Conformational Interconversion of the trans-4-Hydroxynonenal-Derived (6S8R11S) 1N2-Deoxyguanosine Adduct When Mismatched with Deoxyadenosine in DNA

摘要

The (6S,8R,11S) 1,N²-HNE-dG 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 dA. The (6S,8R,11S) adduct maintained the ring-closed 1,N²-HNE-dG structure. This was in contrast to when this adduct was correctly paired with dC, conditions under which it underwent ring opening and re-arrangement to diastereomeric minor groove hemiacetals [Huang, H., Wang, H., Qi, N., Lloyd, R.S., Harris, T.M., Rizzo, C.J., & Stone, M.P. (2008) J. Am. Chem. Soc. 130, 10898–10906]. The (6S,8R,11S) adduct exhibited a syn/anti conformational equilibrium about the glycosyl bond. The syn conformation was predominant in acidic solution. Structural analysis of the syn conformation revealed that X⁷ formed a distorted base pair with the complementary protonated A¹⁸. The HNE moiety was located in the major groove. Structural perturbations were observed at the neighbor C⁶•G¹⁹ and A⁸•T¹⁷ base pairs. At basic pH, the anti conformation of X⁷ was the major species. At X⁷ the 1,N²-HNE-dG intercalated and displaced the complementary A¹⁸ in the 5′-direction, resulting in a bulge at the X⁷•A¹⁸ base pair. The HNE aliphatic chain was oriented towards the minor groove. The Watson-Crick hydrogen bonding of the neighboring A⁸•T¹⁷ base pair was also disrupted.