NMR solution structure of a nonanucleotide duplex with a dG mismatch opposite a 10R adduct derived from trans addition of a deoxyadenosine N6-amino group to (-)-(7S,8R,9R,10S)-7,8-dihydroxy-9,10-epoxy-7,8,9,10- tetrahydrobenzo[a]pyrene.
A nonanucleotide in which (-)-(7S,8R,9R,10S)-7,8-dihydroxy-9,10-epoxy- 7,8,9,10-tetrahydrobenzo[a]pyrene (7-hydroxy group and epoxide oxygen are trans) is covalently bonded to the exocyclic N6-amino group of deoxyadenosine through trans addition at C10 of the epoxide (10R adduct) has been synthesized. The modified oligonucleotide d(GGTCA*CGAG) was incorporated into the duplex d(GGTCA*CGAG).d(CTCGGGACC), containing a dG mismatch opposite the modified base (dA*). Proton assignments for the solution structure of the duplex containing the 10R adduct were made using 2D TOCSY and NOESY NMR spectra. The complete hybrid relaxation matrix program, MORASS2.0, was used to generate NOESY distance constraints for iterative refinement using distance-restrained molecular dynamics calculations with AMBER4.0. The iteratively refined structure showed the hydrocarbon intercalated from the major groove immediately below the dC4-dG15 base pair and oriented toward the 5'-end of the modified strand. The modified dA is in an anti configuration, with the dG of the GA mismatch turned out into the major groove. Chemical shifts of the hydrocarbon protons and unusual chemical shifts of sugar protons were accounted for by this orientation of the adduct. The information available currently provides the foundation for the rational explanation of observed benzo[a]pyrene (BaP) structures and predictions for other BaP dG and dA adducts.
Schurter
E J
EJ
Department of Chemistry, Purdue University, West Lafayette, Indiana 47907.
Yeh
H J
HJ
Sayer
J M
JM
Lakshman
M K
MK
Yagi
H
H
Jerina
D M
DM
Gorenstein
D G
DG
D001483:Base Sequence; D001580:Benzopyrenes / Q000737:chemistry*; D004249:DNA Damage; D003839:Deoxyadenosines / Q000737:chemistry*; D004852:Epoxy Compounds / Q000737:chemistry; D006358:Hot Temperature; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009691:Nucleic Acid Denaturation; D009838:Oligodeoxyribonucleotides / Q000737:chemistry*
D001580:Benzopyrenes; D003839:Deoxyadenosines; D004852:Epoxy Compounds; D009838:Oligodeoxyribonucleotides