NMR determination of the conformation of a trimethylene interstrand cross-link in an oligodeoxynucleotide duplex containing a 5'-d(GpC) motif.
Malondialdehyde interstrand cross-links in DNA show strong preference for 5'-d(CpG) sequences. The cross-links are unstable and a trimethylene cross-link has been used as a surrogate for structural studies. A previous structural study of the 5'-d(CpG) cross-link in the sequence 5'-d(AGGCGCCT), where G is the modified nucleotide, by NMR spectroscopy and molecular dynamics using a simulated annealing protocol showed the guanine residues and the tether lay approximately in a plane such that the trimethylene tether and probably the malondialdehyde tether, as well, could be accommodated without major disruptions of duplex structure [Dooley et al. J. Am Chem. Soc. 2001, 123, 1730-1739]. The trimethylene cross-link has now been studied in a GpC motif using the reverse sequence. The structure lacks the planarity seen with the 5'-d(CpG) sequence and is skewed about the trimethylene cross-link. Melting studies indicate that the trimethylene cross-link is thermodynamically less stable in the GpC motif than in the 5-d(CpG). Furthermore, lack of planarity of the GpC cross-link precludes making an isosteric replacement of the trimethylene tether by malondialdehyde. A similar argument can be used to explain the 5'-d(CpG) preference for interchain cross-linking by acrolein.
Dooley
Patricia A
PA
Department of Chemistry and Center in Molecular Toxicology, Vanderbilt University, Nashville, TN 37235, USA.
Zhang
Mingzhou
M
Korbel
Gregory A
GA
Nechev
Lubomir V
LV
Harris
Constance M
CM
Stone
Michael P
MP
Harris
Thomas M
TM
D020029:Base Pairing; D001483:Base Sequence; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003198:Computer Simulation; D018899:CpG Islands; D003432:Cross-Linking Reagents / Q000737:chemistry*; D003521:Cyclopropanes / Q000737:chemistry*; D004247:DNA / Q000737:chemistry*; D008315:Malondialdehyde / Q000737:chemistry; D008956:Models, Chemical; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods; D009690:Nucleic Acid Conformation; D009838:Oligodeoxyribonucleotides / Q000737:chemistry*; D013816:Thermodynamics
D003432:Cross-Linking Reagents; D003521:Cyclopropanes; D009838:Oligodeoxyribonucleotides; D008315:Malondialdehyde; D004247:DNA; C030797:cyclopropane