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

Olajos, Gábor and Hetényi, Anasztázia and Wéber, Edit and Németh, Lukács and Szakonyi, Zsolt and Fülöp, Ferenc and Martinek, Tamás (2015) Induced Folding of Protein-Sized Foldameric β-Sandwich Models with Core β-Amino Acid Residues. CHEMISTRY-A EUROPEAN JOURNAL, 21 (16). pp. 6173-6180. ISSN 0947-6539

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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.

Item Type: Article
Uncontrolled Keywords: PROTEINS; Thermal denaturations; Structural stabilities; NMR chemical shifts; molecular dynamics simulations; Hydrogen bonding network; STABILITY; Molecular dynamics; Hydrophobicity; Hydrogen bonds; DYES; DICHROISM; circular dichroism spectroscopy; Chemical bonds; chemical analysis; CHAINS; PROTEIN STRUCTURES; Protein Folding; Protein Engineering; PEPTIDOMIMETICS; amino acids
Subjects: Q Science / természettudomány > QD Chemistry / kémia
Depositing User: MTMT SWORD
Date Deposited: 30 Aug 2017 07:30
Last Modified: 30 Aug 2017 07:30

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