MOLECULAR MODELING IN CARCINOGENESIS

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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.