Conformational interconversion of the trans-4-hydroxynonenal-derived (6S,8R,11S) l,N ²-deoxyguanosine adduct when mismatched with deoxyadenosine in DNA

The (6S,8R,11S) l,N ²-HNE-dGuo adduct of trans-4-hydroxynonenal (HNE) was incorporated into the duplex 5′-d(GCTAGCXAGTCC)-3′- 5′-d(GGACTAGCTAGC)-3′ [X = 6S,8R,11S) HNE-dG], in which the lesion was mismatched opposite dAdo. The (6S,8/?,115) adduct maintained the ring-closed 1,N ²- HNE-dG structure. This was in contrast to when this adduct was correctly paired with dCyd, conditions under which it underwent ring opening and rearrangement to diastereomeric minor groove cyclic hemiacetals [Huang, H., Wang, H., Qi, N., Lloyd, R. S., Harris, T. M., Rizzo, C. J., and Stone, M. P. (2008) J. Am. Chem. Soc. 130,10898-10906]. The (6S,8R,11S) adduct exhibited a synlanti conformational equilibrium about the glycosyl bond. The syn conformation was predominant in acidic solution. Structural analysis of the syn conformation revealed that X ⁷ formed a distorted base pair with the complementary protonated A ¹⁸. The HNE moiety was located in the major groove. Structural perturbations were observed at the neighbor C ⁶·G ¹⁹ and A ⁸·T ¹⁷ base pairs. At basic pH, the anti conformation of X ⁷ was the major species. The 1,N ²-HNE-dG intercalated and displaced the complementary A ¹⁸ in the 5′-direction, resulting in a bulge at the X ⁷·A ¹⁸ base pair. The HNE aliphatic chain was oriented toward the minor groove. The Watson - Crick hydrogen bonding of the neighboring A ⁸·T ¹⁷ base pair was also disrupted.