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Issue 8, 2016
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Tunable helicity, stability and DNA-binding properties of short peptides with hybrid metal coordination motifs

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Abstract

Given the prevalent role of α-helical motifs on protein surfaces in mediating protein–protein and protein–DNA interactions, there have been significant efforts to develop strategies to induce α-helicity in short, unstructured peptides to interrogate such interactions. Toward this goal, we have recently introduced hybrid metal coordination motifs (HCMs). HCMs combine a natural metal-binding amino acid side chain and a synthetic chelating group that are appropriately positioned in a peptide sequence to stabilize an α-helical conformation upon metal coordination. Here, we present a series of short peptides modified with HCMs consisting of a His and a phenanthroline group at i and i + 7 positions that can induce α-helicity in a metal-tunable fashion as well as direct the formation of discrete dimeric architectures for recognition of biological targets. We show that the induction of α-helicity can be further modulated by secondary sphere interactions between amino acids at the i + 4 position and the HCM. A frequently cited drawback of the use of peptides as therapeutics is their propensity to be quickly digested by proteases; here, we observe an enhancement of up to ∼100-fold in the half-lives of the metal-bound HCM-peptides in the presence of trypsin. Finally, we show that an HCM-bearing peptide sequence, which contains the DNA-recognition domain of a bZIP protein but is devoid of the obligate dimerization domain, can dimerize with the proper geometry and in an α-helical conformation to bind a cognate DNA sequence with high affinities (Kd ≥ 65 nM), again in a metal-tunable manner.

Graphical abstract: Tunable helicity, stability and DNA-binding properties of short peptides with hybrid metal coordination motifs

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Supplementary files

Article information


Submitted
22 Feb 2016
Accepted
07 May 2016
First published
18 May 2016

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2016,7, 5453-5461
Article type
Edge Article

Tunable helicity, stability and DNA-binding properties of short peptides with hybrid metal coordination motifs

S. J. Smith, R. J. Radford, R. H. Subramanian, B. R. Barnett, J. S. Figueroa and F. A. Tezcan, Chem. Sci., 2016, 7, 5453 DOI: 10.1039/C6SC00826G

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