Aromatic peptide amphiphiles are gaining popularity as building blocks for the bottom-up fabrication of nanomaterials, including gels. These materials combine the simplicity of small molecules with ...the versatility of peptides, with a range of applications proposed in biomedicine, nanotechnology, food science, cosmetics, etc. Despite their simplicity, a wide range of self-assembly behaviours have been described. Due to varying conditions and protocols used, care should be taken when attempting to directly compare results from the literature. In this review, we rationalise the structural features which govern the self-assembly of aromatic peptide amphiphiles by focusing on four segments, (i) the N-terminal aromatic component, (ii) linker segment, (iii) peptide sequence, and (iv) C-terminus. It is clear that the molecular structure of these components significantly influences the self-assembly process and resultant supramolecular architectures. A number of modes of assembly have been proposed, including parallel, antiparallel, and interlocked antiparallel stacking conformations. In addition, the co-assembly arrangements of aromatic peptide amphiphiles are reviewed. Overall, this review elucidates the structural trends and design rules that underpin the field of aromatic peptide amphiphile assembly, paving the way to a more rational design of nanomaterials based on aromatic peptide amphiphiles.
We demonstrate the formation of supramolecular peptide nanofibers that display dynamic instability; i.e., they are formed by competing assembly and disassembly reactions, where assembly is favored ...away from equilibrium. The systems are based on competitive catalytic transacylation and hydrolysis, producing a self-assembling aromatic peptide amphiphile from amino acid precursors that temporarily exceeds the critical gelation concentration, until the competing hydrolytic reaction takes over. Analysis by atomic force microscopy shows consecutive nanofiber formation and shortening. The process results in macroscopically observable temporary hydrogelation, which may be repeated upon refueling the system with further addition of the chemically activated amino acid precursor. Nonequilibrium nanostructures open up opportunities for mimicry of the behavior of dynamic gels found in natural systems and provide components for future adaptive nanotechnologies.
Peptide-based supramolecular systems chemistry seeks to mimic the ability of life forms to use conserved sets of building blocks and chemical reactions to achieve a bewildering array of functions. ...Building on the design principles for short peptide-based nanomaterials with properties, such as self-assembly, recognition, catalysis, and actuation, are increasingly available. Peptide-based supramolecular systems chemistry is starting to address the far greater challenge of systems-level design to access complex functions that emerge when multiple reactions and interactions are coordinated and integrated. We discuss key features relevant to systems-level design, including regulating supramolecular order and disorder, development of active and adaptive systems by considering kinetic and thermodynamic design aspects and combinatorial dynamic covalent and noncovalent interactions. Finally, we discuss how structural and dynamic design concepts, including preorganization and induced fit, are critical to the ability to develop adaptive materials with adaptive and tunable photonic, electronic, and catalytic properties. Finally, we highlight examples where multiple features are combined, resulting in chemical systems and materials that display adaptive properties that cannot be achieved without this level of integration.
With improved understanding of the design rules for self-assembling peptides, new challenges will be faced to incorporate these materials into dynamic systems of higher complexity and functionality. ...In this highlight article we discuss very recent advances in these areas. Three areas are covered: (i) molecular networks based on peptides and their interactions including (bio-) catalytically driven systems; (ii) supramolecular functionality, both in the context of biological and nanotechnology applications; (iii) approaches to effectively interface peptides with synthetic and biological materials. We also discuss challenges and opportunities for the design of a new generation of peptide nanomaterials for the next decade.
Structural adaption in living systems is achieved by competing catalytic pathways that drive assembly and disassembly of molecular components under the influence of chemical fuels. We report on a ...simple mimic of such a system that displays transient, sequence‐dependent formation of supramolecular nanostructures based on biocatalytic formation and hydrolysis of self‐assembling tripeptides. The systems are catalyzed by α‐chymotrypsin and driven by hydrolysis of dipeptide aspartyl‐phenylalanine‐methyl ester (the sweetener aspartame, DF‐OMe). We observed switch‐like pathway selection, with the kinetics and consequent lifetime of transient nanostructures controlled by the peptide sequence. In direct competition, kinetic (rather than thermodynamic) component selection is observed.
Off the beaten track: Sequence‐dependent kinetic pathway selection in chemically fueled catalytic self‐assembly of tripeptides is demonstrated, in which the control of the lifetime of the nanostructures is dictated by chemical design. Mimicking the unique features of these systems may open up opportunities to create supramolecular systems for non‐equilibrium motility and shape control.
This Minireview concerns recent advances in the design, synthesis, and application of low molecular‐weight peptidic hydrogelators. The sequence‐specific combinations of amino acid side chain ...functionalities combined with hydrogen bonding of amide backbones and hydrophobic (aromatic) capping groups give these peptidic molecules the intrinsic tendency to self‐assemble. The most prevalent designs include N‐capped amino acid residues, bolamphiphilic peptides, and amphipathic peptides. Factors such as hydrophobic effects, the Hofmeister effect, and tunable ionization influence their aggregation properties. The self‐assembly of simple bio‐inspired building blocks into higher organized structures allows comparisons to be drawn with proteins and their complex functionalities, providing preliminary insights into complex biological functions and also enabling their application in a wide range of fields including catalysis, biomedical applications, and mimicry of natural dissipative systems. The Minireview is concluded by a short summary and outlook, highlighting the advances and steps required to bridge the gaps in the understanding of such systems.
