This project is concerned with determining theoretical factors involved in mutagenesis and in the initial steps of carcinogenesis. The proliferation of new experimental techniques in genetic engineering is providing innovative pathways for studying the dependence of chemically induced mutational events on DNA sequence. Computer modeling is being used to examine the physical chemical factors contributing to site specificity of DNA damage by chemical agents. The same techniques are also being employed to determine changes in molecular properties of oncogene proteins as a consequence of specific mutations and to determine structural modifications in the HIV-1 protease upon inhibitor binding or crystal solvation. Specifically, computer intensive quantum mechanical calculations are employed to determine the properties of small molecules. These results are then used to paramaterize empirical force fields that can in turn be used to model the mechanical properties of large molecules such as meaningful segments of DNA and proteins with molecular mechanics/dynamics and computer graphics. Software development/modifications are effected to model our large molecular systems. Research issues of ongoing interest include the characterization of local structures of DNA sequences (native and chemically modified) that contain known mutational hotspots from mammalian oncogenes and bacterial systems, the examination of the molecular details of the initial attack by mutational metabolites, sequence dependent DNA bending, understanding of the consequences o single amino acid changes on the function of critical proteins such as the p2l ras oncogene protein and understanding the important determinants in inhibitor binding to HIV-1 protease.
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