Towards Supramolecular Catalysis with Small Self-assembled Peptides

Self-assembly of small peptides offers unique opportunities for the bottom-up construction of supramolecular catalysts that aim to emulate the efficiency and selectivity of natural enzymes. Small, information-rich, simple molecules based on amino acids can self-organise autonomously into complex systems with emergent catalytic properties. The power of noncovalent interactions can be used to construct supramolecular peptidic tertiary structures. Moreover, specific functional groups present in amino acid side-chains may present either a catalytic activity by themselves or be able to bind cofactors such as metal ions. In this scenario, although relevant progress has been achieved in recent years, promising applications in biomaterials science are foreseen. In this review, we discuss the state-of-the-art of this approach at the interface between supramolecular chemistry and peptide science.     

Synthesis and characterization of well-defined poly(l-lactide) functionalized graphene oxide sheets with high grafting ratio prepared through click chemistry and supramolecular interactions

Two simple and effective methods, “click” chemistry and supramolecular interactions, are demonstrated here to synthesize well-defined poly(l-lactide) (PLLA) functionalized graphene oxide (GO) sheets. We provide a simple method to introduce azide groups on GO sheets by the ring opening reaction of sodium azide with the epoxide groups of GO. The GO-N₃ sheets can easily undergo “click” reaction with alkyne-terminated PLLA by “grafting onto” method to produce GO/PLLA composites with high grafting ratio and exfoliated structure. Interestingly, GO-N₃ can be grafted with oxygen-containing polymers such as PLLA, polymethyl methacrylate (PMMA) or polyethylene oxide (PEO) via supramolecular interactions between the azide groups and these oxygen atoms on polymers, producing GO/polymer composites with low grafting ratio and intercalated structure. These “grafting onto” methods are useful to produce a variety of GO/polymer composites with different structure via “click” reaction or supramolecular interactions, which have potential applications in material science.     

NMR Studies on Li+, Na+ and K+ Complexes of Orthoester Cryptand o-Me2-1.1.1

Cryptands, a class of three-dimensional macrobicyclic hosts ideally suited for accommodating small guest ions, have played an important role in the early development of supramolecular chemistry. In contrast to related two-dimensional crown ethers, cryptands have so far only found limited applications, owing in large part to their relatively inefficient multistep synthesis. We have recently described a convenient one-pot, template synthesis of cryptands based on O,O,O-orthoesters acting as bridgeheads. Here we report variable-temperature, ¹H-1D EXSY and titration NMR studies on lithium, sodium, and potassium complexes of one such cryptand (o-Me₂-1.1.1). Our results indicate that lithium and sodium ions fit into the central cavity of the cryptand, resulting in a comparably high binding affinity and slow exchange with the bulk. The potassium ion binds instead in an exo fashion, resulting in relatively weak binding, associated with fast exchange kinetics. Collectively, these results indicate that orthoester cryptands such as o-Me₂-1.1.1 exhibit thermodynamic and kinetic properties in between those typically found for classical crown ethers and cryptands and that future efforts should be directed towards increasing the binding constants.     

Modulating Secondary Structure Motifs Through Photo-Labile Peptide Staples

Peptide-protein interactions (PPIs) are facilitated by the well-defined three-dimensional structure of bioactive peptides, interesting compounds for the development of new therapeutic agents. Their secondary structure and thus their propensity to engage in PPIs can be influenced by the introduction of peptide staples on the side chains. In particular, light-controlled staples based on azobenzene photoswitches and their structural influence on helical peptides have been studied extensively. In contrast, photolabile staples bearing photocages as a structural key motif, have mainly been used to block supramolecular interactions. Their influence on the secondary structure of the target peptide is under-investigated. Thus, in this study we use a combination of spectroscopic techniques and in silico simulations to systematically study a series of helical peptides with varying length of the photo-labile staple to obtain a detailed insight into the structure-property relationship in such photoresponsive biomolecules.     

