SOLUTION STRUCTURE OF A DNA DUPLEX CONTAINING THE EXOCYCLIC LESION 3,N-4-ETHENO-2'-DEOXYCYTIDINE OPPOSITE 2'-DEOXYGUANOSINE

Vinyl chloride reacts with cellular DNA producing 3,N-4-etheno-2'-deox ycytidine (epsilon C) along with other exocyclic adducts. The solution structure of an oligodeoxynucleotide duplex containing an epsilon C . dG base pair was determined by high-resolution NMR spectroscopy and m olecular dynamics simulations. NMR data indicated that the duplex adop ts a right-handed helical structure having all residues in anti orient ation around the glycosylic torsion angle. The epsilon C adduct has a sugar pucker in the C3'-endo/C4'-exo region while the rest of the resi dues are in the C2'-endo/C3'-exo range, NOE interactions established W atson-Crick alignments for canonical base pairs of the duplex. The imi no proton of the lesion-containing base pair resonated as a sharp sign al 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 perturb ations of the sugar-phosphate backbone. The adduct is displaced and sh ifted toward the major groove of the helix while its partner on the co mplementary strand remains stacked. The epsilon C-(anti). dG(anti) bas e pair alignment is sheared and stabilized by the formation of hydroge n bonds. The biological implications of structures of epsilon C-contai ning DNA duplexes are discussed.