The Hamilton Receptor in Supramolecular Polymer Sciences.

Supramolecular polymers are polymeric materials of monomeric fragments, held jointly by reversible and directional non-covalent interactions such as multiple hydrogen-bonding, charge transfer effects, host-guest interactions, metal coordination, and aromatic stacking. This review article on the Hamilton-based supramolecular polymers aims to shed light on the molecular recognition achievements by the Hamilton-based polymeric systems, evaluate Hamilton receptor's future prospects, and capitalize its potential applications in supramolecular chemistry. To the best of our knowledge, this is the first elaborative and sole manuscript in which polymeric Hamilton receptors are being exposed in detail. The first portion of this manuscript is related to the importance and urgency of polymers along with the historic background of Hamilton receptors. The middle section discloses the potential applications of Hamilton-type receptors in various fields, e.g., dendrimers, mechanically polymeric rotaxanes, and self-assemblies. The final section of the manuscript discloses the future aspects and the importance of novel polymer-based Hamilton-type receptors in the modern era. We believe that this first review in this emerging yet immature field will be useful to inspire scientists around the world to find the unseen future prospects, thereby boosting the field related to this valued artificial receptor in the province of supramolecular chemistry and also in other domains of scientific fields and technology, as well.

Artificial Tactile Receptor System for Sensitive Pressure-Neural Spike Conversion.

An artificial tactile receptor is crucial for e-skin in next-generation robots, mimicking the mechanical sensing, signal encoding, and preprocessing functionalities of human skin. In the neural network, pressure signals are encoded in spike patterns and efficiently transmitted, exhibiting low power consumption and robust tolerance for bit error rates. Here, we introduce a highly sensitive artificial tactile receptor system integrating a pressure sensor, axon-hillock circuit, and neurotransmitter release device to achieve pressure signal coding with patterned spikes and controlled neurotransmitter release. Owing to the heightened sensitivity of the axon-hillock circuit to pressure-mediated current signals, the artificial tactile receptor achieves a detection limit of 10 Pa that surpasses the human tactile receptors, with a wide response range from 10 to 5 × 105 Pa. Benefiting from the appreciable pressure-responsive performance, the potential application of an artificial tactile receptor in robotic tactile perception has been demonstrated, encompassing tasks such as finger touch and human pulse detection.

Biomimetic Multimodal Receptors for Comprehensive Artificial Human Somatosensory System.

Electronic skin (e-skin) capable of acquiring environmental and physiological information has attracted interest for healthcare, robotics, and human-machine interaction. However, traditional 2D e-skin only allows for in-plane force sensing, which limits access to comprehensive stimulus feedback due to the lack of out-of-plane signal detection caused by its 3D structure. Here, a dimension-switchable bioinspired receptor is reported to achieve multimodal perception by exploiting film kirigami. It offers the detection of in-plane (pressure and bending) and out-of-plane (force and airflow) signals by dynamically inducing the opening and reclosing of sensing unit. The receptor's hygroscopic and thermoelectric properties enable the sensing of humidity and temperature. Meanwhile, the thermoelectric receptor can differentiate mechanical stimuli from temperature by the voltage. The development enables a wide range of sensory capabilities of traditional e-skin and expands the applications in real life.

Semisynthesis of Aminomethyl-Insulin: An Atom-Economic Strategy to Increase the Affinity and Selectivity of a Protein for Recognition by a Synthetic Receptor.

Advancements in the molecular recognition of insulin by nonantibody-based means would facilitate the development of methodology for the continuous detection of insulin for the management of diabetes mellitus. Herein, we report a novel insulin derivative that binds to the synthetic receptor cucurbit[7]uril (Q7) at a single site and with high nanomolar affinity. The insulin derivative was prepared by a four-step protein semisynthetic method to present a 4-aminomethyl group on the side chain of the PheB1 position. The resulting aminomethyl insulin binds to Q7 with an equilibrium dissociation constant value of 99 nM in neutral phosphate buffer, as determined by isothermal titration calorimetry. This 6.8-fold enhancement in affinity versus native insulin was gained by an atom-economical modification (-CH2NH2). To the best of our knowledge, this is the highest reported binding affinity for an insulin derivative by a synthetic receptor. This strategy for engineering protein affinity tags induces minimal change to the protein structure while increasing affinity and selectivity for a synthetic receptor.

Binding of synthetic carbohydrate receptors to enveloped virus glycans: Insights from molecular dynamics simulations.

