Highly compressible glass-like supramolecular polymer networks.

Supramolecular polymer networks are non-covalently crosslinked soft materials that exhibit unique mechanical features such as self-healing, high toughness and stretchability. Previous studies have focused on optimizing such properties using fast-dissociative crosslinks (that is, for an aqueous system, dissociation rate constant kd > 10 s-1). Herein, we describe non-covalent crosslinkers with slow, tuneable dissociation kinetics (kd < 1 s-1) that enable high compressibility to supramolecular polymer networks. The resultant glass-like supramolecular networks have compressive strengths up to 100 MPa with no fracture, even when compressed at 93% strain over 12 cycles of compression and relaxation. Notably, these networks show a fast, room-temperature self-recovery (< 120 s), which may be useful for the design of high-performance soft materials. Retarding the dissociation kinetics of non-covalent crosslinks through structural control enables access of such glass-like supramolecular materials, holding substantial promise in applications including soft robotics, tissue engineering and wearable bioelectronics.

Theoretical prediction of nanomolar and sequence-selective binding of synthetic supramolecular cucurbit[7]uril to N-terminal Leu-containing tripeptides.

Molecular recognition towards peptides and proteins with high affinity by synthetic supramolecular hosts is important but challenging. In this work, we investigate the molecular recognition of the synthetic cucurbit[7]uril (CB[7]) to 17 designed N-terminal Leu-containing tripeptides in aqueous medium by molecular dynamics (MD) simulation and screen out tripeptides with high binding affinity. It is found that, compared to LGG, only the third residue is Arg (R), the binding affinity of CB[7] to LGR reaches nanomolar level with binding equilibrium constant (Ka) of 1.1 × 109 M-1. The CB[7] recognition to the N-terminal Leu-containing tripeptides is highly sequence dependent; whether changing the sequence order (from LGR to LRG) or increasing the sequence length (from LGR to LGGR), Ka decreases by about three orders of magnitude. Interestingly, substituting N-terminal Leu for its isomer Ile, the binding of CB[7] to tripeptides weakens significantly with Ka decreasing by 3-8 orders of magnitude. Thus CB[7] can effectively distinguish N-terminal Leu-containing tripeptides from N-terminal Ile-containing tripeptides. Importantly, we predict that when R is as C-terminus, regardless of N-terminal residue being of aromatic type or Leu, the binding strength is always close to the nanomolar level. Therefore, R can be introduced to rationally design novel peptides with high binding affinity to CB[7] in practical applications.

Molecular Engineering of Noncovalent Dimerization.

Dimers are probably the simplest model to facilitate the understanding of fundamental physical and chemical processes that take place in much-expanded systems like aggregates, crystals, and other solid states. The molecular interplay within a dimer differentiates it from the corresponding monomeric state and determines its features. Molecular engineering of noncovalent dimerization through applied supramolecular restrictions enables additional control over molecular interplay, particularly over its dynamic aspect. This Perspective introduces the recent effort that has been made in the molecular engineering of noncovalent dimerization, including supramolecular dimers, folda-dimers, and macrocyclic dimers. It showcases how the variation in supramolecular restrictions endows molecular-based materials with improved performance and/or functions like enhanced emission, room-temperature phosphorescence, and effective catalysis. We particularly discuss pseudostatic dimers that can sustain molecular interplay for a long period of time, yet are still flexible enough to adapt to variations. The pseudostatic feature allows for active species to decay along an alternate pathway, thereby spinning off emerging features that are not readily accessible from conventional dynamic systems.

On-Resin Recognition of Aromatic Oligopeptides and Proteins through Host-Enhanced Heterodimerization.

Peptide dimerization is ubiquitous in natural protein conjugates and artificial self-assemblies. A major challenge in artificial systems remains achieving quantitative peptide heterodimerization, critical for next-generation biomolecular purification and formulation of therapeutics. Here, we employ a synthetic host to simultaneously encapsulate an aromatic and a noncanonical l-perfluorophenylalanine-containing peptide through embedded polar-π interactions, constructing an unprecedented series of heteropeptide dimers. To demonstrate the utility, this heteropeptide dimerization strategy was applied toward on-resin recognition of N-terminal aromatic residues in peptides as well as insulin, both exhibiting high recycling efficiency (>95%). This research unveils a generic approach to exploit quantitative heteropeptide dimers for the design of supramolecular (bio)systems.

