We are using minimized potential energy calculations with our program DUPLEX and molecular dynamics simulations with AMBER to determine the most stable conformations of DNA segments modified by the prototype mutagenic aromatic amines: 2-aminofluorene and 2- acetylaminofluorene. An extensive literature describes the genetic effects of this pair, which have been termed """"""""superb tools for the exploration of the mechanisms of carcinogenesis"""""""". Our underlying hypothesis is that the structures of such damaged DNAs contribute to their mutagenic potential, and that an understanding of the details of structure will ultimately enable us to predict many of the genetic effects of chemical mutagens. The DNA species that we will examine model the stages of replication that lead to a mutagenic outcome, according to current theories. During the past few years, hypotheses have emerged which provide possible rationales for frameshift mutations (deletions in particular) and some base substitutions, in terms of the specific structures involved at the replications fork. Effects of the base sequence surrounding the modification on the nature of the structure of a particular chemical lesion will also be assessed, to gain insight into the sequence preferences (""""""""hot spots"""""""" for the various kinds of mutagenic change. The results of the computations will produce atomic resolution views of the structures, together with their energy rankings. We expect that an examination of the changes produced in DNA by adducts derived from these amines will allow us to identify a well defined number of characteristic alterations. Our efforts at this stage will largely involve DNA alone, but in a few cases (as computational resources permit) we shall examine DNA in a complex with a fragment of a polymerase. As we gain understanding of the changes in DNA produced by AF and AAF modification, we will test our hypothesis by comparing our data with the growing collection of data on site-specific mutagenesis on these substances, and predicting nutational effects not yet tested experimentally.
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