Well gel: The self‐assembly of simple bio‐inspired building blocks into higher organized structures enables comparison with proteins and their complex functionalities providing preliminary insights into complex biological functions and also rendering their application to a wide range of fields from catalysis and biomedical applications to mimicking natural dissipative systems.
We have investigated the self-assembly behavior of fluorenyl-9-methoxycarbonyl (Fmoc)–FG, Fmoc–GG, and Fmoc–GF and compared it to that of Fmoc–FF using potentiometry, fluorescence and infrared ...spectroscopy, transmission electron microscopy, wide-angle X-ray scattering, and oscillatory rheometry. Titration experiments revealed a substantially shifted apparent pK a transition for Fmoc–FG, Fmoc–GG, and Fmoc–GF. The apparent pK a values observed correlated with the hydrophobicity (log P) of the Fmoc–dipeptide molecules. Fmoc–GG and Fmoc–GF were found to self-assemble only in their protonated form (below their apparent pK a), while Fmoc–FG formed self-assembled structures above and below its apparent pK a. Fmoc–GG and Fmoc–FG were found to form hydrogels below their apparent pK a transitions in agreement with the entangled fibers morphologies revealed by TEM. Unlike Fmoc–FF and Fmoc–GG, Fmoc–FG showed unusual gelation behavior as gels were found to form upon heating. Fmoc–GF formed precipitates instead of a hydrogel below its apparent pK a in agreement with the formation of micrometer scale sheetlike structures observed by TEM. The fact that all four Fmoc–dipeptides were found to self-assemble suggests that the main driving force behind the self-assembly process is a combination of the hydrophobic and π–π interactions of the fluorenyl moieties with a secondary role for hydrogen bonding of the peptidic components. The nature of the peptidic tail was found to have a pronounced effect on the type of self-assembled structure formed. This work indicates that the substitution of phenylalanine by glycine significantly impacts on the mode of assembly and illustrates the versatility of aromatic peptide amphiphiles in the formation of structurally diverse nanostructures.
Nature utilizes both order and disorder (or controlled disorder) to achieve exceptional materials properties and functions, while synthetic supramolecular materials mostly exploit just supramolecular ...order, thus limiting the structural diversity, responsiveness and consequent adaptive functions that can be accessed. Herein, we review the emerging field of supramolecular biomaterials where disorder and order deliberately co‐exist, and can be dynamically regulated by considering both entropic and enthalpic factors in design. We focus on sequence‐structure relationships that govern the (cooperative) assembly pathways of protein and peptide building blocks in these materials. Increasingly, there is an interest in introducing dynamic features in protein and peptide‐based structures, such as the remarkable thermo‐responsiveness and exceptional mechanical properties of elastin materials. Simultaneously, advances in the field of intrinsically disordered proteins (IDPs) give new insights about their involvement in intracellular liquid‐liquid phase separation and formation of disordered, dynamic coacervate structures. These have inspired efforts to design biomaterials with similar dynamic properties. These hybrid ordered/disordered materials employ a combination of intramolecular and supramolecular order/disorder features for construction of assemblies that are dynamically reconfigurable. The assembly of these dynamic structures is mainly entropy‐driven, relying on electrostatic and hydrophobic interactions and is mediated in part through the adopted (unstructured) protein conformation or by introducing an oppositely charged guest for peptide building blocks. Examples include design of protein building blocks composed of disordered repeat sequences of elastin‐like polypeptides in combination with ordered regions that adopt a secondary structure, the co‐assembly of proteins with peptide amphiphiles to achieve reconfigurable, yet highly stable membranes or tyrosine‐containing tripeptides with sequence‐controlled order/disorder that upon enzymatic oxidation give rise to melanin‐like polymeric pigments with customizable properties. The resulting hybrid materials with controlled disorder can be metastable, and sensitive to various external stimuli giving rise to insights that are especially attractive for the design of responsive and adaptive materials.
This review details recent developments in the design of supramolecular materials with customizable properties that can be coordinated in space and time. We highlight examples where both kinetic and ...thermodynamic considerations are incorporated in design, to address three challenges: control of order/disorder in supramolecular assembly; formation of structures with distinct functional domains; formation of out-of-equilibrium structures with controlled lifetimes. The examples that are discussed are based on self-assembling peptide and saccharide-based amphiphiles. These biomolecular amphiphiles are of low complexity and ideally suited to fundamental, systematic studies while they are also considered for applications in environmental remediation, food science, cosmetics and nanomedicine.
We report on a simple carbohydrate amphiphile able to self-assemble into nanofibers upon enzymatic dephosphorylation. The self-assembly can be triggered by alkaline phosphatase (ALP) in solution or ...in situ by the ALP produced by osteosarcoma cell line, SaOs2. In the latter case, assembly and localized gelation occurs mainly on the cell surface. The gelation of the pericellular environment induces a reduction of the SaOs2 metabolic activity at an initial stage (≤7 h) that results in cell death at longer exposure periods (≥24 h). We show that this effect depends on the phosphatase concentration, and thus, it is cell-selective with prechondrocytes ATDC5 (that express ∼15–20 times lower ALP activity compared to SaOs2) not being affected at concentrations ≤1 mM. These results demonstrate that simple carbohydrate derivatives can be used in an antiosteosarcoma strategy with limited impact on the surrounding healthy cells/tissues.
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