Host-Guest Induced Peptide Folding with Sequence-Specific Structural Chirality.

Controlling the spatial and temporal behavior of peptide segments is essential in the fabrication of functional peptide-based materials and nanostructures. To achieve a desired structure, complex sequence design is often required, coupled with the inclusion of unnatural amino acids or synthetic modifications. Herein, we investigate the structural properties of 1:1 inclusion complexes between specific oligopeptides and cucurbit[8]uril (CB[8]), inducing the formation of turns, and by alteration of the peptide sequence, tunable structural chirality. We also explore extended peptide sequence binding with CB[8], demonstrating a simple approach to construct a peptide hairpin.

Host-Enhanced Phenyl-Perfluorophenyl Polar-π Interactions.

Phenyl-perfluorophenyl polar-π interactions have been revisited for the design and fabrication of functional supramolecular systems. The relatively weak associative interactions (ΔG ≈ -1.0 kcal/mol) have limited their use in aqueous self-assembly to date. Herein, we propose a strategy to strengthen phenyl-perfluorophenyl polar-π interactions by encapsulation within a synthetic host, thus increasing the binding affinity to ΔG= -15.5 kcal/mol upon formation of heteroternary complexes through social self-sorting. These heteroternary complexes were used as dynamic, yet strong, cross-linkers in the fabrication of supramolecular gels, which exhibited excellent viscoelasticity, stretchability, self-recovery, self-healing, and energy dissipation. This work unveils a general approach to exploit host-enhanced polar-π interactions in the design of robust aqueous supramolecular systems.

Applying support-vector machine learning algorithms toward predicting host-guest interactions with cucurbit[7]uril.

Machine learning is a valuable tool in the development of chemical technologies but its applications into supramolecular chemistry have been limited. Here, the utility of kernel-based support vector machine learning using density functional theory calculations as training data is evaluated when used to predict equilibrium binding coefficients of small molecules with cucurbit[7]uril (CB[7]). We find that utilising SVMs may confer some predictive ability. This algorithm was then used to predict the binding of drugs TAK-580 and selumetinib. The algorithm did predict strong binding for TAK-580 and poor binding for selumetinib, and these results were experimentally validated. It was discovered that the larger homologue cucurbit[8]uril (CB[8]) is partial to selumetinib, suggesting an opportunity for tunable release by introducing different concentrations of CB[7] or CB[8] into a hydrogel depot. We qualitatively demonstrated that these drugs may have utility in combination against gliomas. Finally, mass transfer simulations show CB[7] can independently tune the release of TAK-580 without affecting selumetinib. This work gives specific evidence that a machine learning approach to recognition of small molecules by macrocycles has merit and reinforces the view that machine learning may prove valuable in the development of drug delivery systems and supramolecular chemistry more broadly.

Quantitative Supramolecular Heterodimerization for Efficient Energy Transfer.

The challenge of quantitatively forming self-assembled heterodimers without other equilibrium by-products is overcome through self-sorting favored by the introduction of designed shape-complementary moieties. Such a supramolecular strategy based on cucurbit[8]uril-directed dimerization is further applied to generate hetero-chromophore dimers quantitatively, leading to efficient energy transfer (>85 %) upon photoexcitation.

Oligopeptide-CB[8] complexation with switchable binding pathways.

Host-guest complexes exhibiting a 1 : 1 binding stoichiometry need not consist of a single host and guest. A series of oligopeptides, which were previously reported to have abnormally high binding enthalpies were investigated to deduce whether they exist as a 2 : 2 quaternary or a 1 : 1 binary complex with cucurbit[8]uril (CB[8]). Through a systematic study of the sequence-specific binding pathways of peptide-CB[8] association, a phenylalanine-leucine dipeptide was found to be capable of switching from a 1 : 1 stoichiometric complex to a 2 : 1 complex. By studying the differences in size-based diffusion properties of these two binding modes, the presence of a 1 : 1 pairwise inclusion complex was verified for the regime where CB[8] is in excess. Findings in this study can be utilised to 'customise' the precise CB[8]-oligopeptide self-assembly pathway, acting as a useful toolbox in the design of supramolecular systems.

