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

2 Citations (Scopus)
7 Downloads (Pure)

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.
Original languageEnglish
Pages (from-to)2757-2763
Number of pages7
JournalChemistry - A European Journal
Volume25
Issue number11
Early online date8 Nov 2018
DOIs
Publication statusPublished - 21 Feb 2019

Keywords

  • DNA-binding polyamides
  • DNA binding
  • polyamide binding

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