Structures of the (+)- and (-)-trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydrobenzo(a)pyre ne adducts to guanine-N2 in a duplex dodecamer.

The structures of the mirror image (+)- and (-)-trans-anti-adducts of 7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene to guanine N2 have been of great interest because the high biological activity of 7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene in mammalian mutagenesis and tumorigenesis has been attributed to the predominant (+)-trans-anti-adduct. We have carried out new potential energy minimization studies, involving wide-scale conformational searches on small modified DNA subunits, followed by energy-minimized build-up techniques, to generate atomic resolution views of these adducts. These energy-minimized duplex dodecamers were then subjected to 100-ps molecular dynamic simulations with solvent and salt to yield animated molecular structures. The most favored computed structure for the (+)-adduct places the pyrenyl moiety in the B-DNA minor groove, with its long axis directed toward the 5' end of the modified strand, and with a pronounced bend in the helix axis. In the (-)-adduct, there are 2 favored structures. One places the pyrenyl moiety in the minor groove, whereas the other positions it in the major groove; in both cases, the pyrenyl long axis is directed more toward the 3' end of the modified strand, and with much less helix axis bend. Structures with intercalation character computed for these adducts are less preferred. The favored computed structures agree with spectroscopic data on the (+)- and (-)-trans-anti-adducts, whereas recent experimental evidence suggests that cis-adducts assume intercalation-type structures. Perhaps the conformational distinctions elucidated for the (+)- and (-)-trans anti-adducts play a role in their differential tumorigenic properties in mammalian systems.