Supramolecular Polymers – we've Come Full Circle

Since the first polymers were discovered, scientists have debated their structures. Before Hermann Staudinger published the brilliant concept of macromolecules, polymer properties were generally believed to be based on the colloidal aggregation of small particles or molecules. From 1920 onwards, polymers and macromolecules are synonymous with each other; i. e. materials made by many covalent bonds connecting monomers in 2 or 3 dimensions. Although supramolecular interactions between macromolecular chains are evidently important, e. g. in nylons, it was unheard of to proposing polymeric materials based on the interaction of small molecules. Breakthroughs in supramolecular chemistry, however, showed that polymer materials can be made by small molecules using strong directional secondary interactions; the field of supramolecular polymers emerged. In a way, we have come full circle. In this essay we give a personal story about the birth of supramolecular polymers, with special emphasis on their structures, way of formation, and the dynamic nature of their bonding. The adaptivity of supramolecular polymers has become a major asset for novel applications, e. g. in the direction for the sustainable use of polymers, but also in biomedicine and electronics as well as self-healing materials. The lessons learned in the past years include aspects that forecast a bright future for the use of supramolecular interactions in polymer materials in general and for supramolecular polymers in particular. In order to give full tribute to Staudinger in the year celebrating 100 years of macromolecules, we will show that many of the concepts of macromolecular polymers apply to supramolecular polymers, with only one important difference with fascinating consequences: the dynamic nature of the bonds that form polymer chains.     

Formation of 2D supramolecular architectures at electrochemical solid/liquid interfaces

The controlled formation of supramolecular architectures on chloride pre-covered Cu(1 0 0) has been studied by means of in situ scanning tunneling microscopy (STM) in an electrochemical environment. On top of the c(2 × 2)-Cl layer, ordered arrays of supramolecular cavitand structures could be obtained either by a surface assisted assembly of monomer building-blocks (1,1′-dibenzyl-4,4′-bipyridinium molecules) or by a direct adsorption of supramolecular assemblies (metallo-supramolecular squares) from the solution phase. Besides the omnipresent van-der-Waals-like interactions additional electrostatic interactions between the anionic chloride layer and the positively charged (metallo)-organic molecules are supposed to have strong impact on the 2D phase behavior in both cases.The obtained supramolecular entities with their cavities oriented towards the solution phase can be regarded as potential host assemblies for the specific inclusion of guest molecules.     

Amino-Acid-Anthraquinone Click Chemistry Conjugates Selectively Target Human Telomeric G-Quadruplexes

Guanine-rich sequences are known to fold into G-quadruplex (G4) arrangements, which are present in oncogenes and in the telomeric regions of chromosomes. In particular, G4s represent an obstacle to functioning of telomerase, an enzyme overexpressed in cancer cells causing their immortalization. Therefore, G4 stabilization using small molecules represents an appealing strategy for the medicinal chemist. Ligands based on an anthraquinone scaffold, to which peptidic side chains were attached by an amide bond, were previously reported. We envisioned improving this ligand concept leveraging the click chemistry approach, which, besides representing a flexible, high yielding synthetic strategy, allows an elongation of the side chains and an increase of π–π stacking and H-bond interactions with the nucleobases through the triazole ring. Compounds were tested for their ability to interact with G4 DNA with a multiple analytical approach, demonstrating an elevated aptitude to stabilize the G4 and high selectivity over double stranded DNA.     

Trifluoroethanol may form a solvent matrix for assisted hydrophobic interactions between peptide side chains

Several models for interactions between trifluoroethanol (TFE)and peptides and proteins have recently been proposed, but nonehave been able to rationalize the puzzling observations thaton the one hand TFE can stabilize some hydrophobic interactionsin secondary structures, but on the other can also melt thehydrophobic cores of globular proteins. The former is illustratedin this paper by the effect of TFE on a short elastin peptide,GVG(VPGVG)₃, which forms type II ß-turns stabilized byhydrophobic interactions between two intra-turn valine sidechains. This folding, driven by increasing the entropy of bulkwater, is stimulated in TFE–water mixtures and/or by raisingthe temperature. To explain these apparently contradictory observations,we propose a model in which TFE clusters locally assist thefolding of secondary structures by first breaking down interfacialwater molecules on the peptide and then providing a solventmatrix for further side chain–side chain interactions.This model also provides an explanation for TFE-induced transitionsbetween secondary structures, in which the TFE clusters mayredirect non-local to local interactions.     

