NMR determination of the conformation of a trimethylene interstrand cross-link in an oligodeoxynucleotide duplex containing a 5'-d(GpC) motif.

Dooley PA, Zhang M, Korbel GA, Nechev LV, Harris CM, Stone MP, Harris TM
J Am Chem Soc. 2003 125 (1): 62-72

PMID: 12515507 · DOI:10.1021/ja0207798

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.

MeSH Terms (16)

Base Pairing Base Sequence Chemical Phenomena Chemistry, Physical Computer Simulation CpG Islands Cross-Linking Reagents Cyclopropanes DNA Malondialdehyde Models, Chemical Models, Molecular Nuclear Magnetic Resonance, Biomolecular Nucleic Acid Conformation Oligodeoxyribonucleotides Thermodynamics

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