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.
