A Molecular Dynamics Study on Controlling the Self‐Assembly of β‐Sheet Peptides with Designer Nanorings

Recently, a rational approach for constructing β‐barrel protein mimics by the self‐assembly of peptide‐based building blocks has been demonstrated. We performed molecular dynamics simulations of nanoring formation by means of the self‐assembly of designed β‐sheet‐forming peptides. Several factors contributing to the stability of the nanoring structures with respect to size were investigated. Our simulations predicted that an optimal nanoring size may be achieved by minimizing repulsions due to steric hindrance between bulky groups while maintaining favorable hydrogen‐bond interactions between neighboring β‐sheet chains. It was shown that mutations in a test peptide, in which all or half of the tryptophan residues were replaced by phenylalanine, could enable the assembly of stable nanoring structures with smaller pore sizes. Insights into the fundamental factors driving the formation of peptide‐based nanostructures are expected to facilitate the design of novel functional bionanostructures.     

The self‐assembled of cyclic D,L‐α‐peptide systems: Insights into the structure and energetics

Cyclic D,L ‐α‐peptides are able to self‐assemble to nanotubes, although the inherent reason of the stability of this kind of nanotube as well as the intrinsic driving force of self‐assembly of the cyclic D ,L ‐α‐peptides still remain elusive. In this work, using several computational approaches, we investigated the structural and energy characteristics of a series of cyclo[(‐L ‐Phe‐D ‐Ala‐)₄] and cyclo[(‐L ‐Ala‐D ‐Ala‐)₄] oligomers. The results reveal that the thermodynamic stability, cooperativity, and self‐assembly patterns of cyclic D ,L ‐α‐peptide nanotubes are mainly determined by the interactions between cross‐strand side chains instead of those between backbones. For cyclo[(‐L ‐Phe‐D ‐Ala‐)₄] oligomers, the steric interaction between cross‐strand side chains, especially the electrostatic repulsion between the phenyls in Phe residues, brings anticooperative effect into parallel stacking mode, which is responsible for the preference of self‐assembling nanotube in antiparallel vs. parallel stacking orientation. Based on our results, a novel self‐assembling mechanism is put forward—it is the L ‐L antiparallel dimer of cyclo[(‐L ‐Phe‐D ‐Ala‐)₄], instead of the commonly presumed monomer, that acts as the basic building block in self assembly. It explains why these cyclic peptides uniquely self‐assemble to form antiparallel nanotubes. © 2009 Wiley Periodicals, Inc. Int J Quantum Chem, 2010     

Copper(II)‐Mediated Self‐Assembly of Hairpin Peptides and Templated Synthesis of CuS Nanowires

The self‐assembly of peptides and proteins under well‐controlled conditions underlies important nanostructuring processes that could be harnessed in practical applications. Herein, the synthesis of a new hairpin peptide containing four histidine residues is reported and the self‐assembly process mediated by metal ions is explored. The work involves the combined use of circular dichroism, NMR spectroscopy, UV/Vis spectroscopy, AFM, and TEM to follow the structural and morphological details of the metal‐coordination‐mediated folding and self‐assembly of the peptide. The results indicate that by forming a tetragonal coordination geometry with four histidine residues, copper(II) ions selectively trigger the peptide to fold and then self‐assemble into nanofibrils. Furthermore, the copper(II)‐bound nanofibrils template the synthesis of CuS nanowires, which display a near‐infrared laser‐induced thermal effect.     

Intramolecular Charge Interactions as a Tool to Control the Coiled‐Coil‐to‐Amyloid Transformation

