Folding Topology of a Short Coiled-Coil Peptide Structure Templated by an Oligonucleotide Triplex

Chenguang Lou, Niels Johan Christensen, Manuel C Martos-Maldonado, Søren Roi Midtgaard, Maria Ejlersen, Peter W Thulstrup, Kasper K Sørensen, Knud J. Jensen, Jesper Wengel

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Abstract

The rational design of a well-defined protein-like tertiary structure formed by small peptide building blocks is still a formidable challenge. By using peptide-oligonucleotide conjugates (POC) as building blocks, we present the self-assembly of miniature coiled-coil α-helical peptides guided by oligonucleotide duplex and triplex formation. POC synthesis was achieved by copper-free alkyne-azide cycloaddition between three oligonucleotides and a 23-mer peptide, which by itself exhibited multiple oligomeric states in solution. The oligonucleotide domain was designed to furnish a stable parallel triplex under physiological pH, and to be capable of templating the three peptide sequences to constitute a small coiled-coil motif displaying remarkable α-helicity. The formed trimeric complex was characterized by ultraviolet thermal denaturation, gel electrophoresis, circular dichroism (CD) spectroscopy, small-angle X-ray scattering (SAXS), and molecular modeling. Stabilizing cooperativity was observed between the trimeric peptide and the oligonucleotide triplex domains, and the overall molecular size (ca. 12 nm) in solution was revealed to be independent of concentration. The topological folding of the peptide moiety differed strongly from those of the individual POC strands and the unconjugated peptide, exclusively adopting the designed triple helical structure.

Original languageEnglish
JournalChemistry: A European Journal
Volume23
Issue number39
Pages (from-to)9297–9305
ISSN0947-6539
DOIs
Publication statusPublished - 2017

Keywords

  • Journal Article

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