Structures of the (+)- and (-)-fra/is-7,8-Dihydroxy-fl/if/-9,10-epoxy-7,8,9,10- tetrahydrobenzo(a)pyrene Adducts to Guanine-/V2 in a Duplex Dodecamer

The structures of the mirror image (+)- and (-)-m/n.s-a/ir/-adductsof 7,8-dihydroxj-9JO-epox) -7,8,9, 10-tetrahydroben/o(a)p>rene lo guaninc A/2have been of great interest because the high biological activity of 7,8- dih) droxy-9,10-epo\y-7,8,9,10-tetrahydrobenzo(a)py rene in mammalian mutagenesis and tumorigcnesis has been attributed to the predominant (+)-fca/ii-anfi-adduct. \Ve have carried out new potential energy mini mization studies, involving wide-scale conformational searches on small modified DNA subunits, followed by energy-minimized build-up tech niques, to generate atomic resolution views of these adducts. These energy-minimi/ed 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 (+)- adduci 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 pyrcnyl long axis is directed more toward the 3' end of the modified strand, and with much less helix axis bend. Structures with intercalation character com puted for these adducts are less preferred. The favored computed struc tures agree with spectroscopic data on the (+)- and (-)-trans-antiadducts, whereas recent experimental evidence suggests that m-adducts assume intercalation-type structures. Perhaps the conformational distinc tions elucidated for the (+)- and (-)-trans-anti-adducts play a role in their differential tumorigenic properties in mammalian systems.