N- series. The results indicate a novel structure-function relationship, which provides insights into how bulky DNA adducts are accommodated by UvrABC proteins.
机译：进行了系统的光谱和计算研究，以探测由衍生自模型致癌物质7-氟-2-苯甲酸二氟芴（ FAF）。我们准备并表征了八个12-MEL DNA双链体（-AG * N系列，D [CTTCTAG * NCCTC]; -CG * N系列，D [CTTCTCG * NCCTC]），其中鸟嘌呤（G *）是站点 - 用FAF进行特别修改，具有不同的侧翼碱基（n = g，a，c，t）。通过CD，UV和动态F-19 NMR光谱检查S / B异质性。所有修改的双工研究遵循S和B在序列相关的方式之间的典型动态交换。具体地，在3'侧面位点处的嘌呤碱基促进S构象（G> A> C> T）。模拟分析表明，S / B能量屏障在14-16千卡/摩尔范围内。发现相关时间（IOTA = L / K）在20摄氏度的毫秒范围内。范德瓦尔斯能力场计算表明致癌物和邻近碱基对之间的堆叠相互作用的重要性。量子力学计算显示总相互作用能量（包括静电和溶剂化效应）与S / B人口比之间的相关性存在。 S / B平衡似乎以特定的方式调节基于大肠杆菌UVRABC的核苷酸切除修复的效率：即，在B型上的S均匀的S致力于的修复敏感性，并且用于-CG * n-系列。结果表明了一种新颖的结构功能关系，提供了通过UVRABC蛋白能够容纳庞大DNA加合物的洞察。

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