Can envelope glycans be targeted to stop viral pandemics? Here we address this question by using molecular dynamics simulations to study the binding between 10 synthetic carbohydrate receptors (SCRs) and the 33 N-glycans most commonly found on the surfaces of enveloped viruses, including Zika virus and SARS-CoV-2. Based on association quotients derived from these simulations, we classified the SCRs as weak binders, promiscuous binders, or selective binders. The SCRs almost exclusively associate at the Man3GlcNAc2 core, which is common to all N-glycans, but the binding affinity between the SCR⋅glycan pair depends on the noncovalent interactions between the heterocycle rings and the glycan antennae. Systematic variations in the glycan and SCR structures reveal relationships that could guide the design of SCRs to attain affinity and selectivity towards a chosen envelope glycan target. With these results, envelope glycans, which are currently considered "undruggable", could become viable targets for new therapeutic strategies.

Synthetic Receptors Based on Abiotic Cyclo(pseudo)peptides.

Work on the use of cyclic peptides or pseudopeptides as synthetic receptors started even before the field of supramolecular chemistry was firmly established. Research initially focused on the development of synthetic ionophores and involved the use of macrocycles with a repeating sequence of subunits along the ring to facilitate the correlation between structure, conformation, and binding properties. Later, nonnatural amino acids as building blocks were also considered. With growing research in this area, cyclopeptides and related macrocycles developed into an important and structurally diverse receptor family. This review provides an overview of these developments, starting from the early years. The presented systems are classified according to characteristic structural elements present along the ring. Wherever possible, structural aspects are correlated with binding properties to illustrate how natural or nonnatural amino acids affect binding properties.

When Molecules Meet in Water-Recent Contributions of Supramolecular Chemistry to the Understanding of Molecular Recognition Processes in Water.

Molecular recognition processes in water differ from those in organic solvents in that they are mediated to a much greater extent by solvent effects. The hydrophobic effect, for example, causes molecules that only weakly interact in organic solvents to stay together in water. Such water-mediated interactions can be very efficient as demonstrated by many of the synthetic receptors discussed in this review, some of which have substrate affinities matching or even surpassing those of natural binders. However, in spite of considerable success in designing such receptors, not all factors determining their binding properties in water are fully understood. Existing concepts still provide plausible explanations why the reorganization of water molecules often causes receptor-substrate interactions in water to be strongly exothermic rather than entropically favored as predicted by the classical view of the hydrophobic effect.

Cholesteric Molecular Tweezer Artificial Receptor for Rapid and Highly Selective Detection of Ag+ in Food Samples.

Chiral cholesteric molecular tweezer 7a was synthesized, and its recognition properties for Ag+, Al3+, Ca2+ etc., were investigated by UV and fluorescence spectra. The results showed that in ethanol/Tris (1/1, v/v, pH 7.0) buffer solution, the host molecular tweezer 7a had a specific recognition ability for Ag+, the detection limit was up to 1 × 10-6 mol/L, and other metal ions had little effect on Ag+ recognition. At the same time, the naked-eye detection of Ag+ was realized by the light red color of the complex solution. Furthermore, the mechanism of recognition of Ag+ by molecular tweezer 7a was studied by a nuclear magnetic titration test and computer molecular simulation, and a rapid detection method of Ag+ using host molecular tweezer 7a was established. Through the determination of Ag+ in milk powder, quinoa and other food samples, it was proved that this novel method had a good application prospect for the detection of Ag+ in food.

Metallocalix[4]arene Polymers for Gravimetric Detection of N-Nitrosodialkylamines.

N-Nitrosamines are found in food, drugs, air, water, and soil. They pose a significant risk to human health because of their carcinogenicity; consequently, materials that can be used to selectively and sensitively detect nitrosamines are needed. In this work, we designed and synthesized two polymers bearing calix[4]arene or 4-tert-butylcalix[4]arene tungsten-imido complexes (PCalixH and PCalixtBu) as N-nitrosodimethylamine (NDMA) receptors. The interaction between metallocalix[4]arene monomers/polymers and NDMA was confirmed by 1H NMR and IR spectroscopy. Single-crystal X-ray analysis further revealed that the host-guest interaction is based on binding of the terminal oxygen of NDMA to tungsten within the calixarene cavity. Gravimetric detection of NDMA was performed on a quartz crystal microbalance (QCM) in air. Both polymers show responses to NDMA, with PCalixtBu exhibiting a low theoretical limit of detection of 5 ppb for NDMA. The sensor also shows high selectivity toward NDMA and moderate humidity tolerance. This work provides a sensitive sensor for detection of NDMA and also offers a class of new, selective, and efficient NDMA receptors for the future design of NDMA sensors and NDMA extraction materials.

