Exploring cross-α amyloids: from functional roles to design innovations.

Amyloids are filamentous protein aggregates that have traditionally been associated with neurodegenerative diseases, although they are also known to play pivotal functional roles across diverse forms of life. Although the cross-β structure has represented the hallmark of amyloidal assemblies, a cross-α structure was recently characterized as a functional microbial amyloid, and further work has shown that de novo designed sequences also assemble into cross-α amyloids, emphasizing cross-α as an alternative paradigm for self-assembly into ordered aggregates. In this review, we summarize recent discoveries of cross-α amyloids both in nature and artificially designed systems, and we describe their fundamental structural organization, self-assembly mechanisms, and biological functions.

Conformation Controlled Hydrogelation of Minimalistic α, γ Hybrid Peptide.

A majority of short peptide (≤7 amino acids) hydrogels are primarily assembled via cross β-structure formation. In contrast to the natural trend, herein, we report the formation of supramolecular hydrogel from the ultrashort hybrid folded peptide composed of canonical α-amino acid and noncanonical γ-amino acid, Fmoc-γPhe-Phe-OH. The designed hybrid peptide hydrogel is composed of entangled fibers, has viscoelastic properties, exhibits proteolytic stability, and exhibits cytocompatibility with L929 fibroblast cells.

Peptide hydrogen-bonded organic frameworks.

Hydrogen-bonded porous frameworks (HPFs) are versatile porous crystalline frameworks with diverse applications. However, designing chiral assemblies or biocompatible materials poses significant challenges. Peptide-based hydrogen-bonded porous frameworks (P-HPFs) are an exciting alternative to conventional HPFs due to their intrinsic chirality, tunability, biocompatibility, and structural diversity.

Metal-driven folding and assembly of a minimal β-sheet into a 3D-porous honeycomb framework.

In contrast to short helical peptides, constrained peptides, and foldamers, the design and fabrication of crystalline 3D frameworks from the β-sheet peptides are rare because of their high self-aggregation propensity to form 1D architectures. Herein, we demonstrate the formation of a 3D porous honeycomb framework through the silver coordination of a minimal β-sheet forming a peptide having terminal metal coordinated 4- and 3-pyridyl ligands.

Facet Engineering for Amplified Spontaneous Emission in Metal Halide Perovskite Nanocrystals.

Auger recombination and thermalization time are detrimental in reducing the gain threshold of optically pumped semiconductor nanocrystal (NC) lasers for future on-chip nanophotonic devices. Here, we report the design strategy of facet engineering to reduce the gain threshold of amplified spontaneous emission by manyfold in NCs of the same concentration and edge length. We achieved this hallmark result by controlling the Auger recombination rates dominated by processes involving NC volume and thermalization time to the emitting states by optimizing the number of facets from 6 (cube) to 12 (rhombic dodecahedron) and 26 (rhombicuboctahedrons) in CsPbBr NCs.

Molecular Engineering of Rigid Hydrogels Co-assembled from Collagenous Helical Peptides Based on a Single Triplet Motif.

The potential of ultra-short peptides to self-assemble into well-ordered functional nanostructures makes them promising minimal components for mimicking the basic ingredient of nature and diverse biomaterials. However, selection and modular design of perfect sequences are extremely tricky due to their vast possible combinatorial space. Moreover, a single amino acid substitution can drastically alter the supramolecular packing structure of short peptide assemblies.

Room-Temperature Anomalous Coherent Excitonic Optical Stark Effect in Metal Halide Perovskite Quantum Dots.

Nonresonant optical driving of confined semiconductors can open up exciting opportunities for experimentally realizing strongly interacting photon-dressed (Floquet) states through the optical Stark effect (OSE) for coherent modulation of the exciton state. Here we report the first room-temperature observation of the Floquet biexciton-mediated anomalous coherent excitonic OSE in CsPbBr quantum dots (QDs). Remarkably, the strong exciton-biexciton interaction leads to a coherent red shift and splitting of the exciton resonance as a function of the drive photon frequency, similar to Autler-Townes splitting in atomic and molecular systems.

Disordered Protein Stabilization by Co-Assembly of Short Peptides Enables Formation of Robust Membranes.

