Solution Structure of the Aminofluorene [AF]-Intercalated Conformer of the syn-[AF]-C8-dG Adduct Opposite dC in a DNA Duplex

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Abstract
We report below on a conformational equilibrium between AF-intercalated and AF-external states in slow exchange for the [AF]dG lesion positioned opposite dC in the d(C-[AF]G-C)·d(G-C-G) sequence context. The slow exchange between states is attributed to interconversion between syn glycosidic torsion angle in the AF-intercalated and anti torsion angle in AF-external conformers of the [AF]dG opposite dC containing duplex. The present paper describes an NMR-molecular mechanics study that defines the solution structure of the AF-intercalated conformer for the case of [AF]dG adduct positioned opposite dC in the d(C-[AF]G-C)·d(G-C-G) sequence context. The structure is of the base displacement-intercalation type where the aminofluorene ring is intercalated into the helix between intact Watson−Crick dG·dC base pairs, which results in a displacement of the modified guanine ring into the major groove where it stacks with the major groove edge of its 5‘-flanking cytosine in the adduct duplex. The conformational equilibrium between AF-intercalated conformer (∼70%) with a syn alignment and AF-external conformer (∼30%) with an anti alignment for the [AF]dG adduct positioned opposite dC in the d(C-[AF]G-C)·d(G-C-G) sequence context can be contrasted with our earlier demonstration that the population is 100% for the AP-intercalated conformer with a syn alignment at the N-(deoxyguanosin-8-yl)-2-aminopyrene ([AP]dG) adduct site positioned opposite dC in the same sequence context [Mao, B., Vyas, R. R., Hingerty, B. E., Broyde, S., Basu, A. K., and Patel, D. J. (1996) Biochemistry, 35, 12659−12670]. This shift in population may reflect the much larger size of the pyrenyl ring of the [AP]dG adduct compared to the fluorenyl ring of the [AF]dG adduct which in turn might provide for a greater overlap of the aromatic amine with the flanking base pairs in the intercalated conformer of the former adduct in DNA.