Solution structure of the aminofluorene [AF]-intercalated conformer of the syn-[AF]-C8-dG adduct opposite dC in a DNA duplex.
We report below on a conformational equilibrium between AF-intercalated and AF-external states in slow exchange for the [AF]dG lesion positioned opposite dC in the d(C-[AF]G-C).d(G-C-G) sequence context. The slow exchange between states is attributed to interconversion between syn glycosidic torsion angle in the AF-intercalated and anti torsion angle in AF-external conformers of the [AF]dG opposite dC containing duplex. The present paper describes an NMR-molecular mechanics study that defines the solution structure of the AF-intercalated conformer for the case of [AF]dG adduct positioned opposite dC in the d(C-[AF]G-C).d(G-C-G) sequence context. The structure is of the base displacement-intercalation type where the aminofluorene ring is intercalated into the helix between intact Watson-Crick dG.dC base pairs, which results in a displacement of the modified guanine ring into the major groove where it stacks with the major groove edge of its 5'-flanking cytosine in the adduct duplex. The conformational equilibrium between AF-intercalated conformer (approximately 70%) with a syn alignment and AF-external conformer (approximately 30%) with an anti alignment for the [AF]dG adduct positioned opposite dC in the d(C-[AF]G-C).d(G-C-G) sequence context can be contrasted with our earlier demonstration that the population is 100% for the AP-intercalated conformer with a synalignment at the N-(deoxyguanosin-8-yl)-2-aminopyrene ([AP]dG) adduct site positioned opposite dC in the same sequence context [Mao, B., Vyas, R. R., Hingerty, B. E., Broyde, S., Basu, A. K., and Patel, D. J. (1996) Biochemistry, 35, 12659-12670]. This shift in population may reflect the much larger size of the pyrenyl ring of the [AP]dG adduct compared to the fluorenyl ring of the [AF]dG adduct which in turn might provide for a greater overlap of the aromatic amine with the flanking base pairs in the intercalated conformer of the former adduct in DNA.
Mao
B
B
Cellular Biochemistry and Biophysics Program, Memorial Sloan Kettering Cancer Center, New York 10021, USA.
Hingerty
B E
BE
Broyde
S
S
Patel
D J
DJ
D002244:Carbon; D002273:Carcinogens / Q000737:chemistry; D018736:DNA Adducts / Q000737:chemistry*; D003841:Deoxycytidine / Q000737:chemistry*; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000737:chemistry*; D005449:Fluorenes / Q000737:chemistry*; D007364:Intercalating Agents; D009682:Magnetic Resonance Spectroscopy; D008432:Mathematical Computing; D008958:Models, Molecular; D015394:Molecular Structure; D009690:Nucleic Acid Conformation; D009692:Nucleic Acid Heteroduplexes / Q000737:chemistry*; D010758:Phosphorus; D011522:Protons; D012996:Solutions
D002273:Carcinogens; D018736:DNA Adducts; D005449:Fluorenes; D007364:Intercalating Agents; D009692:Nucleic Acid Heteroduplexes; D011522:Protons; D012996:Solutions; D003841:Deoxycytidine; D010758:Phosphorus; C012177:2-aminofluorene; D002244:Carbon; D003849:Deoxyguanosine