NMR Solution Structure of an Oligodeoxynucleotide Duplex Containing the Exocyclic Lesion 3,N4-Etheno-2‘-deoxycytidine Opposite Thymidine: Comparison with the Duplex Containing Deoxyadenosine Opposite the Adduct

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Abstract
The exocyclic 3,N4-etheno-2‘-deoxycytidine adduct was incorporated at the center of the oligodeoxynucleotide duplex d(C-G-T-A-C-εC-C-A-T-G-C)·d(G-C-A-T-G-T-G-T-A-C-G), and its solution structure was analyzed using high-resolution proton NMR spectroscopy and molecular dynamics simulations. The experimental data indicate that the oligodeoxynucleotide duplex adopts a right-handed helical structure with sugar puckers in the C2‘-endo/C3‘-exo range and Watson−Crick hydrogen bond alignments for all base pairs. NOE connectivities established a syn orientation for the glycosidic torsion angle of the exocyclic adduct. Restrained molecular dynamics simulations, using the full relaxation matrix approach, produced a three-dimensional model in agreement with the experimental data. The structure shows only minor perturbations in the sugar-phosphate backbone and a 27° bend of the helical axis at the lesion site. On the refined model a well-formed hydrogen bond between T(N3H) and εC(N4) stabilizes the εC(syn)·T(anti) base pair alignment, reflecting the preference of the adduct for the syn orientation. Furthermore, the εC(syn)·T(anti) base pair stacks with flanking base pairs. We discuss a correlation between the mutagenic properties of the adduct and the three-dimensional structure of the εC·dA and εC·T duplexes.