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Aliphatic/aromatic amino acid pairings for polyamide recognition in the minor groove of DNA

Turner, James M. and Swalley, Susanne E. and Baird, Eldon E. and Dervan, Peter B. (1998) Aliphatic/aromatic amino acid pairings for polyamide recognition in the minor groove of DNA. Journal of the American Chemical Society, 120 (25). pp. 6219-6226. ISSN 0002-7863. doi:10.1021/ja980147e.

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Selective placement of an aliphatic β-alanine (β) residue paired side-by-side with either a pyrrole (Py) or imidazole (Im) aromatic amino acid is found to compensate for sequence composition effects for recognition of the minor groove of DNA by hairpin pyrrole−imidazole polyamides. A series of polyamides were prepared which contain pyrrole and imidazole aromatic amino acids, as well as γ-aminobutyric acid (γ) “turn” and β-alanine “spring” aliphatic amino acid residues. The binding affinities and specificities of these polyamides are regulated by the placement of paired β/β, Py/β, and Im/β residues. Quantitative footprint titrations demonstrate that replacing two Py/Py pairings in a 12-ring hairpin (6-γ-6) with two Py/β pairings affords 10-fold enhanced affinity and similar sequence specificity for an 8-bp target sequence. The 6-γ-6 hairpin ImPyImPyPyPy-γ-ImPyPyPyPyPy-β-Dp, which contains six consecutive amino acid pairings, is unable to discriminate a single-base-pair mismatch site 5‘-TGTTAACA-3‘ from a 5‘-TGTGAACA-3‘ match site. The hairpin polyamide Im-β-ImPyPyPy-γ-ImPyPyPy-β-Py-β-Dp binds to the 8-bp match sequence 5‘-TGTGAACA-3‘ with an equilibrium association constant of Ka = 2.4 × 1010 M-1 and ≥48-fold specificity versus the 5‘-TGTTAACA-3‘ single-base-pair mismatch site. Modeling indicates that the β-alanine residue relaxes ligand curvature, providing for optimal hydrogen bond formation between the floor of the minor groove and both Im residues within the Im-β-Im polyamide subunit. This observation provided the basis for design of a hairpin polyamide, Im-β-ImPy-γ-Im-β-ImPy-β-Dp, which incorporates Im/β pairings to recognize a “problematic” 5‘-GCGC-3‘ sequence at subnanomolar concentrations. These results identify Im/β and β/Im pairings that respectively discriminate G·C and C·G from A·T/T·A as well as Py/β and β/Py pairings that discriminate A·T/T·A from G·C/C·G. These aliphatic/aromatic amino acid pairings will facilitate the design of hairpin polyamides which recognize both a larger binding site size as well as a more diverse sequence repertoire.

Item Type:Article
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Dervan, Peter B.0000-0001-8852-7306
Additional Information:© 1998 American Chemical Society. Received January 13, 1998. Publication Date (Web): June 12, 1998. We are grateful to the National Institutes of Health (GM-27681) for research support and a traineeship award (GM-08501) to S.E.S., J. Edward Richter for an undergraduate fellowship to J.M.T., and the Howard Hughes Medical Institute for a predoctoral fellowship to E.E.B.
Funding AgencyGrant Number
NIH Predoctoral FellowshipGM-08501
J. Edward RichterUNSPECIFIED
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Issue or Number:25
Record Number:CaltechAUTHORS:20160510-093114771
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Official Citation:Aliphatic/Aromatic Amino Acid Pairings for Polyamide Recognition in the Minor Groove of DNA James M. Turner, Susanne E. Swalley, Eldon E. Baird, and Peter B. Dervan Journal of the American Chemical Society 1998 120 (25), 6219-6226 DOI: 10.1021/ja980147e
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:66858
Deposited By: Victoria Brennan
Deposited On:18 May 2016 19:47
Last Modified:11 Nov 2021 00:23

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