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

摘要

The mimicry of protein-sized -sheet structures with unnatural peptidic sequences (foldamers) is a considerable challenge. In this work, the de novo designed betabellin-14 -sheet has been used as a template, and residue mutations were carried out in the hydrophobic core (positions 12 and 19). -Residues with diverse structural properties were utilized: Homologous (3)-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 /-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 -sheet formation in the 64-residue foldameric systems. Core replacement with (1R,2S)-ACHC was found to be unique among the -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 -sandwich. The novel -sandwich model containing 25% unnatural building blocks afforded protein-like thermal denaturation behavior.