Tailoring minimal synthetic receptors to reconstitute signaling properties through multiple tyrosine motifs.

As intracellular signal transduction is important for determining cell fate, artificial control of signaling properties through engineered receptors is attractive in the fields of synthetic biology and cell therapy. In this study, we tailored minimal synthetic receptors to reconstitute signaling properties by incorporating multiple tyrosine motifs. The size of molecular parts including the linker between the tyrosine motifs was minimized as much as possible to create the minimal synthetic receptors. By combining the membrane localization signal sequence, a mutant of FK506-binding protein, a JAK-binding domain, tyrosine motifs, and linkers, we successfully reconstituted simple receptor chains that were activated by dimerization via a synthetic small-molecule ligand capable of membrane permeation. Furthermore, up to four signaling molecules of interest were able to be recruited and activated by the minimal synthetic receptors. Thus, the tailored minimal synthetic receptors could be utilized to analyze the role of specific signaling molecules/pathways in controlling cell fate and to efficiently induce specific cell fate for therapeutic applications in the future.

Molecular Recognition in Water Using Macrocyclic Synthetic Receptors.

Molecular recognition in water using macrocyclic synthetic receptors constitutes a vibrant and timely research area of supramolecular chemistry. Pioneering examples on the topic date back to the 1980s. The investigated model systems and the results derived from them are key for furthering our understanding of the remarkable properties exhibited by proteins: high binding affinity, superior binding selectivity, and extreme catalytic performance. Dissecting the different effects contributing to the proteins' properties is severely limited owing to its complex nature. Molecular recognition in water is also involved in other appreciated areas such as self-assembly, drug discovery, and supramolecular catalysis. The development of all these research areas entails a deep understanding of the molecular recognition events occurring in aqueous media. In this review, we cover the past three decades of molecular recognition studies of neutral and charged, polar and nonpolar organic substrates and ions using selected artificial receptors soluble in water. We briefly discuss the intermolecular forces involved in the reversible binding of the substrates, as well as the hydrophobic and Hofmeister effects operating in aqueous solution. We examine, from an interdisciplinary perspective, the design and development of effective water-soluble synthetic receptors based on cyclic, oligo-cyclic, and concave-shaped architectures. We also include selected examples of self-assembled water-soluble synthetic receptors. The catalytic performance of some of the presented receptors is also described. The latter process also deals with molecular recognition and energetic stabilization, but instead of binding ground-state species, the targets become elusive counterparts: transition states and other high-energy intermediates.

Flexible Synthetic Carbohydrate Receptors as Inhibitors of Viral Attachment.

Carbohydrate-receptor interactions are often involved in the docking of viruses to host cells, and this docking is a necessary step in the virus life cycle that precedes infection and, ultimately, replication. Despite the conserved structures of the glycans involved in docking, they are still considered "undruggable", meaning these glycans are beyond the scope of conventional pharmacological strategies. Recent advances in the development of synthetic carbohydrate receptors (SCRs), small molecules that bind carbohydrates, could bring carbohydrate-receptor interactions within the purview of druggable targets. Here we discuss the role of carbohydrate-receptor interactions in viral infection, the evolution of SCRs, and recent results demonstrating their ability to prevent viral infections in vitro. Common SCR design strategies based on boronic ester formation, metal chelation, and noncovalent interactions are discussed. The benefits of incorporating the idiosyncrasies of natural glycan-binding proteins-including flexibility, cooperativity, and multivalency-into SCR design to achieve nonglucosidic specificity are shown. These studies into SCR design and binding could lead to new strategies for mitigating the grave threat to human health posed by enveloped viruses, which are heavily glycosylated viroids that are the cause of some of the most pressing and untreatable diseases, including HIV, Dengue, Zika, influenza, and SARS-CoV-2.

Selective Recognition of Amino Acids and Peptides by Small Supramolecular Receptors.

To this day, the recognition and high affinity binding of biomolecules in water by synthetic receptors remains challenging, while the necessity for systems for their sensing, transport and modulation persists. This problematic is prevalent for the recognition of peptides, which not only have key roles in many biochemical pathways, as well as having pharmacological and biotechnological applications, but also frequently serve as models for the study of proteins. Taking inspiration in nature and on the interactions that occur between several receptors and peptide sequences, many researchers have developed and applied a variety of different synthetic receptors, as is the case of macrocyclic compounds, molecular imprinted polymers, organometallic cages, among others, to bind amino acids, small peptides and proteins. In this critical review, we present and discuss selected examples of synthetic receptors for amino acids and peptides, with a greater focus on supramolecular receptors, which show great promise for the selective recognition of these biomolecules in physiological conditions. We decided to focus preferentially on small synthetic receptors (leaving out of this review high molecular weight polymeric systems) for which more detailed and accurate molecular level information regarding the main structural and thermodynamic features of the receptor biomolecule assemblies is available.

