Molecular mechanics simulations on covalent complexes between polycyclic carcinogens and B-DNA.

We present molecular mechanics simulations on models of covalent complexes between the diol-epoxides of the carcinogens benzo[a]pyrene, benzo[e]pyrene and benzo[c]phenanthrene and a DNA pentamer d(GCGCG).d(CGCGC). In all the models, the carcinogen diol-epoxides lie in the minor groove with alkylation to the exocyclic amino group of the guanine. The theoretical calculations on the benzo[a]pyrene adducts to the pentamer are qualitatively consistent with the experimentally observed relative reactivities between various isomers. The adduct with the (+)trans isomer, which is the most carcinogenic of the benzo[a]pyrene stereoisomers, is calculated to be the energetically most favored. The relative energetic preferences in the adducts of benzo[e]pyrene diol-epoxides to the pentanucleotide parallel those of benzo[a]pyrene. However, there is no obvious explanation for the lack of biological activity in the diol-epoxides of the former carcinogen from the theoretical calculations. In the case of adducts with the diol-epoxides of benzo[c]phenanthrene, the energetically most favored structures are isomers with significant biological activity. The distortions in the double helix are more significant in the complexes with the diol-epoxides of this carcinogen compared to those in the complexes with the diol-epoxides of the other two carcinogens.