Dual Stimuli-Responsive Cross-Linked AIE Supramolecular Polymer Constructed through Hierarchical Self-Assembly

Herein, we report the successful construction of a new family of dual stimuli-responsive AIE cross-linked supramolecular polymer through the strategy of hierarchical self-assembly. A novel dipyridyl donor building block G1 containing tetraphenylethylene (TPE) moiety was designed and synthesized. Notably, two nitrile units were attached onto G1 , which were employed as the guest for the further host-guest interaction with pillar[n]arene derivatives. The rhomboidal metallacycle G2 with four nitrile units was firstly constructed through coordination-driven self-assembly. Subsequently, the cross-linked supramolecular polymers H₂⊃G2 were then generated through host-guest interactions. It should be noted that the obtained supramolecular polymer displayed interesting AIE properties due to the restriction of TPE intramolecular motions within the polymeric network. More importantly, by taking advantages of dynamic nature of both coordination bonds and host-guest interactions, the resultant supramolecular polymer displayed dual stimuli-responsive fluorescent transitions under different stimuli such as the competitive guest and halide anion.     

DNA-functionalized thermoresponsive bioconjugates synthesized via ATRP and click chemistry

Diblock and miktoarm star-shaped thermoresponsive copolymers composed of single-stranded DNA (ssDNA) and poly(N-isopropylacrylamide) were successfully synthesized with combination of atom transfer radical polymerization (ATRP) and click chemistry. This approach should be generalizable to other DNA-functionalized copolymers. Such copolymers self-assemble into spherical micelles with ssDNA corona in aqueous solution above the lower critical solution temperature. The micellar size can be tuned from the macromolecular architecture. These DNA-encoded micellar particles are able to encapsulate and release hydrophobic guest molecules upon changing temperature.     

C3‐Symmetrical π‐Scaffolds: Useful Building Blocks to Construct Helical Supramolecular Polymers

In this review, we highlight some relevant examples of C₃‐symmetrical molecules that have been reported to form supramolecular polymers and helical aggregates. In particular, the number and type of non‐covalent forces are key to bias the supramolecular polymerization leading from a simple isodesmic or cooperative mechanism to a more complex self‐assembly process, i. e. pathway complexity. Furthermore, the attachment of stereogenic centres at the peripheral side chains of the C₃‐systems provokes efficient transfer and amplification of chirality phenomena when directional and specific non‐covalent interactions operate. Interestingly, the incorporation of hydrophilic side chains induces the formation of organized aggregates in aqueous media with potential biomedical applications. Overall, the examples shown in this review on C₃‐symmetrical scaffolds illustrate the relevance of this molecular shape in the development of functional supramolecular structures.     

Halogen bonds in 2D supramolecular self-assembly of organic semiconductors

Weak interactions between bromine, sulphur, and hydrogen are shown to stabilize 2D supramolecular monolayers at the liquid-solid interface. Three different thiophene-based semiconducting organic molecules assemble into close-packed ultrathin ordered layers. A combination of scanning tunneling microscopy (STM) and density functional theory (DFT) elucidates the interactions within the monolayer. Electrostatic interactions are identified as the driving force for intermolecular BrBr and BrH bonding. We find that the SS interactions of the 2D supramolecular layers correlate with the hole mobilities of thin film transistors of the same materials.     

Effect of matrix−nanoparticle supramolecular interactions on the morphology and mechanical properties of polymer foams

In this study, we report the fabrication of supramolecular polymer nanocomposite foams with a uniform cell structure, high cell density and high expansion ratio using a soft matrix of poly(methyl acrylate‐co‐2‐hydroxyethyl methacrylate) and silica nanoparticle fillers, both functionalized with ureido‐pyrimidinone (UPy) supramolecular groups. Microcellular structures were formed using a batch foaming process at 90 °C under a 9 MPa nitrogen atmosphere. Nanocomposites were characterized and compared before and after the foaming process to investigate the effect of supramolecular interactions on the thermomechanical properties and morphology of the foams. TEM images revealed that while strong inter‐filler supramolecular interactions do not have a positive effect on their dispersion state, matrix?filler interactions derived from hydrogen bonding UPy motifs result in a rather uniform distribution of nanoparticles. Competing filler?filler and matrix?filler supramolecular interactions can be balanced and optimized by adjusting UPy populations along the chains and on the surface of nanoparticles. At a given chain functionality, increasing the nanoparticle loading up to an optimum concentration improves the mechanical properties and formability of the system. Above such concentration strong interactions between fillers, which are not compensated by the matrix, result in large aggregates and consequently undermine the material performance. Supramolecular polymer foams illustrate a similar thermal and viscoelastic behavior to that of neat samples but after foaming, due to the formation of a cellular structure and rearrangement or dissociation of UPy dimers under the foaming conditions, the elastic modulus is reduced. © 2018 Society of Chemical Industry     

