Induced Folding of Protein‐Sized Foldameric β‐Sandwich Models with Core β‐Amino Acid Residues |
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| Authors: | Gábor Olajos Dr Anasztázia Hetényi Dr Edit Wéber Lukács J Németh Dr Zsolt Szakonyi Prof?Dr Ferenc Fülöp Prof?Dr Tamás A Martinek |
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| Affiliation: | 1. Institute of Pharmaceutical Analysis, SZTE‐MTA Lendület Foldamer Research Group, University of Szeged, 6720 Szeged (Hungary);2. Department of Medical Chemistry, University of Szeged, 6720 Szeged (Hungary);3. Institute of Pharmaceutical Chemistry, University of Szeged, 6720 Szeged (Hungary) |
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| 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‐dimethylbicyclo3.1.1]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. |
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| Keywords: | amino acids peptidomimetics protein engineering protein folding protein structures |
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