Molecular self-assembly is a spontaneous natural process resulting in highly ordered nano to microarchitectures. We report temperature-independent formation of robust stable membranes obtained by the spontaneous interaction of intrinsically disordered elastin-like polypeptides (ELPs) with short aromatic peptides at temperatures both below and above the conformational transition temperature of the ELPs. The membranes are stable over time and display durability over a wide range of parameters including temperature, pH, and ultrasound energy.

Inhibitor-Mediated Structural Transition in a Minimal Amyloid Model.

Despite the fundamental clinical importance of amyloid fibril formation, its mechanism is still enigmatic. Crystallography of minimal amyloid models was a milestone in the understanding of the architecture and biological activities of amyloid fibers. However, the crystal structure of ultimate dipeptide-based amyloids is not yet reported.

Homocysteine fibrillar assemblies display cross-talk with Alzheimer's disease β-amyloid polypeptide.

High levels of homocysteine are reported as a risk factor for Alzheimer's disease (AD). Correspondingly, inborn hyperhomocysteinemia is associated with an increased predisposition to the development of dementia in later stages of life. Yet, the mechanistic link between homocysteine accumulation and the pathological neurodegenerative processes is still elusive.

Molecular engineering of piezoelectricity in collagen-mimicking peptide assemblies.

Realization of a self-assembled, nontoxic and eco-friendly piezoelectric device with high-performance, sensitivity and reliability is highly desirable to complement conventional inorganic and polymer based materials. Hierarchically organized natural materials such as collagen have long been posited to exhibit electromechanical properties that could potentially be amplified via molecular engineering to produce technologically relevant piezoelectricity. Here, by using a simple, minimalistic, building block of collagen, we fabricate a peptide-based piezoelectric generator utilising a radically different helical arrangement of Phe-Phe-derived peptide, Pro-Phe-Phe and Hyp-Phe-Phe, based only on proteinogenic amino acids.

Solid-state packing dictates the unexpected solubility of aromatic peptides.

The understanding and prediction of the solubility of biomolecules, even of the simplest ones, reflect an open question and unmet need. Short aromatic tripeptides are among the most highly aggregative biomolecules. However, in marked contrast, Ala-Phe-Ala (AFA) was surprisingly found to be non-aggregative and could be solubilized at millimolar concentrations.

Liquid-Liquid Phase Separation of Tau Protein Is Encoded at the Monomeric Level.

Liquid-liquid phase separation (LLPS) is involved in both physiological and pathological processes. The intrinsically disordered protein Tau and its K18 construct can undergo LLPS in a distinct temperature-dependent manner, and the LLPS of Tau protein can initiate Tau aggregation. However, the underlying mechanism driving Tau LLPS remains largely elusive.

Modulation of physical properties of organic cocrystals by amino acid chirality.

Amino acid chirality plays an important role in conveying directionality and specificity to their supramolecular organization. However, the impact of enantiopure and racemic amino acids on the favorable packing and macroscopic properties of organic cocrystals with nonchiral coformers is poorly understood. Herein, we performed a systematic study of the effect of chirality on the macroscopic properties of acetylated alanine (AcA) single crystals and cocrystals with a nonchiral photo-sensitive bipyridine derivative (BPE).

The effect of amide bond orientation and symmetry on the self-assembly and gelation of discotic tripeptides.

A series of discotic tripeptides containing a rigid aromatic core and l-phenylalanine have been developed. The orientation of the amide bonds yielded variations of the structure and self-assembly properties of the compounds. The aggregation behavior of the discotic tripeptides was studied by various spectroscopic techniques.

Tunable Mechanical and Optoelectronic Properties of Organic Cocrystals by Unexpected Stacking Transformation from H- to J- and X-Aggregation.

Molecular stacking modes, generally classified as H-, J-, and X-aggregation, play a key role in determining the optoelectronic properties of organic crystals. However, the control of stacking transformation of a specific molecule is an unmet challenge, and prediction of the performance in different stacking modes is extraordinarily difficult to achieve. In particular, the existence of hybrid stacking modes and their combined effect on physicochemical properties of molecular crystals are not fully understood.

Collagen-Inspired Helical Peptide Coassembly Forms a Rigid Hydrogel with Twisted Polyproline II Architecture.

Collagen, the most abundant protein in mammals, possesses notable cohesion and elasticity properties and efficiently induces tissue regeneration. The Gly-Pro-Hyp canonical tripeptide repeating unit of the collagen superhelix has been well-characterized. However, to date, the shortest tripeptide repeat demonstrated to attain a helical conformation contained 3-10 peptide repeats.

