Reductionist Approach in Peptide-Based Nanotechnology.

The formation of ordered nanostructures by molecular self-assembly of proteins and peptides represents one of the principal directions in nanotechnology. Indeed, polyamides provide superior features as materials with diverse physical properties. A reductionist approach allowed the identification of extremely short peptide sequences, as short as dipeptides, which could form well-ordered amyloid-like ß-sheet-rich assemblies comparable to supramolecular structures made of much larger proteins. Some of the peptide assemblies show remarkable mechanical, optical, and electrical characteristics. Another direction of reductionism utilized a natural noncoded amino acid, α-aminoisobutryic acid, to form short superhelical assemblies. The use of this exceptional helix inducer motif allowed the fabrication of single heptad repeats used in various biointerfaces, including their use as surfactants and DNA-binding agents. Two additional directions of the reductionist approach include the use of peptide nucleic acids (PNAs) and coassembly techniques. The diversified accomplishments of the reductionist approach, as well as the exciting future advances it bears, are discussed.

A synthetic porphyrin as an effective dual antidote against carbon monoxide and cyanide poisoning.

Simultaneous poisoning by carbon monoxide (CO) and hydrogen cyanide is the major cause of mortality in fire gas accidents. Here, we report on the invention of an injectable antidote against CO and cyanide (CN-) mixed poisoning. The solution contains four compounds: iron(III)porphyrin (FeIIITPPS, F), two methyl-ß-cyclodextrin (CD) dimers linked by pyridine (Py3CD, P) and imidazole (Im3CD, I), and a reducing agent (Na2S2O4, S). When these compounds are dissolved in saline, the solution contains two synthetic heme models including a complex of F with P (hemoCD-P) and another one of F with I (hemoCD-I), both in their iron(II) state. hemoCD-P is stable in its iron(II) state and captures CO more strongly than native hemoproteins, while hemoCD-I is readily autoxidized to its iron(III) state to scavenge CN- once injected into blood circulation. The mixed solution (hemoCD-Twins) exhibited remarkable protective effects against acute CO and CN- mixed poisoning in mice (~85% survival vs. 0% controls). In a model using rats, exposure to CO and CN- resulted in a significant decrease in heart rate and blood pressure, which were restored by hemoCD-Twins in association with decreased CO and CN- levels in blood. Pharmacokinetic data revealed a fast urinary excretion of hemoCD-Twins with an elimination half-life of 47 min. Finally, to simulate a fire accident and translate our findings to a real-life scenario, we confirmed that combustion gas from acrylic cloth caused severe toxicity to mice and that injection of hemoCD-Twins significantly improved the survival rate, leading to a rapid recovery from the physical incapacitation.

Single-crystal-to-single-crystal translation of a helical supramolecular polymer to a helical covalent polymer.

Polymers possessing helical conformation in the solid state are in high demand. We report a helical peptide-polymer via the topochemical ene-azide cycloaddition (TEAC) polymerization. The molecules of the designed Gly-Phe-based dipeptide, decorated with ene and azide, assemble in its crystals as ß-sheets and as supramolecular helices in two mutually perpendicular directions. While the NH…O H-bonding facilitates ß-sheet-like stacking along one direction, weak CH…N H-bonding between the azide-nitrogen and vinylic-hydrogen of molecules belonging to the adjacent stacks arranges them in a head-to-tail manner as supramolecular helices. In the crystal lattice, the azide and alkene of adjacent molecules in the supramolecular helix are suitably preorganized for their TEAC reaction. The dipeptide underwent regio- and stereospecific polymerization upon mild heating in a single-crystal-to-single-crystal fashion, yielding a triazoline-linked helical covalent polymer that could be characterized by single-crystal X-ray diffraction studies. Upon heating, the triazoline-linked polymer undergoes denitrogenation to aziridine-linked polymer, as evidenced by differential scanning calorimetry, thermogravimetric analysis, and solid-state NMR analyses.

Light-Powered Propeller-like Transporter for Boosted Transmembrane Ion Transport.

