Structural and kinetic profiling of allosteric modulation of duplex DNA induced by DNA-binding polyamide analogues

Khalid Aman, Giacomo Padroni, John A. Parkinson, Thomas Welte, Glenn A. Burley

Research output: Contribution to journalArticle

Abstract

A combined structural and quantitative biophysical profile of the DNA binding affinity, kinetics and sequence-selectivity of hairpin polyamide analogues is described. DNA duplexes containing either target polyamide binding sites or mismatch sequences are immobilized on a microelectrode surface. Quantitation of the DNA binding profile of polyamides containing N-terminal 1-alkylimidazole (Im) units exhibit picomolar binding affinities for their target sequences, whereas 5-alkylthiazole (Nt) units are an order of magnitude lower (low nanomolar). Comparative NMR structural analyses of the polyamide series shows that the steric bulk distal to the DNA-binding face of the hairpin iPr-Nt polyamide plays an influential role in the allosteric modulation of the overall DNA duplex structure. This combined kinetic and structural study provides a foundation to develop next-generation hairpin designs where the DNA-binding profile of polyamides is reconciled with their physicochemical properties.
LanguageEnglish
Pages2757-2763
Number of pages7
JournalChemistry - A European Journal
Volume25
Issue number11
Early online date8 Nov 2018
DOIs
Publication statusPublished - 21 Feb 2019

Fingerprint

Nylons
Polyamides
DNA
Modulation
Kinetics
Microelectrodes
Binding sites
Binding Sites
Nuclear magnetic resonance

Keywords

  • DNA-binding polyamides
  • DNA binding
  • polyamide binding

Cite this

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title = "Structural and kinetic profiling of allosteric modulation of duplex DNA induced by DNA-binding polyamide analogues",
abstract = "A combined structural and quantitative biophysical profile of the DNA binding affinity, kinetics and sequence-selectivity of hairpin polyamide analogues is described. DNA duplexes containing either target polyamide binding sites or mismatch sequences are immobilized on a microelectrode surface. Quantitation of the DNA binding profile of polyamides containing N-terminal 1-alkylimidazole (Im) units exhibit picomolar binding affinities for their target sequences, whereas 5-alkylthiazole (Nt) units are an order of magnitude lower (low nanomolar). Comparative NMR structural analyses of the polyamide series shows that the steric bulk distal to the DNA-binding face of the hairpin iPr-Nt polyamide plays an influential role in the allosteric modulation of the overall DNA duplex structure. This combined kinetic and structural study provides a foundation to develop next-generation hairpin designs where the DNA-binding profile of polyamides is reconciled with their physicochemical properties.",
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Structural and kinetic profiling of allosteric modulation of duplex DNA induced by DNA-binding polyamide analogues. / Aman, Khalid; Padroni, Giacomo; Parkinson, John A.; Welte, Thomas ; Burley, Glenn A.

In: Chemistry - A European Journal, Vol. 25, No. 11, 21.02.2019, p. 2757-2763.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Structural and kinetic profiling of allosteric modulation of duplex DNA induced by DNA-binding polyamide analogues

AU - Aman, Khalid

AU - Padroni, Giacomo

AU - Parkinson, John A.

AU - Welte, Thomas

AU - Burley, Glenn A.

PY - 2019/2/21

Y1 - 2019/2/21

N2 - A combined structural and quantitative biophysical profile of the DNA binding affinity, kinetics and sequence-selectivity of hairpin polyamide analogues is described. DNA duplexes containing either target polyamide binding sites or mismatch sequences are immobilized on a microelectrode surface. Quantitation of the DNA binding profile of polyamides containing N-terminal 1-alkylimidazole (Im) units exhibit picomolar binding affinities for their target sequences, whereas 5-alkylthiazole (Nt) units are an order of magnitude lower (low nanomolar). Comparative NMR structural analyses of the polyamide series shows that the steric bulk distal to the DNA-binding face of the hairpin iPr-Nt polyamide plays an influential role in the allosteric modulation of the overall DNA duplex structure. This combined kinetic and structural study provides a foundation to develop next-generation hairpin designs where the DNA-binding profile of polyamides is reconciled with their physicochemical properties.

AB - A combined structural and quantitative biophysical profile of the DNA binding affinity, kinetics and sequence-selectivity of hairpin polyamide analogues is described. DNA duplexes containing either target polyamide binding sites or mismatch sequences are immobilized on a microelectrode surface. Quantitation of the DNA binding profile of polyamides containing N-terminal 1-alkylimidazole (Im) units exhibit picomolar binding affinities for their target sequences, whereas 5-alkylthiazole (Nt) units are an order of magnitude lower (low nanomolar). Comparative NMR structural analyses of the polyamide series shows that the steric bulk distal to the DNA-binding face of the hairpin iPr-Nt polyamide plays an influential role in the allosteric modulation of the overall DNA duplex structure. This combined kinetic and structural study provides a foundation to develop next-generation hairpin designs where the DNA-binding profile of polyamides is reconciled with their physicochemical properties.

KW - DNA-binding polyamides

KW - DNA binding

KW - polyamide binding

U2 - 10.1002/chem.201805338

DO - 10.1002/chem.201805338

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