This proposal outlines a plan to continue to examine the relationship between the stereoselectivity of the diol epoxides of the benzo(a)pyrene, BPDEs, and their steric (spacial) fit in intercalation, kinked and modified DNA sites and to extend these studies to other PAHs. To generate receptor sites, general mathematical methods to calculate nucleic acid structures has been developed by the PI. Intercalation sites and kinked DNA have been identified. Crankshaft motion, bulged bases and the generalized placement of base pairs are produced. These structures serve as binding sites for molecules that interact non-covalently and covalently with DNA. Of the four isomers, we have shown that BPDE I(+) is selected after the intercalation step for adduct formation to N2 on G and that adduct formation to N6 on A and 06 on G favors the BPDE I(-) isomer. Stereoselectivity occurs during intercalative covalent binding. Attention will be focused on the diol epoxides of the carcinogenic benzo(a)pyrene, and then the study will be extended to chrysene, benzo(a)anthracene, benzo(c)phenanthrene and benzo(a,h)anthracene and to the non-carcinogenic compounds benzo(e)pyrene and triphenylene. The model is consistent with the experimental observations of unwinding of the DNA, local bending (or kinking) at the site of adduct formation and orientation of the pyrene with the local helical axis. To facilitate these studies original techniques and extensive computer graphics methods have been developed to interactively manipulate the molecules and to present the results via stereographic projections. Steric contours and electrostatic contours on the steric surface are used to demonstrate molecular fit and electrostatic interactions.
| Miller, K J; Taylor, E R; Dommen, J et al. (1985) Stereoselectivity of benzo[a]pyrene diol epoxides by DNA for adduct formation with N2 on guanine. Prog Clin Biol Res 172A:187-97 |
| Miller, K J; Rein, F H; Taylor, E R et al. (1985) Generation of nucleic acid structures and binding of molecules to DNA. Ann N Y Acad Sci 439:64-80 |