Membrane-active molecular machines represent a recently emerging, yet important line of expansion in the field of artificial transmembrane transporters. Their hitherto demonstrated limited types (molecular swing, ion fishers, shuttlers, rotors, etc.) certainly call for new inspiring developments. Here, we report a very first motorized ion-transporting carrier-type transporter, i.e., a modularly tunable, light-powered propeller-like transporter derived from Feringa's molecular motor for consistently boosting transmembrane ion transport under continuous UV light irradiation. Based on the EC50 values, the molecular propeller-mediated ion transport activities under UV light irradiation for 300 s are 2.31, 1.74, 2.29, 2.80, and 2.92 times those values obtained without irradiation for Li+, Na+, K+, Rb+, and Cs+ ions, respectively, with EC50 value as low as 0.71 mol % for K+ ion under light irradiation.

On-Chip Fabrication of Colloidal Suprastructures by Assembly and Supramolecular Interlinking of Microgels.

In this report, a versatile method is demonstrated to create colloidal suprastructures by assembly and supramolecular interlinking of microgels using droplet-based microfluidics. The behavior of the microgels is systematically investigated to evaluate the influence of their concentration on their distribution between the continuous, the droplet phase, and the interface. At low concentrations, microgels are mainly localized at the water-oil interface whereas an excess of microgels results, following the complete coverage of the water-oil interface, in their distribution in the continuous phase. To stabilize the colloidal suprastructure, on-chip gelation is introduced by adding natural polyphenol tannic acid (TA) in the water phase. TA forms interparticle linking between the poly(N-vinylcaprolactam) (PVCL) microgels by supramolecular interactions. The combination of supramolecular interlinking with the variation of the microgel concentration in microfluidic droplets enables on-chip fabrication of defined colloidal suprastructures with morphologies ranging from colloidosomes to colloidal supraballs. The obtained supracolloidal structures exhibit a pH-responsive behavior with a disintegration at alkaline conditions within a scale of seconds. The destabilization process results from the deprotonation of phenolic groups and destruction of hydrogen bonds with PVCL chains at higher pH.

Microfluidic-Assisted Self-Assembly of Molecular Hydrogelator at Water-Water Interfaces for Continuous Fabrication of Supramolecular Microcapsules.

Control over the self-assembly of small molecules at specific areas is of great interest for many high-tech applications, yet remains a formidable challenge. Here, how the self-assembly of hydrazone-based molecular hydrogelators can be specifically triggered at water-water interfaces for the continuous fabrication of supramolecular microcapsules by virtue of the microfluidic technique is demonstrated. The non-assembling hydrazide- and aldehyde-based hydrogelator precursors are distributed in two immiscible aqueous polymer solutions, respectively, through spontaneous phase separation. In the presence of catalysts, hydrazone-based hydrogelators rapidly form and self-assemble into hydrogel networks at the generated water-water interfaces. Relying on the microfluidic technique, microcapsules bearing a shell of supramolecular hydrogel are continuously produced. The obtained microcapsules can effectively load enzymes, enabling localized enzymatic growth of supramolecular fibrous supramolecular structures, reminiscent of the self-assembly of biological filaments within living cells. This work may contribute to the development of biomimetic supramolecular carriers for applications in biomedicine and fundamental research, for instance, the construction of protocells.

High-Affinity Host-Guest Recognition for Efficient Assembly and Enzymatic Responsiveness of DNA Nanostructures.

The combination of multiple orthogonal interactions enables hierarchical complexity in self-assembled nanoscale materials. Here, efficient supramolecular polymerization of DNA origami nanostructures is demonstrated using a multivalent display of small molecule host-guest interactions. Modification of DNA strands with cucurbit[7]uril (CB[7]) and its adamantane guest, yielding a supramolecular complex with an affinity of order 1010 m-1 , directs hierarchical assembly of origami monomers into 1D nanofibers. This affinity regime enables efficient polymerization; a lower-affinity ß-cyclodextrin-adamantane complex does not promote extended structures at a similar valency. Finally, the utility of the high-affinity CB[7]-adamantane interactions is exploited to enable responsive enzymatic actuation of origami nanofibers assembled using peptide linkers. This work demonstrates the power of high-affinity CB[7]-guest recognition as an orthogonal axis to drive self-assembly in DNA nanotechnology.

