The objective of the proposed work is to determine the distortion imposed on DNA by the covalent linkage of polycyclic aromatic hydrocarbons and amines that are known environmental mutagens and carcinogens. The initiation of cancer is believed to occur by covalent binding of these chemicals to DNA, but the factors that determine whether a particular lesion will lead to cancer are not understood. It is likely that the conformation of the carcinogen-DNA adducts will determine whether or not the damage is repaired, and whether a mutation that can lead to cancer will ensue on replication. Yet, very little is currently known about the conformations of carcinogen-DNA adducts. The method to be employed is minimized semi-empirical potential energy calculations. DNA adducts that have been chemically identified will be studied, including the benz[a] pyrene and 2-acetylaminofluorene adducts. In the first stage of the calculations, a global conformation search involving about 1000 trials will be made for dinucleoside monophosphate adducts. The low energy forms obtained will then be computationally incorporated in a dodecameric duplex polymer for total energy refinement. Then, the reasonable assumption that the lesion merges into a helical structure identified by crystallographic, or fiber diffraction analysis, or predicted theoretically, will be made. This assumption is necessary because of the enormous number of conformational variables in a duplex dodecamer. The base sequences to be studied on the dimer level are dCpdG, dGpdC and dApdA, which have been identified as high reactivity loci. In the larger polymer studies the base sequences observed to be mutational hotspots or high reactivity sites will be investigated, as well as sequences observed in A, B and Z DNA crystals, and the sequence observed in the point mutation of the human bladder carcinoma oncogene. The results of this investigation on the conformational influence of a series of carcinogen-DNA adducts should reveal unifying conformational features that distinguish mutagenic and carcinogenic adducts from begin ones.
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