Mining 2:2 Complexes from 1:1 Stoichiometry: Formation of Cucurbit[8]uril-Diarylviologen Quaternary Complexes Favored by Electron-Donating Substituents.

A 1:1 binding stoichiometry of a host-guest complex need not consist of a single host and guest. Diarylviologens containing electron-donating substituents complexed with cucurbit[8]uril (CB[8]) in a 1:1 stoichiometry exhibit abnormally large binding enthalpies compared to typical enthalpy changes observed for 1:1 binary complexes. Here, several CB[8]-mediated host-guest complexes, which were previously reported as 1:1 binary complexes, are verified to be 2:2 quaternary complexes by a combination of isothermal titration calorimetry, 1H, NOESY, and ROESY NMR, and ion mobility mass spectrometry, clearly indicating a binding motif of two partially overlapping diarylviologens held in place with two CB[8] molecules. Formation of 2:2 quaternary complexes is favored by electron-donating substituents, while electron-withdrawing substituents typically result in 1:1 binary complexes. The stacking of two highly conjugated diarylviologens in one quaternary motif affords the complexes enhanced conductance when considered as a single-molecular conductor. Moreover, an additional conducting signal previously observed for this "supramolecular" conductor can be readily understood with our 2:2 complexation model, corresponding to a parallel conductance pathway. Therefore, a 2:2 quaternary complex model grants a greater understanding of such supramolecular complexes, enabling the design of engineered, hierarchical structures and functional materials.

Smart supramolecular sensing with cucurbit[n]urils: probing hydrogen bonding with SERS.

Rigid gap nano-aggregates of Au nanoparticles formed using cucurbit[n]uril (CB[n]) molecules are used to investigate the competitive binding of ethanol and methanol in an aqueous environment. We show it is possible to detect as little as 0.1% methanol in water and a ten times higher affinity to methanol over ethanol, making this a useful technology for quality control in alcohol production. We demonstrate strong interaction effects in the SERS peaks, which we demonstrate are likely from the hydrogen bonding of water complexes in the vicinity of the CB[n]s.

Cucurbit[7]uril as a Supramolecular Artificial Enzyme for Diels-Alder Reactions.

The ability to mimic the activity of natural enzymes using supramolecular constructs (artificial enzymes) is a vibrant scientific research field. Herein, we demonstrate that cucurbit[7]uril (CB[7]) can catalyse Diels-Alder reactions for a number of substituted and unreactive N-allyl-2-furfurylamines under biomimetic conditions, without the need for protecting groups, yielding powerful synthons in previously unreported mild conditions. CB[7] rearranges the substrate in a highly reactive conformation and shields it from the aqueous environment, thereby mimicking the mode of action of a natural Diels-Alderase. These findings can be directly applied to the phenomenon of product inhibition observed in natural Diels-Alderase enzymes, and pave the way toward the development of novel, supramolecular-based green catalysts.

Supramolecular Chemistry of Cucurbiturils: Tuning Cooperativity with Multiple Noncovalent Interactions from Positive to Negative.

Rational control of the cooperativity of multiple noncovalent interactions often plays an important role in the design and construction of supramolecular self-assemblies and materials, especially in precision supramolecular engineering. However, it still remains a challenge to control the cooperativity of multiple noncovalent interactions through tuning the hydrophobic effect. In this work, we demonstrate that the binding cooperativity of cucurbit[8]uril(CB[8])-mediated homoternary complexes is strongly influenced by the amphiphilicity of guest molecule side groups on account of an interplay between both classical (entropy-driven) and nonclassical (enthalpy-driven) hydrophobic effects. To this end, we rationally designed and prepared a series of guest molecules bearing a benzyl group as the CB[8] homoternary binding motif with various hydrophilic and hydrophobic side groups for cooperative control. By gradually tuning side groups of the guest molecules from hydrophilic to hydrophobic, we are able to control the binding from positive to negative cooperativity. An advanced molecular recognition process and self-assembling system can be developed by adjusting the positive and negative cooperativity. The ability to regulate and control the binding cooperativity will enrich the field of supramolecular chemistry, and employing cooperativity-controlled multiple noncovalent interactions in precision supramolecular engineering is highly anticipated.