Highly Efficient, Tripodal Ion-Pair Receptors for Switching Selectivity between Acetates and Sulfates Using Solid-Liquid and Liquid-Liquid Extractions.

A tripodal, squaramide-based ion-pair receptor 1 was synthesized in a modular fashion, and 1H NMR and UV-vis studies revealed its ability to interact more efficiently with anions with the assistance of cations. The reference tripodal anion receptor 2, lacking a crown ether unit, was found to lose the enhancement in anion binding induced by presence of cations. Besides the ability to bind anions in enhanced manner by the "single armed" ion-pair receptor 3, the lack of multiple and prearranged binding sites resulted in its much lower affinity towards anions than in the case of tripodal receptors. Unlike with receptors 2 or 3, the high affinity of 1 towards salts opens up the possibility of extracting extremely hydrophilic sulfate anions from aqueous to organic phase. The disparity in receptor 1 binding modes towards monovalent anions and divalent sulfates assures its selectivity towards sulfates over other lipophilic salts upon liquid-liquid extraction (LLE) and enables the Hofmeister bias to be overcome. By changing the extraction conditions from LLE to SLE (solid-liquid extraction), a switch of selectivity from sulfates to acetates was achieved. X-ray measurements support the ability of anion binding by cooperation of the arms of receptor 1 together with simultaneous binding of cations.

A fluorescent artificial receptor with specific imprinted cavities to selectively detect colistin.

A novel and facile fluorescent artificial receptor on the basis of the molecularly imprinted polymer-coated graphene quantum dots was engineered successfully to detect colistin. The colistin imprinted graphene quantum dots (CMIP-GQDs) was synthesized by vinyl-based radical polymerization between functional monomers and crosslinker at around the template molecule on the surface of graphene quantum dots. The size of bare, CNIP-GQDs, and CMIP-GQDs was about 4.8 ± 0.6 nm, 18.4 ± 1.7 nm, and 19.7 ± 1.3 nm, respectively. The CMIP-GQDs, which showed the strong fluorescence emission at 440 nm with the excitation wavelength fixed at 380 nm, had excellent selectivity and specificity to rapidly recognize and detect colistin. The linear range of fluorescence quenching of this fluorescent artificial receptor for detection colistin was 0.016-2.0 µg mL-1 with a correlation coefficient (R2) of 0.99919, and the detection limit was 7.3 ng mL-1 in human serum samples. The designed receptor was successfully applied to detect colistin in human serum samples and it achieved excellent recoveries shifted from 93.8 to 105%. Graphical abstract.

Protein Assays on Organic Electronics: Rational Device and Material Designs for Organic Transistor-Based Sensors.

Artificial receptor-based protein assays have various attractive features such as a long-term stability, a low-cost production process, and the ease of tuning the target specificity. However, such protein sensors are still immature compared with conventional immunoassays. To enhance the application potential of synthetic sensing materials, organic field-effect transistors (OFETs) are some of the suitable platforms for protein assays because of their solution processability, durability, and compact integration. Importantly, OFETs enable the electrical readout of the protein recognition phenomena of artificial receptors on sensing electrodes. Thus, we believe that OFETs functionalized with artificial protein receptors will be a powerful tool for the on-site analyses of target proteins. In this Minireview, we summarize the recent progress of the OFET-based protein assays including the rational design strategies for devices and sensing materials.

Highly Sensitive and Selective Fluorescent Probes for Cu(II) Detection Based on Calix[4]arene-Oxacyclophane Architectures.

A new topological design of fluorescent probes for sensing copper ion is disclosed. The calix[4]arene-oxacyclophane (Calix-OCP) receptor, either wired-in-series in arylene-alt-ethynylene conjugated polymers or standing alone as a sole molecular probe, display a remarkable affinity and selectivity for Cu(II). The unique recognition properties of Calix-OCP system toward copper cation stem from its pre-organised cyclic array of O-ligands at the calixarene narrow rim, which is kept in a conformational rigid arrangement by a tethered oxacyclophane sub-unit. The magnitude of the binding constants (Ka = 5.30 - 8.52 × 104 M-1) and the free energy changes for the inclusion complexation (-ΔG = 27.0 - 28.1 kJmol-1), retrieved from fluorimetric titration experiments, revealed a high sensitivity of Calix-OCP architectures for Cu(II) species. Formation of supramolecular inclusion complexes was evidenced from UV-Vis spectroscopy. The new Calix-OCP-conjugated polymers (polymers 4 and 5), synthesized in good yields by Sonogashira-Hagihara methodologies, exhibit high fluorescence quantum yields (ΦF = 0.59 - 0.65). Density functional theory (DFT) calculations were used to support the experimental findings. The fluorescence on-off behaviour of the sensing systems is tentatively explained by a photoinduced electron transfer mechanism.

