NMR characterization of hairpin polyamide complexes with the minor groove of DNA

Rafael Peláez Lamamie De Clairac, Bernhard H. Geierstanger, Milan Mrksich, Peter B. Dervan, David E. Wemmer

Research output: Contribution to journalArticle

111 Scopus citations

Abstract

Polyamides containing N-methylimidazole (Im) and N-methylpyrrole (Py) amino acids can be combined in antiparallel side-by-side dimeric complexes for sequence-specific recognition in the minor groove of DNA. Covalently linking polyamide subunits has led to designed ligands with both increased affinity and specificity. Simple aliphatic amino acid linkers serve as internal guide residues for turn vs extended binding in a head-to-tail-linked polyamide motif. Polyamides of sequence composition ImPyPy-X-PyPyPy containing linkers of incremental length (X = 3-aminopropionic acid (β), 4-aminobutyric acid (γ), or 5-aminovaleric acid (δ)) in complex with an undecamer DNA duplex containing a 5'-(A,T)G(A,T)3-3' target site were structurally characterized using NMR spectroscopy. Previous quantitative DNase I footprinting studies identified γ as the highest affinity of these 'turn' linkers. NMR titrations and 2D NOESY data combined with restrained molecular modeling reveal that polyamides with β, γ, and δ linkers all may adopt a hairpin structure. Modeling supports the idea that the linkers in the β and δ complexes adopt an energetically less favorable turn geometry than the γ linker and confirms that the three-carbon γ linker is sufficient and optimal for the hairpin conformation.

Original languageEnglish (US)
Pages (from-to)7909-7916
Number of pages8
JournalJournal of the American Chemical Society
Volume119
Issue number34
DOIs
StatePublished - Aug 27 1997

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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    Lamamie De Clairac, R. P., Geierstanger, B. H., Mrksich, M., Dervan, P. B., & Wemmer, D. E. (1997). NMR characterization of hairpin polyamide complexes with the minor groove of DNA. Journal of the American Chemical Society, 119(34), 7909-7916. https://doi.org/10.1021/ja964314r