Diphenylalanine-Derivative Peptide Assemblies with Increased Aromaticity Exhibit Metal-like Rigidity and High Piezoelectricity.

Diphenylalanine (FF) represents the simplest peptide building block that self-assembles into ordered nanostructures with interesting physical properties. Among self-assembled peptide structures, FF nanotubes display notable stiffness and piezoelectric parameters (Young's modulus = 19-27 GPa, strain coefficient = 18 pC/N). Yet, inorganic alternatives remain the major materials of choice for many applications due to higher stiffness and piezoelectricity.

Coassembly-Induced Transformation of Dipeptide Amyloid-Like Structures into Stimuli-Responsive Supramolecular Materials.

Conformational transition of proteins and peptides into highly stable, β-sheet-rich structures is observed in many amyloid-associated neurodegenerative disorders, yet the precise mechanism of amyloid formation at the molecular level remains poorly understood due to the complex molecular structures. Short peptides provide simplified models for studying the molecular basis of the assembly mechanism that governs β-sheet fibrillation processes underlying the formation and inhibition of amyloid-like structures. Herein, we report a supramolecular coassembly strategy for the inhibition and transformation of stable β-sheet-rich amyloid-derived dipeptide self-assemblies into adaptable secondary structural fibrillar assemblies by mixing with bipyridine derivatives.

Nanomechanical Properties and Phase Behavior of Phenylalanine Amyloid Ribbon Assemblies and Amorphous Self-Healing Hydrogels.

Phenylalanine was the minimalistic and first of numerous nonproteinaceous building blocks to be demonstrated to form amyloid-like fibrils. This unexpected organization of such a simple building block into canonical architecture, which was previously observed only with proteins and peptides, has numerous implications for medicine and supramolecular chemistry. However, the morphology of phenylalanine fibrils and their mechanical properties was never characterized in solutions.

Self-Assembly of Aromatic Amino Acid Enantiomers into Supramolecular Materials of High Rigidity.

Most natural biomolecules may exist in either of two enantiomeric forms. Although in nature, amino acid biopolymers are characterized by l-type homochirality, incorporation of d-amino acids in the design of self-assembling peptide motifs has been shown to significantly alter enzyme stability, conformation, self-assembly behavior, cytotoxicity, and even therapeutic activity. However, while functional metabolite assemblies are ubiquitous throughout nature and play numerous important roles including physiological, structural, or catalytic functions, the effect of chirality on the self-assembly nature and function of single amino acids is not yet explored.

Rigid Tightly Packed Amino Acid Crystals as Functional Supramolecular Materials.

The formation of ordered nanostructures by metabolites is gaining increased interest due to the simplicity of the building blocks and their natural occurrence. Specifically, aromatic amino acids possess the ability to form ordered supramolecular interactions due to their limited solubility in aqueous solution. Unexpectedly, l-tyrosine (l-Tyr) is almost 2 orders of magnitude less soluble in water compared to l-phenylalanine (l-Phe).

Mechanically rigid supramolecular assemblies formed from an Fmoc-guanine conjugated peptide nucleic acid.

The variety and complexity of DNA-based structures make them attractive candidates for nanotechnology, yet insufficient stability and mechanical rigidity, compared to polyamide-based molecules, limit their application. Here, we combine the advantages of polyamide materials and the structural patterns inspired by nucleic-acids to generate a mechanically rigid fluorenylmethyloxycarbonyl (Fmoc)-guanine peptide nucleic acid (PNA) conjugate with diverse morphology and photoluminescent properties. The assembly possesses a unique atomic structure, with each guanine head of one molecule hydrogen bonded to the Fmoc carbonyl tail of another molecule, generating a non-planar cyclic quartet arrangement.

Unravelling the role of amino acid sequence order in the assembly and function of the amyloid-β core.

The amino acid sequence plays an essential role in amyloid formation. Here, using the central core recognition module of the Aβ peptide and its reverse sequence, we show that although both peptides assemble into β-sheets, their morphologies, kinetics and cell toxicities display marked differences. In addition, the native peptide, but not the reverse one, shows notable affinity towards bilayer lipid model membranes that modulates the aggregation pathways to stabilize the oligomeric intermediate states and function as the toxic agent responsible for neuronal dysfunction.