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Stereochemical control of the DNA binding affinity, sequence specificity, and orientation preference of chiral hairpin polyamides in the minor groove

Herman, David M. and Baird, Eldon E. and Dervan, Peter B. (1998) Stereochemical control of the DNA binding affinity, sequence specificity, and orientation preference of chiral hairpin polyamides in the minor groove. Journal of the American Chemical Society, 120 (7). pp. 1382-1391. ISSN 0002-7863. doi:10.1021/ja9737228.

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Three-ring polyamides containing pyrrole (Py) and imidazole (Im) amino acids covalently coupled by γ-aminobutyric acid (γ) form six-ring hairpins that recognize five-base-pair sequences in the minor groove of DNA. Selective chiral substitution of the ``gamma-turn'' enhances the properties of polyamide hairpins with regard to DNA affinity and sequence specificity. Polyamides of core sequence composition ImPyPy-γ-PyPyPy which differ by selective stereochemical substitution of the prochiral alpha-position in the γ-turn were prepared. The DNA binding properties of two enantiomeric polyamides were analyzed by footprinting and affinity cleavage on a DNA fragment containing two match sites (5'-TGTTA-3' and 5'-ACATT-3') and one 5'-TGTCA-3' mismatch site. Quantitative footprint titrations demonstrate that replacement of γ-aminobutyric acid by (R)-2,4-diaminobutyric acid enhances DNA binding affinity for the 5'-TGTTA-3' match site 13-fold (K_a = 3.8 x 10^9 M-1). The enhanced affinity is achieved without a compromise in sequence selectivity, which in fact increases and is found to be 100-fold higher relative to binding at a single base pair mismatch sequence, 5'-TGTCA-3'. An (S)-2,4-diaminobutyric acid linked hairpin binds with 170-fold reduced affinity relative to the R-enantiomer and only 5-fold sequence specificity versus a 5'-ACATT-3' reversed orientation site. These effects are modulated by acetylation of the chiral amine substituents. This study identifies structural elements which should facilitate the design of new hairpin polyamides with improved DNA binding affinity, sequence specificity, and orientational selectivity.

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Dervan, Peter B.0000-0001-8852-7306
Additional Information:© 1998 American Chemical Society. Received October 27, 1997. Publication Date (Web): February 7, 1998. We are grateful to the National Institutes of Health (GM-27681) for research support, the National Institutes of Health for a research service award to D.M.H., and the Howard Hughes Medical Institute for a predoctoral fellowship to E.E.B. We thank G.M. Hathaway for MALDI-TOF mass spectrometry.
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Howard Hughes Medical Institute (HHMI)UNSPECIFIED
NIH Predoctoral FellowshipUNSPECIFIED
Issue or Number:7
Record Number:CaltechAUTHORS:20160510-094232994
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Official Citation:Stereochemical Control of the DNA Binding Affinity, Sequence Specificity, and Orientation Preference of Chiral Hairpin Polyamides in the Minor Groove David M. Herman, Eldon E. Baird, and Peter B. Dervan Journal of the American Chemical Society 1998 120 (7), 1382-1391 DOI: 10.1021/ja9737228
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:66865
Deposited By: Victoria Brennan
Deposited On:17 May 2016 23:14
Last Modified:11 Nov 2021 00:23

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