Amylose Dimerization in Solution Can Be Studied Using a Model System.

Amylose, the linear polymer of α-1,4-linked glucopyranose units, is known to crystallize as a parallel double helix, but evidence of this duplex forming in solution has remained elusive for decades. We show how the dimerization of short amylose chains can be detected in solution using NMR spectroscopy when the glucans are labeled at the reducing-end with an aromatic moiety that overcomes chemical shift degeneracy leading to distinct signals for the single-stranded and duplex amylose. A set of α-1,4 glucans with varying lengths of 6, 12, 18, and 22 glucose units and a 4-aminobenzamide label were synthesized, enabling the first systematic thermodynamic study of the association of amylose in solution. The dimerization is enthalpically driven, entropically unfavorable and beyond a minimum length of 12, each additional pair of glucose residues stabilizes the duplex by 0.85 kJ mol-1 . This fundamental knowledge provides a basis for a quantitative understanding of starch structure, gelation and enzymatic digestion, and lays the foundations for the strategic use of α-1,4-glucans in the development of self-assembled materials.

Formation and Stability of Benzylic Amide [2]- and [3]Rotaxanes: an Intercomponent Interactions Study.

One of the most recent focuses in supramolecular chemistry is developing molecules designed to exhibit programmable properties at the molecular level. Rotaxanes, which function as molecular machines with movements controlled by external stimuli, are prime candidates for this purpose. However, the controlled synthesis of rotaxanes, especially amide-benzylic rotaxanes with more than two components, remains an area ripe for exploration. In this study, we aim to elucidate the formation of amide-benzylic [3]rotaxanes using a thread that includes a conventional succinamide station and an innovative triazole-carbonyl station. Including the triazole-carbonyl station introduces new perspectives into the chemistry of rotaxanes, influencing their conformation and dynamics. The synthesis of two-station rotaxanes with varying stoppers demonstrated that the macrocycle consistently occupies the succinamide station, providing greater stability as evidenced by NMR and SC-XRD analyses. The presence of a triazole-carbonyl station facilitated the formation of a second macrocycle exclusively when a secondary amide was employed as the stopper group, presumably due to decreased steric hindrance. Moreover, the second macrocycle directly forms at the triazole-carbonyl station. This investigation reveals that slight modifications in the thread structure can dramatically impact the formation, stability, and interactions between components of rotaxanes.

A Bis-Porphyrin Cavitand Breathing-In to Constrict Bucky Balls.

Bis-porphyrin cages have long been exploited to bind fullerenes selectively for various applications. The major consideration for an effective binding here had been the cavity size. Herein, we structurally demonstrate that a bis-Ni-porphyrin cavitand having even a smaller cavity can host a larger fullerene by a breathing and ruffling mechanism. It has also been shown that both the electronic and steric influence at the meso- positions of the porphyrin in fact dictate the binding character. The smaller cavity of 2NiD exhibits preferential binding for C70 over C60; however, surprisingly, the larger cavities in 2HD and 2NiTD display stronger affinities for C60 over the larger fullerene. We show here that the structural elasticity infused both by the metalloporphyrins and the connecting bridges play a major role in directing the binding. These conclusions have adequately been supported by structural and spectroscopic investigations. Additionally, the suitability of one of the conjugates for photoinduced charge-separation has been investigated using ultrafast transient absorption measurements. 2NiD⊃C60 has a charge separation timescale of ~0.8 ps, while charge recombination occurs at a longer timescale of ~920 ps.

Cage Match: Comparing the Anion Binding Ability of Isostructural Versus Isofunctional Pairs of Metal-Organic Nanocages.

