The carcinogens of choice will be derivatives of polycyclic aromatic amines and hydrocarbons. Their bulk and hydrophobic character makes them ideal for this project in that they may, after binding, induce substantial alterations in the shape of DNA. Two approaches are used in the computations to locate the most stable conformation of a modified DNA: molecular mechanics with the program DUPLEX, and molecular dynamics simulations with AMBER. The former permits a thorough search of conformation space (limited only by available computer time) without the imposition of assumptions or data concerning the final structure. One of the past concerns in this work has been the development of optimal search strategies using DUPLEX; this effort shall continue in the future. The molecular dynamics studies include explicit solvent and salt and provide animation but are very restricted in their search. The efforts at this stage will largely involve modified DNA, but in a few cases (as computational resources permit) DNA in a complex with a fragment of a polymerase will be examined. Within the past several years, hypothesis 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 replication fork. These intermediates will be a particular focus of attention in the coming grant period. Using a limited set of DNA adducts, structural correlations will be sought that parallel existing and emerging genetic data on the same chemical. The particular goal is to provide explanations, in terms of detailed molecular structure, for the types of mutations produced by each alteration and the sequence preferences (""""""""hot spots"""""""") of each mutagen. An ultimate hope is that such knowledge, combined with a greater understanding of human metabolic processes and the important vulnerable sites of tumor-suppresser genes and oncogenes, will afford considerable predictive power of the relative hazard of chemicals around us.
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