Under the influence of a changed environment, amyloid‐forming proteins partially unfold and assemble into insoluble β‐sheet rich fibrils. Molecular‐level characterization of these assembly processes has been proven to be very challenging, and for this reason several simplified model systems have been developed over recent years. Herein, we present a series of three de novo designed model peptides that adopt different conformations and aggregate morphologies depending on concentration, pH value, and ionic strength. The design strictly follows the characteristic heptad repeat of the α‐helical coiled‐coil structural motif. In all peptides, three valine residues, known to prefer the β‐sheet conformation, have been incorporated at the solvent‐exposed b, c, and f positions to make the system prone to amyloid formation. Additionally, pH‐controllable intramolecular electrostatic repulsions between equally charged lysine (peptide A) or glutamate (peptide B) residues were introduced along one side of the helical cylinder. The conformational behavior was monitored by circular dichroism spectroscopic analysis and thioflavin T fluorescence, and the resulting aggregates were further characterized by transmission electron microscopy. Whereas uninterrupted α‐helical aggregates are found at neutral pH, Coulomb repulsions between lysine residues in peptide A destabilize the helical conformation at acidic pH values and trigger an assembly into amyloid‐like fibrils. Peptide B features a glutamate‐based switch functionality and exhibits opposite pH‐dependent folding behavior. In this case, α‐helical aggregates are found under acidic conditions, whereas amyloids are formed at neutral pH. To further validate the pH switch concept, peptide C was designed by including serine residues, thus resulting in an equal distribution of charged residues. Surprisingly, amyloid formation is observed at all pH values investigated for peptide C. The results of further investigations into the effect of different salts, however, strongly support the crucial role of intramolecular charge repulsions in the model system presented herein.     

Silica Nanowires Templated by Amyloid‐like Fibrils

Many peptides self‐assemble to form amyloid fibrils. We previously explored the sequence propensity to form amyloid using variants of a designed peptide with sequence KFFEAAAKKFFE. These variant peptides form highly stable amyloid fibrils with varied lateral assembly and are ideal to template further assembly of non‐proteinaceous material. Herein, we show that the fibrils formed by peptide variants can be coated with a layer of silica to produce silica nanowires using tetraethyl‐orthosilicate. The resulting nanowires were characterized using electron microscopy (TEM), X‐ray fiber diffraction, FTIR and cross‐section EM to reveal a nanostructure with peptidic core. Lysine residues play a role in templating the formation of silica on the fibril surface and, using this library of peptides, we have explored the contributions of lysine as well as arginine to silica templating, and find that sequence plays an important role in determining the physical nature and structure of the resulting nanowires.     

Biocatalytic Self‐Assembly of Supramolecular Charge‐Transfer Nanostructures Based on n‐Type Semiconductor‐Appended Peptides

The reversible in situ formation of a self‐assembly building block (naphthalenediimide (NDI)–dipeptide conjugate) by enzymatic condensation of NDI‐functionalized tyrosine ( NDI‐Y ) and phenylalanine‐amide ( F‐NH₂ ) to form NDI‐YF‐NH₂ is described. This coupled biocatalytic condensation/assembly approach is thermodynamically driven and gives rise to nanostructures with optimized supramolecular interactions as evidenced by substantial aggregation induced emission upon assembly. Furthermore, in the presence of di‐hydroxy/alkoxy naphthalene donors, efficient charge‐transfer complexes are produced. The dynamic formation of NDI‐YF‐NH₂ and electronic and H‐bonding interactions are analyzed and characterized by different methods. Microscopy (TEM and AFM) and rheology are used to characterize the formed nanostructures. Dynamic nanostructures, whose formation and function are driven by free‐energy minimization, are inherently self‐healing and provide opportunities for the development of aqueous adaptive nanotechnology.     

Peptide‐Based Methods for the Preparation of Nanostructured Inorganic Materials

With their unique sequence‐specific self‐assembly and their substrate recognition properties, peptides play critical roles in controlling the biomineralization of inorganic nanostructures in natural systems and in directing the assembly of important soft matter. These attributes render them particularly useful molecules for the fabrication of new materials. Researchers from many scientific disciplines now use peptides to direct the synthesis of new inorganic nanostructures and the assembly of soft biomaterials. In this Review we describe the developments in this field and focus on the versatility of peptides and their ability to direct the composition and structure of new inorganic materials.     