Affinities of six anions (mesylate, acetate, trifluoroacetate, p-toluenecarboxylate, p-toluenesulfonate, and perfluorooctanoate) for three related Pt2+ -linked porphyrin nanocages were measured to probe the influence of different noncovalent recognition motifs (e. g., hydrogen bonding, electrostatics, π bonding) on anion binding. Two new hosts of M6 L3 12+ (1b) and M4 L2 8+ (2) composition (M=(en)Pt2+ , L=(3-py)4 porphyrin) were prepared in a one-pot synthesis and allowed comparison of hosts that differ in structure while maintaining similar N-H hydrogen-bond donor ability. Comparisons of isostructural hosts that differ in hydrogen-bonding ability were made between 1b and a related M6 L3 12+ nanoprism (1a, M=(tmeda)Pt2+ ) that lacks N-H groups. Considerable variation in association constants (K1 =1.6×103  M-1 to 1.3×108  M-1 ) and binding mode (exo vs. endo) were found for different host-guest combinations. Strongest binding was seen between p-toluenecarboxylate and 1b, but surprisingly, association of this guest with 1a was only slightly weaker despite the absence of NH⋅⋅⋅O interactions. The high affinity between p-toluenecarboxylate and 1a could be turned off by protonation, and this behavior was used to toggle between the binding of this guest and the environmental pollutant perfluorooctanoate, which otherwise has a lower affinity for the host.

An Unusual Macrocyclic Hexamer of an Iso-Tellurazole N-Oxide Featuring CTe O Chalcogen Bonds is Formed by κ6 -O Complexation to Fe(II) and Ni(II).

Studies of the supramolecular chemistry of iso-tellurazole N-oxides have been confined to non-polar media until now. To overcome that limitation, an iso-tellurazole N-oxide was derivatized with a primary alcohol group; the compound is soluble in polar solvents and stable in acidic to neutral aqueous media. Nickel (II) and iron (II) form macrocyclic complexes with six molecules of that iso-tellurazole N-oxide in a hitherto not-observed macrocyclic arrangement defined by CTe⋅⋅⋅O chalcogen bonds and κ6 -O bound to the metal ion. This behaviour is in sharp contrast with the κn -Te (n=1,2,4) complexes formed by soft metal ions.

Fluorescence color change of supramolecular polymer networks controlled by crown ether-cation recognition.

We report a fluorescent supramolecular polymer networks (SPNs) system based on crown ether-cation recognition. The polymer side chains bear ammonium cations, which can be recognized by host molecules with a B15C5 unit and a quinoline group at each end. The quinoline group makes the host molecule exhibit blue fluorescence. After the formation of SPNs, the recognition of the crown ether-cation transforms the blue fluorescence into yellow fluorescence. The accompanying fluorescence color change during the formation of SPNs makes it with potential applications in the fields of display, printing, information storage, and bioimaging.

Synthesis of Asymmetric Ionic Hybrid Detergents enables Micelles with Scalable Properties including Cell Compatibility.

Ionic detergents enable applications and cause harm in biospheres due to cell toxicity. The utility of covalent combinations between ionic and non-ionic detergent headgroups in modulating cell toxicity remains speculative due to the yet rarely explored synthesis. We close this gap and establish the modular synthesis of ionic/non-ionic hybrid detergents. We restructure a combinatorial methallyl dichloride one-pot coupling into a two-step coupling, which reduces by-products, improves product yields, and enables the gram-scale preparation of asymmetric, cationic/non-ionic and anionic/non-ionic hybrid detergents. Our modular synthesis delivers new modalities for the design of ionic detergents, including an unprecedented scaling of properties that determine applications, such as charge, critical micelle concentration, solubilizing properties, hard water tolerance, and cell compatibility. We uncover that shielding the charge in ionic headgroups can switch the detergent species that is toxic to cells from monomers to mixtures of monomers and micellar assemblies. Establishing the chemistry of ionic/non-ionic hybrid detergents provides a missing evolutionary link in the structural comparison of ionic and non-ionic detergents, enables an easy synthesis access to yet unexplored chemical spaces of asymmetric hybrid materials, and delivers new modalities for designing the toxicity of supramolecular nanomaterials.

Structure-Activity Relationships in Supramolecular Hosts Targeting Bacterial Phosphatidylethanolamine (PE) Lipids.

