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Orientation Preferences of Pyrrole−Imidazole Polyamides in the Minor Groove of DNA

White, Sarah and Baird, Eldon E. and Dervan, Peter B. (1997) Orientation Preferences of Pyrrole−Imidazole Polyamides in the Minor Groove of DNA. Journal of the American Chemical Society, 119 (38). pp. 8756-8765. ISSN 0002-7863. https://resolver.caltech.edu/CaltechAUTHORS:20160510-100726329

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Abstract

In order to determine whether there is an orientation preference of pyrrole−imidazole (Py−Im) polyamide dimers with respect to the 5‘−3‘ direction of the backbone in the DNA helix, equilibrium association constants (K_a) were determined for a series of six-ring hairpin polyamides which differ with respect to substitution at the N and C termini. Affinity cleaving experiments using hairpin polyamides of core sequence composition ImPyPy-γ-PyPyPy with an EDTA·Fe(II) moiety at the C-terminus reveal a single binding orientation at each formal match site, 5‘-(A,T)G(A,T)_3-3‘ and 5‘-(A,T)C(A,T)_3-3‘. A positive charge at the C-terminus and no substitution at the N-terminus imidazole affords the maximum binding orientation preference, calculated from K_a(5‘-TGTTA-3‘)/K_a(5‘-TCTTA-3‘), with the N-terminal end of each three-ring subunit located toward the 5‘ side of the target DNA strand. Removal of the positive charge, rearrangement of the positive charge to the N-terminus or substitution at the N-terminal imidazole decreases the orientation preference. These results suggest that second generation design principles superimposed on the simple pairing rules can further optimize the sequence-specificity of Py-Im polyamides for double helical DNA.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.dloi.org/10.1021/ja971569bDOIArticle
http://pubs.acs.org/doi/abs/10.1021/ja971569bPublisherArticle
ORCID:
AuthorORCID
Dervan, Peter B.0000-0001-8852-7306
Additional Information:© 1997 American Chemical Society. Received May 14, 1997. Publication Date (Web): September 24, 1997. Abstract published in Advance ACS Abstracts, September 15, 1997. Acknowledgment. We are grateful to the National Institutes of Health (GM-2768) for research support, the National Science Foundation for a predoctoral fellowship to S.W., and the Howard Hughes Medical Institute for a predoctoral fellowship to E.E.B. We thank G. M. Hathaway for MALDI-TOF mass spectrometry.
Funders:
Funding AgencyGrant Number
NIHGM-27681
NSF Predoctoral FellowshipUNSPECIFIED
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Issue or Number:38
Record Number:CaltechAUTHORS:20160510-100726329
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20160510-100726329
Official Citation:Orientation Preferences of Pyrrole−Imidazole Polyamides in the Minor Groove of DNA Sarah White, Eldon E. Baird, and Peter B. Dervan Journal of the American Chemical Society 1997 119 (38), 8756-8765 DOI: 10.1021/ja971569b
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:66871
Collection:CaltechAUTHORS
Deposited By: Victoria Brennan
Deposited On:18 May 2016 21:58
Last Modified:26 Nov 2019 11:15

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