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

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 β(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 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.

An overview of peptide and peptoid foldamers in medicinal chemistry

“…b-Sheet forming a/b-peptides were designed too [123][124][125][126][127][128]. Importantly, these structures might be useful in PPI modification where water-accessible flat surfaces play a crucial role.…”

Towards “bionic” proteins: replacement of continuous sequences from HIF-1α with proteomimetics to create functional p300 binding HIF-1α mimics

“…In protein prosthesis, 6,7 backbone engineering 8 allows individual residues or sequences within proteins to be replaced with non-natural residues. [9][10][11][12][13] Notable examples include the incorporation of b-amino acid residues in the B1 domain of Streptococcal protein G (GB1) 14 and Betabellin-14, 15 the re-engineering of a heterodimeric chorismate mutase enzyme 16 using sequence based design, the replacement of loop regions in GB1 using PEG 17 and the incorporation of an entire b-amino acid topological mimic of an a-helix into IL8. 18 a-Helix mimetics [19][20][21][22][23] employ a suitably functionalised generic scaffold to reproduce the spatial projection and composition of key side chains found at a helical interface between two proteins.…”

Foldameric probes for membrane interactions by induced β-sheet folding

“…Replacing  residues with a hydrophobic surface area similar to (1R,2S)-ACHC (1c and 1d) resulted in a high original -sheet content and a low inducibility, which highlighted the importance of the compatibility of the sidechain with the hydrophobic core. 16 The cyclic side-chain fitted into the peripheral regions of the inner core, but substitution in the centre of the tightly packed core was unfavourable (1a, 1b, 2a and 2b). It has previously been shown that appropriate orientation of the side-chains facilitates the hydrophobic interactions that play crucial roles in -sheet folding, and they are scaled up by increasing temperature.…”