Solution structure of a DNA duplex containing the exocyclic lesion 3,N⁴-etheno-2'-deoxycytidine opposite 2'-deoxyguanosine

Vinyl chloride reacts with cellular DNA producing 3,N⁴-etheno-2'- deoxycytidine (εC) along with other exocyclic adducts. The solution structure of an oligodeoxynucleotide duplex containing an εC·dG base pair was determined by high-resolution NMR spectroscopy and molecular dynamics simulations. NMR data indicated that the duplex adopts a right-handed helical structure having all residues in anti orientation around the glycosylic torsion angle. The εC adduct has a sugar pucker in the C3-endo/C4'-exo region while the rest of the residues are in the C2'-endo/C3'-exo range. NOE interactions established Watson-Crick alignments for canonical base pairs of the duplex. The imino proton of the lesion-containing base pair resonated as a sharp signal that was resistant to water exchange, suggesting hydrogen bonding. Restrained molecular dynamics simulations generated three- dimensional models in excellent agreement with the spectroscopic data. The refined structures are slightly bent at the lesion site without major perturbations of the sugar-Phosphate backbone. The adduct is displaced and shifted toward the major groove of the helix while its partner on the complementary strand remains stacked. The εC-(anti)·dG(anti) base pair alignment is sheared and stabilized by the formation of hydrogen bonds. The biological implications of structures of εC-containing DNA duplexes are discussed.