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Published August 27, 1997 | Supplemental Material
Journal Article Open

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

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 gamma 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 βand δcomplexes adopt an energetically less favorable turn geometry than the γlinker and confirms that the three-carbon γ linker is sufficient and optimal for the hairpin conformation.

Additional Information

© 1997 American Chemical Society. Received December 16, 1996. Publication Date (Web): August 27, 1997. Abstract published in AdVance ACS Abstracts, August 15, 1997. We are grateful to National Institutes of Health (GM-43129 D.E.W. and GM-27681 P.B.D.) and the National Foundation for Cancer Research for research support, to the Ralph M. Parson Foundation for a graduate fellowship to M.M., and to the U.S. Department of Energy, National Science Foundation and Keck Foundation for instrumentation grants. R.P.L.deC. gratefully acknowledges a postdoctoral fellowship from the Fundación Ramón Areces. R.P.L.deC., B.H.G., and D.E.W. also thank T. D. Cole for helpful discussions and assistance in the early stages of the project.

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