Covalent Self‐Assembly and One‐Step Photocrosslinking of Tyrosine‐Rich Oligopeptides to Form Diverse Nanostructures

We present covalently self‐assembled peptide hollow nanocapsule and peptide lamella. These biomimetic dityrosine peptide nanostructures are synthesized by one‐step photopolymerization of a tyrosine‐rich short peptide without the aid of a template. This simple approach offers direct synthesis of fluorescent peptide nanocages and free‐standing thin films. The simple crosslinked peptide lamella films provide robust mechanical properties with an elastic modulus of approximately 30 GPa and a hardness of 740 MPa. These nanostructures also allow for the design of peptidosomes. The approach taken here represents a rare example of covalent self‐assembly of short peptides into nano‐objects, which may be useful as microcompartments and separation membranes.     

Oligopeptide‐Assisted Self‐Assembly of Oligothiophenes: Co‐Assembly and Chirality Transfer

The biomolecule‐assisted self‐assembly of semiconductive molecules has been developed recently for the formation of potential bio‐based functional materials. Oligopeptide‐assisted self‐assembly of oligothiophene through weak intermolecular interactions was investigated; specifically the self‐assembly and chirality‐transfer behavior of achiral oligothiophenes in the presence of an oligopeptide with a strong tendency to form β‐sheets. Two kinds of oligothiophenes without (QT) or with (QTDA) carboxylic groups were selected to explore the effect of the end functional group on self‐assembly and chirality transfer. In both cases, organogels were formed. However, the assembly behavior of QT was quite different from that of QTDA. It was found that QT formed an organogel with the oligopeptide and co‐assembled into chiral nanostructures. Conversely, although QTDA also formed a gel with the oligopeptide, it has a strong tendency to self‐assemble independently. However, during the formation of the xerogel, the chirality of the oligopeptide can also be transferred to the QTDA assemblies. Different assembly models were proposed to explain the assembly behavior.     

Biological Glucose Metabolism Regulated Peptide Self‐Assembly as a Simple Visual Biosensor for Glucose Detection

A glucose oxidase (GOx)‐mediated glucose metabolism was in vitro mimicked and employed to regulate the self‐assembly of peptide‐based building blocks. In this new stimuli‐responsive self‐assembly system, two peptide‐based building blocks, respectively, having aspartic acid (gelator 1 ) and lysine (gelator 2 ) residues were designed and prepared. When adding glucose and GOx to the aqueous solution of gelator 1 or the self‐assembled fibrillar hydrogel of gelator 2 to construct glucose metabolism system, the metabolic product (gluconic acid) can trigger the protonation of the peptide molecules and induce the phase transitions of gelators 1 (sol‐gel) and 2 (gel‐sol). Because this glucose metabolism regulated peptide self‐assembly is built on the oxidation of glucose, it can be used as a simple visual biosensor for glucose detection.     

Poly(L‐lysine)‐Induced Aggregation of Single‐Strand Oligo‐DNA‐Modified Gold Nanoparticles

Single‐strand oligo‐DNA‐modified Au nanoparticles (AuNPs) undergo aggregation in the presence of poly(L ‐lysine) (PLL), which is attributed to the interactions between the oligo‐DNA and PLL. These interactions between the oligo‐DNA and PLL were identified to be electrostatic when the lysine residues of PLL were positively charged and to be hydrogen bonding when the residues were deprotonated. The aggregation was promoted with an increase in the pH value at a pH level lower than the pK_a value of PLL (pK_a≈10.0) due to the gradual deprotonation of the lysine residues and thus suppressed electrostatic interactions between the positively charged lysine residues of PLL and the negatively charged backbone phosphate groups of the oligo‐DNA. At pH levels higher than the pK_a value of PLL, the aggregation was identified to be dominated by the hydrogen bonds between the bases of the oligo‐DNA and the deprotonated lysine residues of PLL. This study prompts the possibility that the spectral, and thus color, change of AuNPs upon aggregation can be used as a probe to follow the interactions between oligo‐DNA and polypeptides.     

