Biomimetic peptide self-assembly for functional materials

Abstract

Natural biomolecular systems have evolved to form a rich variety of supramolecular materials and machinery fundamental to cellular function. The assembly of these structures commonly involves interactions between specific molecular building blocks, a strategy that can also be replicated in an artificial setting to prepare functional materials. The self-assembly of synthetic biomimetic peptides thus allows the exploration of chemical and sequence space beyond that used routinely by biology. In this Review, we discuss recent conceptual and experimental advances in self-assembling artificial peptidic materials. In particular, we explore how naturally occurring structures and phenomena have inspired the development of functional biomimetic materials that we can harness for potential interactions with biological systems. As our fundamental understanding of peptide self-assembly evolves, increasingly sophisticated materials and applications emerge and lead to the development of a new set of building blocks and assembly principles relevant to materials science, molecular biology, nanotechnology and precision medicine.

Fig. 1. Supramolecular chemical space accessible to biomimetic self-assembling peptides.

Chemicaiiy simple peptide sequences afford mechanistic understanding of molecular-level interactions in ordered supramolecular structures. Peptide building blocks have informed us about diverse phenomena, including the conversion of homogeneous solutions of peptide building blocks into discrete biomolecular condensates (liquid–liquid phase separation) and ordered fibrillar structures such as amyloid fibrils. A subset of peptides can assemble at interfaces to generate biomimetic membranes of artificial cells and organelles, while others disrupt the membranes of bacterial and cancer cells through pore formation, thus offering a wide range of therapeutic applications. The formation of ordered structures has given rise to the generation of biomimetic fibrils that can hierarchically assemble into complex structures, including 3D matrices used as scaffolds for cell growth and for forming organic–inorganic hybrid materials through incorporating peptide motifs known to be involved in biomineralization processes in nature. LLPS, liquid–liquid phase separation.

Fig. 2. Biomimetic supramolecular peptide scaffolds enable cell adhesion and proliferation.

a | Peptides can seif-assembie into biomimetic matrices that act as scaffolds to generate cell cultures. b,c | Scanning electron micrographs depict osteogenic cell viability and morphology when grown in glycosaminoglycan-mimetic peptide nanofibrils that promote biomineralization (scale bars represent 50 μm). b | Cells grown on sulfonated-peptide-amphiphile fibrils mimicking glycosaminoglycan sulfate. c | Cell proliferation is reduced when lauryl-VVAGE (E-PA) fibrils bearing carboxylate groups are used. This material mimics non-sulfated glycosaminoglycans. d | The cells, falsely coloured here in cyan, adhere to the self-assembled peptide nanofibrils. e | The biocompatibility is evident from the cells extending into the peptide matrix. f | The cells can also remodel the matrix to best suit them. Parts b and c adapted with permission from REF., Elsevier. Parts d-f adapted with permission from REF., Elsevier.

Fig. 3. Self-assembly of membrane and surfactant-like peptides at interfaces.

a | A peptide self-assembly can stabilize a liquid-liquid interface. b | Transmission electron micrographs of the surfactant peptides A₆D (left) and V₆D (right), which form a dense network several micrometres long. c | On a smaller scale, these materials form open-ended tubes (left), micelles and spherical vesicles budding off the nanotubes in H₂O (right). d | KL4 models built using backbone torsion angle restraints from solid-state NMR data. KL4 conformer from measurements with two different lipids, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) (top and bottom, correspondingly). e | Transmission electron micrographs of diblock copolypeptide-surfactant complexes, indicating a lamellar order of periodicity. Parts b and c adapted with permission from REF., PNAS. Part d adapted with permission from REF., Elsevier. Part e adapted with permission from REF., American Chemical Society.

Fig. 4. Self-assembling biomimetic-peptide-based antimicrobial nanostructures.

a | Different peptide-membrane interactions are proposed to give rise to antibacterial functions. b | The MAX1 peptide undergoes environmentally triggered folding, selfassembly and non-covalent fibril-crosslinking processes to give a hydrogel. c | The supramolecular nanofibres formed by self-assembling peptide amphiphiles present cationic peptide sequences that are essential to their proposed mode of action. d | Scanning electron micrographs of Escherichia coli with and without diphenylalanine. This dipeptide forms nanostructures that have clear effects on bacterial morphology. FF, diphenylalanine. Part b adapted from REF., Springer Nature Limited. Part c adapted with permission from REF., American Chemical Society. Part d adapted from REF., CC BY 4.0.

Fig. 5. Mechanisms of liquid–liquid phase separation and condensation.

a | A homogeneous peptide solution can undergo liquid–liquid phase separation (LLPS) to give metastable condensates. These, in turn, can undergo a phase transition to form thermodynamically favoured solid fibrils. b | LLPS involves several weak forces, including electrostatic, cation–π, dipole–dipole and π–π interactions. c | Treating a solution of peptide RRASLRRASL with polyU RNA leads to complex coacervation on account of electrostatic forces, among other interactions (top). Bright-field (bottom left) and fluorescence (bottom right) images highlight aggregation into coacervate phase droplets. d | Schematics and bright-field-microscopy images presenting the effect of oligonucleotide hybridization, ion concentration and temperature on LLPS of poly(Lys) peptides. e | Transmission electron micrographs of Fmoc-Ala undergoing LLPS and phase transition to form increasingly organized structures. The transition from the kinetically trapped nucleation precursors to the nanofibrils is accompanied by a decrease in Gibbs free energy. DIC, differential interference contrast. Part b adapted with permission from REF., Elsevier. Part c adapted from REF., Springer Nature Limited. Part d adapted with permission from REF., American Chemical Society. Part e adapted with permission from REF., Wiley.

Fig. 6. Peptides as biomineralization scaffolds and organic–inorganic composite agents.

a | Self-assembled peptides can serve as templates for the deposition of inorganic materials. b | For example, Fmoc-protected 3,4-dihydroxy-L-phenylalanine dipeptide affords a hydrogel that reduces Ag⁺ ions over 3 days to give Ag crystals, as evidenced in transmission electron micrographs. c | Scanning electron micrographs of mineralized bone-like nodules on nanofibres of a glycosaminoglycan-mimicking peptide. d | Cryogenic transmission electron microscopy and selected-area electron diffraction (SAED) of hydroxyapatite mineralized at amphiphilic peptides. Black and white arrows indicate the location of the organic template and the position of inorganic crystals, respectively. SAED arrows indicate the oriented (002) reflection (1: (002), 2: {211}, 3: (004)). e | Formation of SiO₂ nanoparticles directed by self-assembled silaffin R5 peptide structures. Part b adapted with permission from REF., American Chemical Society (https://pubs.acs.org/doi/10.1021/nn502240r). Part c adapted with permission from REF., Elsevier. Part d adapted with permission from REF., Wiley. Part e adapted with permission from REF., Wiley.