Self-Assembly of a Functional Oligo(Aniline)-Based Amphiphile into Helical Conductive Nanowires.

A tetra(aniline)-based cationic amphiphile, TANI-NHC(O)C5H10N(CH3)3(+)Br(-) (TANI-PTAB) was synthesized, and its emeraldine base (EB) state was found to self-assemble into nanowires in aqueous solution. The observed self-assembly is described by an isodesmic model, as shown by temperature-dependent UV-vis investigations. Linear dichroism (LD) studies, combined with computational modeling using time-dependent density functional theory (TD-DFT), suggests that TANI-PTAB molecules are ordered in an antiparallel arrangement within nanowires, with the long axis of TANI-PTAB arranged perpendicular to the nanowire long axis. Addition of either S- or R- camphorsulfonic acid (CSA) to TANI-PTAB converted TANI to the emeraldine salt (ES), which retained the ability to form nanowires. Acid doping of TANI-PTAB had a profound effect on the nanowire morphology, as the CSA counterions' chirality translated into helical twisting of the nanowires, as observed by circular dichroism (CD). Finally, the electrical conductivity of CSA-doped helical nanowire thin films processed from aqueous solution was 2.7 mS cm(-1). The conductivity, control over self-assembled 1D structure and water-solubility demonstrate these materials' promise as processable and addressable functional materials for molecular electronics, redox-controlled materials and sensing.

Asymmetric and symmetric bolaform supra-amphiphiles: formation of imine bond influenced by aggregation.

A series of bolaform supra-amphilphiles with different symmetries were fabricated through dynamic benzoic imine bond formation. The pH dependence of imine formations of these supra-amphiphiles were characterazied. We found that the extent of the imine formation of these supra-amphiphies were different. The supra-amphiphiles with a poorer symmetry always exhibited a lower imine formation at a given pH. Therefore, the varied extent of imine bond formation indicate the different aggregations of these supra-amphilphiles, which are controlled by the molecular symmetry of the supra-amphiphiles.

Mono-molecule-layer nano-ribbons formed by self-assembly of bolaamphiphiles.

Amphiphilic molecules generally tend to organize spontaneously into spherical or cylindrical micelles/vesicles in appropriate liquid media and conditions, and seldom form two dimensional (2D) planar structures with a regular shape, due to their energetically unfavorable state. Herein, the self-assembly of a new bolaamphiphile bearing a bistriazole-pyrene unit leads to the formation of mono-molecule-layer nano-ribbons. The π-π stacking interaction between the rigid bistriazole-pyrene units and electrostatic screening contributed by the aromatic counterion tosyl groups are responsible for the 2D alignment of the molecules in the aggregate. Partial replacement of the tosyl groups causes a reduction in the width of the nano-ribbons and the coordination of triazole with Pd2+ ions results in the collapse of the self-assembled structure. This study supplies new clues for fabricating molecular level 2D nanostructures by bottom-up supramolecular assembly.

Growth mechanisms of 2D organic assemblies generated from dialkylated melaminium derivatives: the length difference of the two alkyl chains that matters.

This research is aimed to understand the growth mechanisms for self-assembly of dialkylated melamine derivatives. The dialkylated melamine derivatives with different alkyl chains (Mela-m-n) are able to self-assemble with hydrochloric acid in dichloromethane to form 2D organic assemblies, exhibiting similar lamellar structures as Mela-n·HCl with identical alkyl chains. The most interesting finding is that the growth mechanism of Mela-n·HCl with identical alkyl chains is revealed to be layer growth, while Mela-m-n·HCl with asymmetric alkyl chains adopts a spiral growth mechanism. The asymmetric alkyl chains in Mela-m-n may lead to the formation of dislocation, which is responsible for the spiral growth mechanism.