Self-healing supramolecular hydrogels fabricated by cucurbit[8]uril-enhanced π-π interaction

Novel self-healing supramolecular hydrogels have successfully been fabricated through reversible cucurbit[8]uril (CB[8])-enhanced π-π interaction. Naphthaline groups in the side chains of copolymers and CB[8] molecules are employed as cross-linkers to form 1:2 ternary complex by host-guest interaction. Furthermore, the dipole-dipole interaction between the polar carbonyl groups of CB[8] and quaternary ammonium cation also contributes to the formation of self-healing property. It is found that the molar ratio of CB[8] to naphthaline units has a great influence on its self-healing property. This work represents a facile approach for fabricating cucurbituril-based self-healing supramolecular hydrogels, which can be potentially applied in several fields.     

Current Understanding of the Structure,Stability and Dynamic Properties of Amyloid Fibrils

Amyloid fibrils are supramolecular protein assemblies represented by a cross-β structure and fibrous morphology, whose structural architecture has been previously investigated. While amyloid fibrils are basically a main-chain-dominated structure consisting of a backbone of hydrogen bonds, side-chain interactions also play an important role in determining their detailed structures and physicochemical properties. In amyloid fibrils comprising short peptide segments, a steric zipper where a pair of β-sheets with side chains interdigitate tightly is found as a fundamental motif. In amyloid fibrils comprising longer polypeptides, each polypeptide chain folds into a planar structure composed of several β-strands linked by turns or loops, and the steric zippers are formed locally to stabilize the structure. Multiple segments capable of forming steric zippers are contained within a single protein molecule in many cases, and polymorphism appears as a result of the diverse regions and counterparts of the steric zippers. Furthermore, the β-solenoid structure, where the polypeptide chain folds in a solenoid shape with side chains packed inside, is recognized as another important amyloid motif. While side-chain interactions are primarily achieved by non-polar residues in disease-related amyloid fibrils, the participation of hydrophilic and charged residues is prominent in functional amyloids, which often leads to spatiotemporally controlled fibrillation, high reversibility, and the formation of labile amyloids with kinked backbone topology. Achieving precise control of the side-chain interactions within amyloid structures will open up a new horizon for designing useful amyloid-based nanomaterials.     

Inclusion complexes containing poly(?-caprolactone)diol and cyclodextrins. Experimental and theoretical studies

Inclusion complexes (ICs) between poly(?-caprolactone)diol (PEC) with α-cyclodextrin (α-CD) (α-CD-PEC) and γ-cyclodextrin (γ-CD) (γ-CD-PEC) were prepared and characterized by FT-IR, ¹H NMR, thermogravimetry, surface activity and wettability measurements. The thermal stabilities of the inclusion complexes are very similar. The thermal stability of PEC is better than ICs and CDs. Stable monolayers of PEC and α-CD-PEC and γ-CD-PEC complexes have been obtained at the air-water interface using the Langmuir Technique. The surface pressure-area isotherms (π-A) were found to be of different types, depending on the CD utilized. From the surface free energy values of PEC and ICs it was possible to conclude that ICs are more hydrophobic than cyclodextrins. PEC is the most hydrophobic. The surface parameters the minimum area A₀, the critical surface pressure π_c, and static elasticity ?₀ were also estimated for ICs and PEC. In order to describe the experimental results, molecular dynamic simulation (MDS) was performed. In addition, the physical properties that stabilize CD-CD, CD-polymer and CD-solvent interactions were elucidated by MDS. Theoretical results have demonstrated that complexes are stabilized by hydrophobic interactions between the cavity of CDs and the -(CH₂)₅-units of PEC, and also by hydrogen-bond formation between the hydroxyl groups situated along the rim of CD molecules threaded onto the PEC chain. CD-CD hydrogen-bond formation is maximized in 1:2 γ-CD-PEC complex and 1:1 α-CD-PEC complexes.     