Synthesis and Binding of Mannose-Specific Synthetic Carbohydrate Receptors.

Synthetic carbohydrate receptors (SCRs) that selectively recognize cell-surface glycans could be used for detection, drug delivery, or as therapeutics. Here we report the synthesis of seven new C2h symmetric tetrapodal SCRs. The structures of these SCRs possess a conserved biaryl core, and they vary in the four heterocyclic binding groups that are linked to the biaryl core via secondary amines. Supramolecular association between these SCRs and five biologically relevant C1 -O-octyloxy glycans, α/ß-glucoside (α/ß-Glc), α/ß-mannoside (α/ß-Man), and ß-galactoside (ß-Gal), was studied by mass spectrometry, 1 H NMR titrations, and molecular modeling. These studies revealed that selectivity can be achieved in these tetrapodal SCRs by varying the heterocyclic binding group. We found that SCR017 (3-pyrrole), SCR021 (3-pyridine), and SCR022 (2-phenol) bind only to ß-Glc. SCR019 (3-indole) binds only to ß-Man. SCR020 (2-pyridine) binds ß-Man and α-Man with a preference to the latter. SCR018 (2-indole) binds α-Man and ß-Gal with a preference to the former. The glycan guests bound within their SCR hosts in one of three supramolecular geometries: center-parallel, center-perpendicular, and off-center. Many host-guest combinations formed higher stoichiometry complexes, 2:1 glycan⋅SCR or 1:2 glycan⋅SCR, where the former are driven by positive allosteric cooperativity induced by glycan-glycan contacts.

The Power of Assemblies at Interfaces: Nanosensor Platforms Based on Synthetic Receptor Membranes.

Synthetic sensing materials (artificial receptors) are some of the most attractive components of chemical/biosensors because of their long-term stability and low cost of production. However, the strategy for the practical design of these materials toward specific molecular recognition in water is not established yet. For the construction of artificial material-based chemical/biosensors, the bottom-up assembly of these materials is one of the effective methods. This is because the driving forces of molecular recognition on the receptors could be enhanced by the integration of such kinds of materials at the 'interfaces', such as the boundary portion between the liquid and solid phases. Additionally, the molecular assembly of such self-assembled monolayers (SAMs) can easily be installed in transducer devices. Thus, we believe that nanosensor platforms that consist of synthetic receptor membranes on the transducer surfaces can be applied to powerful tools for high-throughput analyses of the required targets. In this review, we briefly summarize a comprehensive overview that includes the preparation techniques for molecular assemblies, the characterization methods of the interfaces, and a few examples of receptor assembly-based chemical/biosensing platforms on each transduction mechanism.

Molecular Recognition and Cocrystallization of Methylated and Halogenated Fragments of Danicalipin A by Enantiopure Alleno-Acetylenic Cage Receptors.

Enantiopure (P)4- and (M)4-configured alleno-acetylenic cage (AAC) receptors offer a highly defined interior for the complexation and structure elucidation of small molecule fragments of the stereochemically complex chlorosulfolipid danicalipin A. Solution (NMR), solid state (X-ray), and theoretical investigations of the formed host-guest complexes provide insight into the conformational preferences of 14 achiral and chiral derivatives of the danicalipin A chlorohydrin core in a confined, mostly hydrophobic environment, extending previously reported studies in polar solvents. The conserved binding mode of the guests permits deciphering the effect of functional group replacements on Gibbs binding energies ΔG. A strong contribution of conformational energies toward the binding affinities is revealed, which explains why the denser packing of larger apolar domains of the guests does not necessarily lead to higher association. Enantioselective binding of chiral guests, with energetic differences ΔΔG293 K up to 0.7 kcal mol-1 between diastereoisomeric complexes, is explained by hydrogen- and halogen-bonding, as well as dispersion interactions. Calorimetric studies (ITC) show that the stronger binding of one enantiomer is accompanied by an increased gain in enthalpy ΔH but at the cost of a larger entropic penalty TΔS stemming from tighter binding.