Induced Folding of Protein-Sized Foldameric β-Sandwich Models with Core β-Amino Acid Residues

Gábor Olajos, Anasztázia Hetényi, Edit Wéber, Lukács J. Németh, Zsolt Szakonyi, Ferenc Fülöp, Tamás A. Martinek

Research output: Article

9 Citations (Scopus)

Abstract

The mimicry of protein-sized β-sheet structures with unnatural peptidic sequences (foldamers) is a considerable challenge. In this work, the de novo designed betabellin-14 β-sheet has been used as a template, and α→β residue mutations were carried out in the hydrophobic core (positions 12 and 19). β-Residues with diverse structural properties were utilized: Homologous β3-amino acids, (1R,2S)-2-aminocyclopentanecarboxylic acid (ACPC), (1R,2S)-2-aminocyclohexanecarboxylic acid (ACHC), (1R,2S)-2-aminocyclohex-3-enecarboxylic acid (ACEC), and (1S,2S,3R,5S)-2-amino-6,6-dimethylbicyclo[3.1.1]heptane-3-carboxylic acid (ABHC). Six α/β-peptidic chains were constructed in both monomeric and disulfide-linked dimeric forms. Structural studies based on circular dichroism spectroscopy, the analysis of NMR chemical shifts, and molecular dynamics simulations revealed that dimerization induced β-sheet formation in the 64-residue foldameric systems. Core replacement with (1R,2S)-ACHC was found to be unique among the β-amino acid building blocks studied because it was simultaneously able to maintain the interstrand hydrogen-bonding network and to fit sterically into the hydrophobic interior of the β-sandwich. The novel β-sandwich model containing 25% unnatural building blocks afforded protein-like thermal denaturation behavior.

Original languageEnglish
Pages (from-to)6173-6180
Number of pages8
JournalChemistry - A European Journal
Volume21
Issue number16
DOIs
Publication statusPublished - ápr. 13 2015

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ASJC Scopus subject areas

  • Catalysis
  • Organic Chemistry

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