Poly(ethylene glycol)-oligodeoxyribonucleotide block copolymers for affinity capillary electrophoretic separation of single-stranded DNAs with a single-base difference

An affinity capillary electrophoretic method was developed to detect a single-base difference of single-stranded DNA (ssDNA). Poly(ethylene glycol)-oligodeoxyribonucleotide block copolymers (PEG-b-ODN) were prepared for use as a novel affinity ligand. We introduced a running buffer solution of PEG-b-ODN into a capillary tube, and electrophoretically separated a mixture of chemically synthesized 20 mer ssDNA (normal ssDNA) and a single-base-substituted 20 mer ssDNA (mutant ssDNA). When the base sequence of PEG-b-ODN was designed to be complementary to part of the normal ssDNA, the migration rate of the normal ssDNA was significantly decreased by reversible hybridization with PEG-b-ODN, depending on the base number of PEG-b-ODN, the salt concentration of the running buffer, and the capillary temperature. In contrast, the mobility of mutant ssDNA did not change because the interaction with PEG-b-ODN was negligible. Optimization of the analytical conditions gave two distinct peaks, one for normal and the other for mutant ssDNA, on the electropherogram, allowing for facile discrimination of the single-base difference. The results indicate that PEG-b-ODN is a promising affinity ligand for the capillary electrophoretic separation of normal and single-base mutated ssDNA.     

Supramolecular Assembly and Binding in Aqueous Solution: Useful Tips Regarding the Hofmeister and Hydrophobic Effects

The self-assembly of structurally discrete entities, and supramolecular chemistry in general, continues to expand into the aqueous realm. To do so, however, requires a firm understanding of the properties of aqueous solution, and how these “change the rules” for binding and assembly relative to organic solvents. In this mini-review we highlight the state-of-the-art understanding of the supramolecular properties of water, and how these influence the design of hosts and self-assembling systems.     

Supracolloidal Assemblies as Sacrificial Templates for Porous Silk-Based Biomaterials

Tissues in the body are hierarchically structured composite materials with tissue-specific properties. Urea self-assembles via hydrogen bonding interactions into crystalline supracolloidal assemblies that can be used to impart macroscopic pores to polymer-based tissue scaffolds. In this communication, we explain the solvent interactions governing the solubility of urea and thereby the scope of compatible polymers. We also highlight the role of solvent interactions on the morphology of the resulting supracolloidal crystals. We elucidate the role of polymer-urea interactions on the morphology of the pores in the resulting biomaterials. Finally, we demonstrate that it is possible to use our urea templating methodology to prepare Bombyx mori silk protein-based biomaterials with pores that human dermal fibroblasts respond to by aligning with the long axis of the pores. This methodology has potential for application in a variety of different tissue engineering niches in which cell alignment is observed, including skin, bone, muscle and nerve.     

Synthesis and characterization of film-forming poly(urethaneimide) cationomers containing quaternary ammonium groups

In a recent work, we have described an original family of poly(urethaneimides) containing tertiary amine groups from a polytetramethylene oxide diol (PTMO1000), N-methyldiethanolamine (MDEA), 4,4′-methylene-bis-phenylisocyanate (MDI) and 4,4′-hexafluoroisopropylidene-bis-phthalic anhydride (6FDA). This paper reports their quaternization with various alkylating agents to give the cationic quaternary ammonium groups. An optimization of the experimental conditions led to three new families of PUI cationomers with a good structural control and high quaternization degrees. These polymers differed in the number of their cationic groups (0 < x ≤ 0.7 equiv.), the type of their counter-ions X⁻ (methyl sulfate, tosylate, triflate, chloride, bromide, iodide) and their steric hindrance by the length of their n-alkyl side chain (C₁-C₆). Complementary NMR techniques, including HSQC and COSY two-dimensional NMR, enabled to characterize the control of the polymer structure and to determine quantitatively the quaternization degree of the PUI cationomers. Properties in solution (solubility and viscosity) and in the solid state (film-forming ability and density) were then examined in relation with the membrane separation application targeted for these new PUI cationomers.