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Toward an understanding of the chemical etiology for DNA minor-groove recognition by polyamides

Marques, Michael A. and Doss, Raymond M. and Urbach, Adam R. and Dervan, Peter B. (2002) Toward an understanding of the chemical etiology for DNA minor-groove recognition by polyamides. Helvetica Chimica Acta, 85 (12). pp. 4485-4517. ISSN 0018-019X. doi:10.1002/hlca.200290024.

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Crescent-shaped polyamides composed of aromatic amino acids, i.e., 1-methyl-1H-imidazole Im, 1-methyl-1H-pyrrole Py, and 3-hydroxy-1H-pyrrole Hp, bind in the minor groove of DNA as 2 : 1 and 1 : 1 ligand/DNA complexes. DNA-Sequence specificity can be attributed to shape-selective recognition and the unique corners or pairs of corners presented by each heterocycle(s) to the edges of the base pairs on the floor of the minor groove. Here we examine the relationship between heterocycle structure and DNA-sequence specificity for a family of five-membered aromatic amino acids. By means of quantitative DNase-I footprinting, the recognition behavior of polyamides containing eight different aromatic amino acids, i.e., 1-methyl-1H-pyrazole Pz, 1H-pyrrole Nh, 5-methylthiazole Nt, 4-methylthiazole Th, 3-methylthiophene Tn, thiophene Tp, 3-hydroxythiophene Ht, and furan Fr, were compared with the polyamides containing the parent-ring amino acids Py, Im, and Hp for their ability to discriminate between the four Watson-Crick base pairs in the DNA minor groove. Analysis of the data and molecular modeling showed that the geometry inherent to each heterocycle plays a significant role in the ability of polyamides to differentiate between DNA sequences. Binding appears sensitive to changes in curvature complementarity between the polyamide and DNA. The Tn/Py pair affords a modest 3-fold discrimination of T⋅A vs. A⋅T and suggests that an S-atom in the thiophene ring prefers to lie opposite T not A.

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Dervan, Peter B.0000-0001-8852-7306
Additional Information:© 2002 Neue Schweizerische Chemische Gesellschaft, Switzerland. Received August 5, 2002. Article first published online: 2 JAN 2003. We are grateful for financial support from the National Institutes of Health and Caltech for a James Irvine Fellowship to R. M. D.
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Issue or Number:12
Record Number:CaltechAUTHORS:20160510-080921048
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Official Citation:Marques, Michael A., Doss, Raymond M., Urbach, Adam R. and Dervan, Peter B. (2002), Toward an Understanding of the Chemical Etiology for DNA Minor-Groove Recognition by Polyamides. HCA, 85: 4485–4517. doi: 10.1002/hlca.200290024
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:66806
Deposited By: Victoria Brennan
Deposited On:10 May 2016 19:42
Last Modified:11 Nov 2021 00:03

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