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Inspired by the key role of super-helical motifs in molecular self-organization, several tandem heptad repeat peptides were used as building blocks to form well-ordered supramolecular nano-assemblies. However, the need for stable helical structures limits the length of the smallest described units to three heptad repeats. Here we describe the first-ever self-assembling single heptad repeat module, based on the ability of the non-coded α-aminoisobutyric acid to stabilize very short peptides in helical conformation. A conformationally constrained peptide comprised of aromatic, but not aliphatic, residues, at the first and fourth positions formed helical fibrillar assemblies. Single crystal X-ray analysis of the peptide demonstrates super-helical packing in which phenylalanine residues formed an ‘aromatic zipper' arrangement at the molecular interface. The modification of the minimal building block with positively charged residues results in tight DNA binding ascribed to the combined factors of helicity, hydrophobicity and charge. The design of these peptides defines a new direction for assembly of super-helical nanostructures by minimal molecular elements.

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The unique physiochemical properties and multiscale organization of layered materials draw the attention of researchers across a wide range of scientific disciplines. Layered structures are commonly found in diverse biological systems where they fulfill various functions. A prominent example of layered biological materials is the organization of proteins and polypeptides into the archetypal aggregated amyloidal structures. While the organization of proteins into amyloid structures was initially associated with various degenerative disorders, it was later revealed that proteins not related to any disease could also form identical layered assemblies. Thus, it appears that the ability of peptides and proteins to produce amyloid-like aggregates represents a generic property of polyamides to assemble into higher order fibrillar structures. In the aggregated state, the peptide backbone forms β-sheet structures which are further organized into layered arrangements. We have recently extended the identified amyloidogenic building blocks to include not only peptides or proteins, but also single amino acids and other metabolites. High resolution spectroscopy and crystallography analyses confirm the clear potential of amino acids and other metabolites to form layered amyloid-like aggregates showing biophysical and biochemical properties similar to protein amyloids. Therefore, the generic propensity of peptides and proteins backbones to assemble into layered organizations may emanate from their basic building block, the amino acid. In this Account, we aim to introduce the concept of supramolecular β-sheet organization of single amino acids and to present an analysis of their layered-structure organization based on single crystal structures. We demonstrate that, despite the different side-chains that considerably vary in their chemical properties, all coded amino acids display a layer-like assembly stabilized by α-amine to α-carboxyl H-bonds, resembling supramolecular β-sheet structures, while the side-chains determine the higher order organization of the layers. Our work presents the first analysis of the β-sheet propensity of single amino acids in their unbound form, indicating an evolutionary predisposition. We classify the amino acids β-sheet propensity on the basis of the interlayer separation distance in the crystal packing, which correlates well with previously reported classifications based on various criteria, such as hydrophobicity, steric bulkiness, and folding. In addition, we demonstrate that the relative direction of α-amine to α-carboxyl H-bonding pattern provides critical insights regarding the stabilization of parallel versus antiparallel β-sheet structures by the various amino acids. Taken together, our analysis of amino acid crystals provides substantial information regarding protein folding and dynamics and could serve as basic rules set for the design of potential building blocks for molecular self-assembly to produce functional materials of tunable properties, an important objective of bottom-up nanotechn...

Extensive work has been invested in the design of bio-inspired peptide emulsifiers. Yet, none of the formulated surfactants were based on the utilization of the robust conformation and self-assembly tendencies presented by the hydrophobins, which exhibited highest surface activity among all known proteins. Here we show that a minimalist design scheme could be employed to fabricate rigid helical peptides to mimic the rigid conformation and the helical amphipathic organization. These designer building blocks, containing natural non-coded α-aminoisobutyric acid (Aib), form superhelical assemblies as confirmed by crystallography and microscopy. The peptide sequence is amenable to structural modularity and provides the highest stable emulsions reported so far for peptide and protein emulsifiers. Moreover, we establish the ability of short peptides to perform the dual functions of emulsifiers and thickeners, a feature that typically requires synergistic effects of surfactants and polysaccharides. This work provides a different paradigm for the molecular engineering of bioemulsifiers.

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Metabolite materials are extremely useful to obtain functional bioinspired assemblies with unique physical properties for various applications in the fields of material science, engineering, and medicine by selfassembly of the simplest biological building blocks. Supramolecular co-assembly has recently emerged as a promising extended approach to further expand the conformational space of metabolite assemblies in terms of structural and functional complexity. Yet, the design of synergistically co-assembled amino acids to produce tailormade functional architectures is still challenging. Herein, we propose a design rule to predict the supramolecular coassembly of naturally occurring amino acids based on their interlayer separation distances observed in single crystals. Using diverse experimental techniques, we demonstrate that amino acids with comparable interlayer separation strongly interact and co-assemble to produce structural composites distinctly different from their individual properties. However, such an interaction is hampered in a mixture of differentially layer-separated amino acids, which self-sort to generate individual characteristic structures. This study provides a different paradigm for the modular design of supramolecular assemblies based on amino acids with predictable properties.

The self-assembly of peptideb uilding blocks represents ac entral direction in bionanotechnology. A b-sheet secondary structure serves as the basis of numerousp eptide-based bionanomaterials owing to their association with several neurodegenerative diseases. Although the a-helix embodies the most common secondary structure motif in proteins, the utilization of this module as ab uilding block for supramolecular aggregation is much less explored. In this Focus Review, we will discussthe advancementm ade so far to induceh igher level organization in helical peptide building blocks.T he primary designs trategies involving coiled coil proteins mimetic approaches, incorporation of noncoded and synthetic amino acids and conjugation of peptides to aliphatic alkyl tails will be dealt with in detail.I n parallel, we will also outlinet he self-assembled materials developed in these progressions.F inally,p ossible future prospects of such assembly modules will be briefed.