Fabrication of Chiral Materials via Self‐Assembly and Biomineralization of Peptides

With different scales of chirality, chiral materials have various particular properties and potential applications in many fields. Peptides are the fundamental building units of biological systems, and a variety of ordered functional nanostructures are produced through self‐assembly and biomineralization of peptides in nature. This Personal Account describes chiral silica materials fabricated by using amphiphilic peptides as building blocks. Three particular biomineralization approaches are described based on different kinds of geometry of amphiphilic peptides: the influence of the specific amino acid proline in the peptide sequence, the hydrophilicity of amphiphilic peptides, and different kinds of hydrophobic tails in amphiphilic peptides. These strategies are useful for designing peptides toward the bottom‐up synthesis of nanomaterials as well as improving the understanding of the mechanism of peptide self‐assembly.     

Secondary‐Structure‐Driven Self‐Assembly of Reactive Polypept(o)ides: Controlling Size,Shape, and Function of Core Cross‐Linked Nanostructures

Achieving precise control over the morphology and function of polymeric nanostructures during self‐assembly remains a challenge in materials as well as biomedical science, especially when independent control over particle properties is desired. Herein, we report on nanostructures derived from amphiphilic block copolypept(o)ides by secondary‐structure‐directed self‐assembly, presenting a strategy to adjust core polarity and function separately from particle preparation in a bioreversible manner. The peptide‐inherent process of secondary‐structure formation allows for the synthesis of spherical and worm‐like core‐cross‐linked architectures from the same block copolymer, introducing a simple yet powerful approach to versatile peptide‐based core–shell nanostructures.     

Influence of hydrogen bonds between sidechains and cooperativity on self‐assembly of the cyclopeptides

The self‐assembly of four cyclic D,L‐octapeptides, [‐(D‐Ala‐Gln)₄‐], [‐(D‐Val‐Gln)₄‐], [‐(D‐Leu‐Gln)₄‐], and [‐(D‐Phe‐Gln)₄‐], was investigated on the theory level in detail. Based on these cyclic peptides, which contain L‐Gln residues and possess C₄ symmetry, a series of oligomers were constructed according to different stacking modes as well as interaction patterns. We employed the semiempirical molecular orbital method AM1 to optimize the structures of all the oligomers, some of which were further studied using density functional method B3PW91/6‐31G to calculate the interaction energies. The studies indicate that when these cyclopeptides aggregate to form oligomers, or even nanotubes, four more hydrogen bonds could form between the sidechains of L‐Gln residues in addition to eight hydrogen bonds formed between the backbones of adjacent two cyclic peptides, a result that would clearly affect the self‐assembling process of cyclic peptides. The main effects can be summarized as follows. First, the dimers of these cyclic peptides with C₄ symmetry are more stable than those with D₄ symmetry due to their additional H‐bonds between Gln sidechains. Second, for the self‐assembly of the cyclopeptides, there is a competition between parallel and antiparallel stacking modes in lower oligomers such as dimers. However, with an increasing degree of oligomerization, energetically there is an increased possibility for the cyclic peptides to take the parallel stacking mode in assembly. Finally, the synergetic effect of weak interactions is the fundamental driving force for cyclic peptides to form stable nanotubes. © 2005 Wiley Periodicals, Inc. Int J Quantum Chem, 2005     

Biocatalytic Self‐Assembly Cascades

The properties of supramolecular materials are dictated by both kinetic and thermodynamic aspects, providing opportunities to dynamically regulate morphology and function. Herein, we demonstrate time‐dependent regulation of supramolecular self‐assembly by connected, kinetically competing enzymatic reactions. Starting from Fmoc‐tyrosine phosphate and phenylalanine amide in the presence of an amidase and phosphatase, four distinct self‐assembling molecules may be formed which each give rise to distinct morphologies (spheres, fibers, tubes/tapes and sheets). By varying the sequence or ratio in which the enzymes are added to mixtures of precursors, these structures can be (transiently) accessed and interconverted. The approach provides insights into dynamic self‐assembly using competing pathways that may aid the design of soft nanostructures with tunable dynamic properties and life times.     

