β-Peptide bundles: Design. Build. Analyze. Biosynthesize.

Abstract

Peptides containing β-amino acids are unique non-natural polymers known to assemble into protein-like tertiary and quaternary structures. When composed solely of β-amino acids, the structures formed, defined assemblies of 14-helices called β-peptide bundles, fold cooperatively in water solvent into unique and discrete quaternary assemblies that are highly thermostable, bind complex substrates and metal ion cofactors, and, in certain cases, catalyze chemical reactions. In this Perspective, we recount the design and elaboration of β-peptide bundles and provide an outlook on recent, unexpected discoveries that could influence research on β-peptides and β-peptide bundles (and β-amino acid-containing proteins) for decades to come.

Helix Propensities of Amino Acid Residues via Thioester Exchange

“…Moreover, we have shown that this operationally convenient approach can be extended to non-proteinogenic subunits, including D-α-amino residues and β-amino acid residues. There is growing interest in the structures and functions of polypeptide analogues containing subunits with unnatural backbones, 2,21 and this interest is magnified by the prospect that these unnatural subunits may be brought into the realm of ribosomal incorporation. 22 The results described above suggest that thioester exchange offers a versatile approach for analyzing the impact of backbone modification on conformational stability.…”

Improved Modeling of Peptidic Foldamers Using a Quantum Chemical Parametrization Based on Torsional Minimum Energy Path Matching

“…Application of these molecules as antimicrobial or anticancer drugs, however, often requires water‐soluble molecules. Recently, several hydrophilic/amphiphilic β‐peptides were reported to fold into stable helical structures . Aiming at a more complete and representative validation of our force field, we have chosen one of the water‐soluble β‐undecapeptides, which forms a H14 helix in water (denoted later on as “AH”, schematically represented in Figure ) .…”

“…Using the same RMSD threshold to separate folded and unfolded conformations, they have obtained À 0.36, À 0.88 and À 1.29 kcal/mol with the 45A3, 53A6 and 54A7 versions of the FF, respectively. 1 We have also investigated how consistent are the obtained trajectories with the published experimental NMR results on this peptide. [27] NOE distances and 3 J couplings have been calculated from the trajectories.…”

“…Recently, several hydrophilic/amphiphilic β-peptides were reported to fold into stable helical structures. [1,[54][55][56] Aiming at a more complete and representative validation of our force field, we have chosen one of the water-soluble β-undecapeptides, which forms a H14 helix in water (denoted later on as "AH", schematically represented in Figure 17). [55] The amino acid sequence of this peptide has been designed in a way that in the H14 helix, where three amino acids correspond to a full turn, the hydrophilic side-chains can form salt bridges, which in turn stabilize the fold.…”

Self‐Assembly of a β‐Peptide Foldamer: The Role of the Surfactant in Three‐Dimensional Shape Selection

“…Artificial β-peptide foldamers with characteristic folded structures have been utilized to construct a wide variety of discrete supramolecular architectures ranging from protein-like tertiary structures to self-assembled nanofibers. [1][2][3][4][5][6] The advantages of β-peptide foldamers as building blocks for supramolecular assembly, such as predictable molecular conformation and controlled self-association, provide valuable opportunities to develop structurally well-defined nanomaterials with desirable mechanical and biochemical properties. [7][8][9][10] Of particular note is the 'foldecture', a new term coined by our group to represent a crystalline 3D microarchitecture formed by the self-assembly of peptide foldamers.…”