Aspirin Suppresses Hepatic Glucagon Signaling Through Decreasing Production of Thromboxane A2.

Excessive hepatic glucose production (HGP) is a major cause of fasting hyperglycemia in diabetes, and antihyperglycemic therapy takes center stage. Nonsteroidal anti-inflammatory drugs, such as acetylsalicylic acid (aspirin), reduce hyperglycemia caused by unrestrained gluconeogenesis in diabetes, but its mechanism is incompletely understood. Here, we reported that aspirin lowers fasting blood glucose and hepatic gluconeogenesis, corresponds with lower thromboxane A2 (TXA2) levels, and the hypoglycemic effect of aspirin could be rescued by TP agonist treatment. On fasting and diabetes stress, the cyclooxygenase (COX)/TXA2/thromboxane A2 receptor (TP) axis was increased in the livers. TP deficiency suppressed starvation-induced hepatic glucose output, thus inhibiting the progression of diabetes, whereas TP activation promoted gluconeogenesis. Aspirin restrains glucagon signaling and gluconeogenic gene expression (phosphoenolpyruvate carboxykinase [PCK1] and glucose-6-phosphatase [G6Pase]) through the TXA2/TP axis. TP mediates hepatic gluconeogenesis by activating PLC/IP3/IP3R signaling, which subsequently enhances CREB phosphorylation via facilitating CRTC2 nuclear translocation. Thus, our findings demonstrate that TXA2/TP plays a crucial role in aspirin's inhibition of hepatic glucose metabolism, and TP may represent a therapeutic target for diabetes.

Bolaamphiphiles bearing bipyridine as mesogenic core: rational exploitation of molecular architectures for controlled self-assembly.

A bolaamphiphile (5,5-B2NBr8) bearing a functional bipyridine moiety as the mesogenic core is reported for the first time. 5,5-B2NBr8 was found to self-assemble into uniform fibrous structure in aqueous solution, when the concentration was higher than cmc. Analogues of 5,5-B2NBr8 with structural differences in chain length, headgroup, mesogenic core, and substituted position were synthesized, elucidating that small variances of the molecular structure could lead to dramatic changes of the resulting assemblies. For example, compound 4,4-B2NBr8 showed only spherical colloidal aggregates rather than fibers as 5,5-B2NBr8 did, while the only difference between them was the position at which the alkyl chains were attached onto bipyridine. A probable model for the fibrous structure of 5,5-B2NBr8 was proposed. Moreover, exploiting the coordination capacity of bipyridine, assembly and disassembly of 5,5-B2NBr8 could be reversibly controlled through the addition of EDTA and Cu(II), respectively.

The lactate receptor GPR81 mediates hepatic lipid metabolism and the therapeutic effect of metformin on experimental NAFLDs.

The lactate receptor G protein-coupled receptor 81 (GPR81) has been recently implicated in lipolysis in adipose tissue. In this study, we accidently discovered the role of GPR81 in hepatic lipid metabolism. Data clearly showed that hepatic GPR81 was markedly up-regulated in fasted mice, whereas it was severely down-regulated in obese mice. Genetic deficiency of GPR81 impaired ketogenic response, enhanced hepatic lipid accumulation, and exacerbated hepatosteatosis under acute fasting conditions. Mechanically, we demonstrated that hepatic GPR81 might function as a modulator of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), activate the downsream transcription of liver carnitine o-palmitoyltransferase 1(L-CPT1), and thereby control the influx of fatty acids into mitochondria for ß-oxidation. Importantly, metformin improved experimental nonalcoholic fatty liver disease (NAFLDs) in a GPR81-dependent manner. Collectively, GPR81 was critical for hepatic lipid homeostasis and activation of hepatic GPR81 might represent a promising strategy for the treatment of obesity and its associated metabolic disorders.