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
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Pr‐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.
DNA‐binding polyamides are molecules that hold great promise as regulators of gene expression. One of the challenges in their therapeutic development is understanding the molecular determinants governing their DNA‐binding profile. This article describes a new biophysical technique (switchSENSE®) to determine the DNA‐binding parameters of polyamide analogues. NMR structural analysis shows that steric bulk distal to the DNA‐binding face plays an influential role in allosteric modulation of the DNA duplex. More information can be found in the Full Paper by T. Welte, G. A. Burley et al. on page 2757.
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