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

Olajos, G [Olajos, Gábor (Gyógyszerkémia), author] Subsidised Research Units of the Hungarian Acad... (USZ / FP / DPhC); Hetényi, A [Hetényi, Anasztázia (NMR spektroszkópi...), author] Department of Medical Chemistry (USZ / ÁOK); Wéber, E [Wéber, Edit (gyógyszerkémia), author] Subsidised Research Units of the Hungarian Acad... (USZ / FP / DPhC); Németh, LJ [Németh, Lukács (biofizikus), author] Subsidised Research Units of the Hungarian Acad... (USZ / FP / DPhC); Szakonyi, Z [Szakonyi, Zsolt (szerves- és gyógy...), author] Department of Pharmaceutical Chemistry (USZ / FP); Fülöp, F [Fülöp, Ferenc (Kémia), author] Department of Pharmaceutical Chemistry (USZ / FP); Martinek, TA ✉ [Martinek, Tamás (Gyógyszerkémia), author] Subsidised Research Units of the Hungarian Acad... (USZ / FP / DPhC)

English Scientific Article (Journal Article)
Published: CHEMISTRY-A EUROPEAN JOURNAL 0947-6539 1521-3765 21 (16) pp. 6173-6180 2015
  • SJR Scopus - Chemistry (miscellaneous): D1
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    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. Dissolving sandwiches: A water-soluble β-sandwich has been constructed by using cyclic β-amino acids in the hydrophobic core (see figure). The structural stability is highly dependent on the side-chain, and the destructuring effects of the β-residues could be minimized by using (1R,2S)-2-aminocyclohexanecarboxylic acid. The β-sandwich displays protein-like thermal denaturation behavior.
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    2020-12-05 11:51