Stereochemistry and position-dependent effects of carcinogens on TATA/TBP binding.
Stereochemistry and position-dependent effects of carcinogens on TATA/TBP binding.
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DOI：
10.1529/biophysj.105.074344
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发表时间：
2006-03
影响因子：
3.4
通讯作者：
Qing Zhang;T. Schlick
中科院分区：
文献类型：
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作者：
Qing Zhang;T. Schlick
真核 RNA 聚合酶需要 TATA 盒结合蛋白 (TBP) 与 TATA 盒（一个八碱基对 DNA 启动子元件）结合以启动转录。与 TATA 盒结合的致癌物加合物会阻碍这一重要过程。苯并[a]芘 (BP) 是一种代表性的化学致癌物，可代谢转化为高反应性苯并[a]芘二醇环氧化物 (BPDE)，进而形成化学立体异构体 BP-DNA 加合物。根据 TATA 结合加合物的位置和立体化学，TATA/TBP 结合可以减少或增加。我们之前的研究从构象自由度和 BP 可用的主沟空间角度解释了位置依赖性效应。在这里，我们进一步探讨了 TATA/TBP 复合物的具体结构变化，以帮助解释构成嵌入加合物的 TATA 碱基的灵活性方面的立体化学效应。使用分子力学泊松-玻尔兹曼表面积 (MM-PBSA) 的热力学分析会产生较大的标准偏差，这使得计算出的结合自由能在误差条内相同，并指出了当前大型高电荷系统（如 DNA/蛋白质复合物）自由能计算的局限性。
The TATA-box binding protein (TBP) is required by eukaryotic RNA polymerases to bind to the TATA box, an eight-basepair DNA promoter element, to initiate transcription. Carcinogen adducts that bind to the TATA box can hamper this important process. Benzo[a]pyrene (BP) is a representative chemical carcinogen that can be metabolically converted to highly reactive benzo[a]pyrene diol epoxides (BPDE), which in turn can form chemically stereoisomeric BP-DNA adducts. Depending on the TATA-bound adduct's location and stereochemistry, TATA/TBP binding can be decreased or increased. Our previous study interpreted the location-dependent effect in terms of conformational freedom and major-groove space available to BP. Here we further explore specific structural changes of the TATA/TBP complex to help interpret the stereochemical effect in terms of the flexibility of the TATA bases that frame the intercalated adduct. Thermodynamic analyses using molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) yield large standard deviations, which make the computed binding free energies the same within the error bars and point to current limitations of free energy calculations of large and highly charged systems like DNA/protein complexes.