MOLECULAR MODELING IN CARCINOGENESIS

诱变剂/致癌物的结构是 它们有效地产生DNA加合物的能力，以及它们的 能够诱发导致癌症的突变。 的 DNA中诱变剂/致癌物的结构可以通过 分子模拟技术 胸腺嘧啶乙二醇、O2烷基胸腺嘧啶、O 4 烷基胸腺嘧啶、O 6甲基鸟嘌呤、乙烯胞嘧啶和苯并[a]芘 讨论了 在许多情况下，分子模型表明， 对生化和遗传结果的潜在解释。 (1)一 胸腺嘧啶乙二醇如何诱导T->C突变的机制是 发现了 (2)一个合理的理由， d（O2 iPrThy）TP与d（O2 MeThy）TP的比值相反 体外DNA聚合酶法检测Ade 表明不存在合理的沃森/克里克样碱基配对 结构来解释复制的高保真度， 乙烯胞嘧啶，这表明保真度必须是由于一些 其他因素。 一个有吸引力的可能性是DNA聚合酶 有一个监督机制，通过这个机制， 收到 (4)Klenow片段体外复制O 6 MeGua， 这表明，这种病变可以采取至少两种构象 它们的复制方式不同。 分子模拟表明，抗-和顺-O 6 MeGua可能 在DNA中具有相似的能量，这表明它们可能是 相关的 (5)我实验室的实验结果 （+）-抗-B [a]PDE的诱变表明， 其加合物可能具有构象。 初步分子 模拟结果显示，计算的 异戊二烯基部分在小沟中的优选取向， 突变的模式 第（4）点和第（5）点中提到的结果 (5)两者都表明诱变剂/致癌物的DNA加合物可以采用 具有不同生物学终点的DNA中的多种构象。 这一概念将通过分子模拟技术进行研究。

The structure of mutagens/carcinogens are important determinants of their ability to generate efficiently DNA adducts, and their ability to induce the mutations that lead to cancer. The structures of mutagens/carcinogens in DNA can be studied by molecular modeling techniques. Progress on studies of thymine glycol, O2 alkylthymines, O4 alkylthymines, O6methylguanine, ethenocytosine, and benzo[a]pyrene are discussed. In numerous cases, molecular modeling suggests potential explanations for biochemical and genetic results. (1) A mechanism for how thymine glycol might induce T->C mutations was uncovered. (2) A sensible rationale for the more rapid incorporator of d (O2iPrThy)TP compared to d(O2MeThy)TP opposite Ade by DNA polymerase in vitro has been found. (3) It has been shown that there is no reasonable Watson/Crick-like base pairing structures to explain the high fidelity of replication of ethenocytosine, which suggests that fidelity must be due to some other factor. One attractive possibility is that DNA polymerases have a surveillance mechanism by which the assess the base being copied. (4) In vitro replication of O6MeGua by Klenow fragment has suggested that this lesion can adopt at least two conformations that are replicated differentially. Molecular modeling suggests that anti- and syn-O6MeGua are likely to be of similar energy in DNA, which suggests that they might be relevant. (5) Experimental results from my laboratory on mutagenesis by (+) -anti-B[a]PDE suggests that there are multiple conformations are possible for its adducts. Preliminary molecular modeling results show a correlation between the calculated preferred orientation of the prenyl moiety in the minor groove and the pattern of mutation. The results mentioned in points (4) and (5) both suggest that DNA adducts of mutagens/carcinogens can adopt multiple conformations in DNA with different biological endpoints. This notion will be studied by molecular modeling techniques.