Chaotropic‐Anion‐Induced Supramolecular Self‐Assembly of Ionic Polymeric Micelles

Traditional micelle self‐assembly is driven by the association of hydrophobic segments of amphiphilic molecules forming distinctive core–shell nanostructures in water. Here we report a surprising chaotropic‐anion‐induced micellization of cationic ammonium‐containing block copolymers. The resulting micelle nanoparticle consists of a large number of ion pairs (≈60 000) in each hydrophobic core. Unlike chaotropic anions (e.g. ClO₄^?), kosmotropic anions (e.g. SO₄^2?) were not able to induce micelle formation. A positive cooperativity was observed during micellization, for which only a three‐fold increase in ClO₄^? concentration was necessary for micelle formation, similar to our previously reported ultra‐pH‐responsive behavior. This unique ion‐pair‐containing micelle provides a useful model system to study the complex interplay of noncovalent interactions (e.g. electrostatic, van der Waals, and hydrophobic forces) during micelle self‐assembly.     

Surface‐Assisted Self‐Assembly Strategies Leading to Supramolecular Hydrogels

Localized molecular self‐assembly processes leading to the growth of nanostructures exclusively from the surface of a material is one of the great challenges in surface chemistry. In the last decade, several works have been reported on the ability of modified or unmodified surfaces to manage the self‐assembly of low‐molecular‐weight hydrogelators (LMWH) resulting in localized supramolecular hydrogel coatings mainly based on nanofiber architectures. This Minireview highlights all strategies that have emerged recently to initiate and localize LMWH supramolecular hydrogel formation, their related fundamental issues and applications.     

DNA–Polymer Nanostructures by RAFT Polymerization and Polymerization‐Induced Self‐Assembly

Nanostructures derived from amphiphilic DNA–polymer conjugates have emerged prominently due to their rich self‐assembly behavior; however, their synthesis is traditionally challenging. Here, we report a novel platform technology towards DNA–polymer nanostructures of various shapes by leveraging polymerization‐induced self‐assembly (PISA) for polymerization from single‐stranded DNA (ssDNA). A “grafting from” protocol for thermal RAFT polymerization from ssDNA under ambient conditions was developed and utilized for the synthesis of functional DNA–polymer conjugates and DNA–diblock conjugates derived from acrylates and acrylamides. Using this method, PISA was applied to manufacture isotropic and anisotropic DNA–polymer nanostructures by varying the chain length of the polymer block. The resulting nanostructures were further functionalized by hybridization with a dye‐labelled complementary ssDNA, thus establishing PISA as a powerful route towards intrinsically functional DNA–polymer nanostructures.     

Gold‐Nanoparticle‐Mediated Jigsaw‐Puzzle‐like Assembly of Supersized Plasmonic DNA Origami

DNA origami has rapidly emerged as a powerful and programmable method to construct functional nanostructures. However, the size limitation of approximately 100 nm in classic DNA origami hampers its plasmonic applications. Herein, we report a jigsaw‐puzzle‐like assembly strategy mediated by gold nanoparticles (AuNPs) to break the size limitation of DNA origami. We demonstrated that oligonucleotide‐functionalized AuNPs function as universal joint units for the one‐pot assembly of parent DNA origami of triangular shape to form sub‐microscale super‐origami nanostructures. AuNPs anchored at predefined positions of the super‐origami exhibited strong interparticle plasmonic coupling. This AuNP‐mediated strategy offers new opportunities to drive macroscopic self‐assembly and to fabricate well‐defined nanophotonic materials and devices.     

A Signal‐Passing DNA‐Strand‐Exchange Mechanism for Active Self‐Assembly of DNA Nanostructures

DNA nanostructured tiles play an active role in their own self‐assembly in the system described herein whereby they initiate a binding event that produces a cascading assembly process. We present DNA tiles that have a simple but powerful property: they respond to a binding event at one end of the tile by passing a signal across the tile to activate a binding site at the other end. This action allows sequential, virtually irreversible self‐assembly of tiles and enables local communication during the self‐assembly process. This localized signal‐passing mechanism provides a new element of control for autonomous self‐assembly of DNA nanostructures.