A computationally designed β-amino acid-containing miniprotein

Abstract

A new miniprotein built from three helices, including one structure based on a ααβαααβ sequence pattern was developed. Its crystal structure revealed a compact conformation with a well-packed hydrophobic core...

Design and Engineering of Miniproteins

“…Rational redesign of natural folds with noncanonical building blocks (referred to as heterogeneous backbone engineering or “foldamerization”) led to the obtaining of a short and stable B1 domain of the G protein (GB1), N-terminal fragment of the villin headpiece (VHP), Trp-cage-like folds, or zinc finger folds . Extensive studies on the backbone modification were carried out in GB1 (Figure , sequence 15 ) with the aim of changing approximately 20% of the sequence with heterogeneous building blocks but still maintaining the tertiary fold .…”

“…Only an analogue with mutation at the end of the helical fragment did not affect the conformational stability of the miniprotein (Figure , sequence 20 ). In another study, the VHP sequence was modified not only by incorporation β-amino acids but also by computational redesign of α-residues . The trans -ACPC units were introduced into the longest C-terminal helix at positions consistent with previously described βαααβααβ motif .…”

“…In another study, the VHP sequence was modified not only by incorporation β-amino acids but also by computational redesign of α-residues. 82 The trans -ACPC units were introduced into the longest C-terminal helix at positions consistent with previously described βαααβααβ motif. 87 The α-residues were changed using the Rosetta FastDesign protocol 52 to optimize the packing of the hydrophobic core ( Figure 6 , sequences 21 and 22 ).…”

Chemical shifts of artificial monomers used to construct heterogeneous‐backbone protein mimetics in random coil and folded states

“…The β-amino acid residue trans-1,2-amino-cyclopentane carboxylic acid (ACPC) is a strong promoter of helical secondary structure [40] and can be incorporated as part of heterogeneous backbones in helical regions of folded protein domains. [31,35,41,42] The γ-amino acid cis-1,3-amino-cyclohexane carboxylic acid (ACC) is adept at promoting extended strand backbone conformations [43] and thus can be incorporated in aligned stripes in protein β-sheet contexts. [44,45] Beyond the cyclic residues, the monomer set also included the noncanonical amino acid ornithine linked to the preceding residue by its side-chain δ-amino group (ORN δ ), an effective turn promoter when replacing dipeptide moieties in hairpins [46] and other structural contexts.…”

Molecular torsion springs: alteration of helix curvature in frustrated tertiary folds

“…32 Using various approaches, steps were made away from purely α-peptidic backbones, and β-amino acids were introduced in tertiary structures. [33][34][35][36][37][38][39] Some helix bundles from β-peptides 40,41 and oligoureas 42,43 have also been reported.…”