Solution structure and 5{prime}-intercalation of the polynuclear aromatic BP residue in a (+)-cis-anti-[BP]-N{sup 6}-dA adduct opposite dT in a DNA duplex

The covalent binding of anti-benzo[a]pyrene-7,8-dihydroxy-9,10-epoxide (BPDE) to cellular DNA gives rise predominantly to WAG and N6-dA adducts. While the latter are formed in minor proportions, the mutagenic potential of these BPDE-N6-dA lesions could be important and dependent on the adduct structure. We have applied a combined NMR-molecular mechanics approach to determine the solution conformation of the minor (+)-cis-anti-[BP]dA adduct positioned opposite dT in the duplex d(C1-T2-C3-T4-C5-[BP-A6]-C7-T8-T9-C10- C11).d(G22-A21-G20-A19-G18-T17-G16-A15-A14-G14-G13-G12). The BP ring system is intercalated to the 5{prime}-side of the [BP]dA6 lesion site without disrupting the flanking Watson-Crick dC5.dG18 and [BP]dA6.dT17 base pairs. This is achieved in part by a buckling and propeller-twisting of the Watson-Crick [BP]dA6.dT17 base pair, as observed in the (+)-trans-anti-[BcPh-dA6.dT17] adduct (BcPh=benzo[c]phenanthrenyl) in the same sequence context, and which is stereochemically similar at the linkage site.