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Recognition of the Minor Groove of DNA by Hairpin Polyamides Containing α-Substituted-β-Amino Acids

Floreancig, Paul E. and Swalley, Susanne E. and Trauger, John W. and Dervan, Peter B. (2000) Recognition of the Minor Groove of DNA by Hairpin Polyamides Containing α-Substituted-β-Amino Acids. Journal of the American Chemical Society, 122 (27). pp. 6342-6350. ISSN 0002-7863. https://resolver.caltech.edu/CaltechAUTHORS:20160510-084515614

[img] PDF (Quantitative DNase I footprinting gels of polyamides 1, 4, 5, and 6 with the 3‘-^(32)P-labeled restriction fragment from pSES 19-1, the MPE footprinting gel of 2 with the 5‘-^(32)P-labeled restriction fragment, and the affinity cleaving gel of 2E with....) - Supplemental Material
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Abstract

Incorporation of the flexible amino acid β-alanine (β) into hairpin polyamides composed of N-methylpyrrole (Py) and N-methylimidazole (Im) amino acids is required for binding to DNA sequences longer than seven base pairs with high affinity and sequence selectivity. Pairing the α-substituted-β-amino acids (S)-isoserine (^SIs), (R)-isoserine (^RIs), β-aminoalanine (Aa), and α-fluoro-β-alanine (Fb) side-by-side with β in hairpin polyamides alters DNA binding affinity and selectivity relative to the parent polyamide containing a β/β pairing. Quantitative DNase I footprinting titration studies on a restriction fragment containing the sequences 5‘-TGCNGTA-3‘ (N = A, T, G, and C) show that the polyamide ImPy^SIsImPy-γ-PyPyβImPy-β-Dp (^SIs/β pairing) binds to N = T (K_a = 4.5 × 10^9 M^(-1)) in preference to N = A (K_a = 6.2 × 10^8 M^(-1)). This result stands in contrast to the essentially degenerate binding of the parent ImPyβImPy-γ-PyPyβImPy-β-Dp (β/β pairing) to N = T and N = A, and to the slight preference of ImPyβImPy-γ-PyPy^SIsImPy-β-Dp (β/^SIs pairing) to N = A over N = T. Additionally, this study reveals that incorporation of ^RIs, Aa, and Fb into polyamides significantly reduces binding affinity. Therefore, DNA binding in the minor groove is sensitive to the stereochemistry, steric bulk, and electronics of the substituent at the α-position of β-amino acids in hairpin polyamides containing β/β pairs.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1021/ja000509uDOIArticle
http://pubs.acs.org/doi/abs/10.1021/ja000509uPublisherArticle
http://pubs.acs.org/doi/suppl/10.1021/ja000509uPublisherSupporting Information
ORCID:
AuthorORCID
Dervan, Peter B.0000-0001-8852-7306
Additional Information:© 2000 American Chemical Society. Received February 10, 2000. Publication Date (Web): June 23, 2000. We are grateful to the National Institutes of Health for research support, the National Institutes of Health for a postdoctoral fellowship (GM18311-02) to P.E.F., the National Institutes of Health for a research traineeship award (GM-08501) to S.E.S., and the National Science Foundation for a predoctoral fellowship to J.W.T. We thank Dr. Gary Hathaway for MALDI-TOF mass spectroscopy and Ms. Meredith Howard for assistance in the preparation of compound 13.
Funders:
Funding AgencyGrant Number
NIH Postdoctoral FellowshipGM-18311-02
NIH Predoctoral FellowshipGM-08501
NSF Predoctoral FellowshipUNSPECIFIED
Issue or Number:27
Record Number:CaltechAUTHORS:20160510-084515614
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20160510-084515614
Official Citation:Recognition of the Minor Groove of DNA by Hairpin Polyamides Containing α-Substituted-β-Amino Acids Paul E. Floreancig, Susanne E. Swalley, John W. Trauger, and Peter B. Dervan Journal of the American Chemical Society 2000 122 (27), 6342-6350 DOI: 10.1021/ja000509u
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:66836
Collection:CaltechAUTHORS
Deposited By: Victoria Brennan
Deposited On:10 May 2016 19:36
Last Modified:26 Nov 2019 11:15

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