The World Health Organization has described the antimicrobial resistance crisis as one of the top ten global public health threats. New antimicrobial agents that can fight infections caused by antimicrobial resistant pathogens are therefore needed. A potential strategy is the development of small molecules that can selectively interact with bacterial membranes (or membranes of other microbial pathogens), and thereby rapidly kill the bacteria. Here, we report the structure-activity relationship within a group of 22 compounds that were designed to bind the bacterial lipid phosphatidylethanolamine (PE). Liposome-based studies reveal that the lipophilicity of the compounds has the strongest effect on both the affinity and selectivity for PE. The best results were obtained for compounds with logP ≈ 3.75, which showed a 5x to 7x selectivity for bacterial PE lipids over human PC (phosphatidylcholine) lipids. Furthermore, these compounds also showed potent antibacterial activity against the Gram-positive bacterium B. cereus, with minimum inhibitory concentrations (MICs) below 10 µM, a concentration where they showed minimal hemolytic activity against human red blood cells. These results not only show the possibility of PE-binding small molecules to function as antibiotics, but also provide guidelines for the development of compounds targeting other types of biologically relevant membrane lipids.

Functional Linkers Support Targeting of Multivalent Tweezers to Taspase1.

Taspase 1 is a unique protease not only pivotal for embryonic development but also implicated in leukemias and solid tumors. As such, this enzyme is a promising while still challenging therapeutic target, and with its protein structure featuring a flexible loop preceding the active site a versatile model system for drug development. Supramolecular ligands provide a promising complementary approach to traditional small-molecule inhibitors. Recently, the multivalent arrangement of molecular tweezers allowed the successful targeting of Taspase 1's surface loop. With this study we now want to take the next logic step und utilize functional linker systems that not only allow the implementation of novel properties but also engage in protein surface binding. Consequently, we chose two different linker types differing from the original divalent assembly: a backbone with aggregation-induced emission (AIE) properties to enable monitoring of binding and a calix[4]arene scaffold initially pre-positioning the supramolecular binding units. With a series of four AIE-equipped ligands with stepwise increased valency we demonstrated that the functionalized AIE linkers approach ligand binding affinities in the nanomolar range and allow efficient proteolytic inhibition of Taspase 1. Moreover, implementation of the calix[4]arene backbone further enhanced the ligands' inhibitory potential, pointing to a specific linker contribution.

A Study on Auto-Catalysis and Product Inhibition: A Nucleophilic Aromatic Substitution Reaction Catalysed within the Cavity of an Octanuclear Coordination Cage.

The ability of an octanuclear cubic coordination cage to catalyse a nucleophilic aromatic substitution reaction on a cavity-bound guest was studied with 2,4-dinitrofluorobenzene (DNFB) as the guest/substrate. It was found that DNFB undergoes a catalysed reaction with hydroxide ions within the cavity of the cubic cage (in aqueous buffer solution, pH 8.6). The rate enhancement of kcat/kuncat was determined to be 22, with cavity binding of the guest being required for catalysis to occur. The product, 2,4-dinitrophenolate (DNP), remained bound within the cavity due to electrostatic stabilisation and exerts two apparently contradictory effects: it initially auto-catalyses the reaction when present at low concentrations, but at higher concentrations inhibits catalysis when a pair of DNP guests block the cavity. When encapsulated, the UV/Vis absorption spectrum of DNP is red-shifted when compared to the spectrum of free DNP in aqueous solution. Further investigations using other aromatic guests determined that a similar red-shift on cavity binding also occurred for 4-nitrophenolate (4NP) at pH 8.6. The red-shift was used to determine the stoichiometry of guest binding of DNP and 4NP within the cage cavity, which was confirmed by structural analysis with X-ray crystallography; and was also used to perform catalytic kinetic studies in the solution-state.

Urea-Comprising Single Core Diketopyrrolopyrrole Derivatives: Exploring the Synthesis, Self-Assembly and Charge Transport Properties.

Supramolecular electronics exploits the distinctive features stemming from noncovalent interactions, guiding the self-assembly of molecules to craft materials endowed with customized electronic functionalities. Hydrogen-bonded materials, characterized by their capacity to establish dynamic and stable networks, introduce an extra dimension to the development of supramolecular electronic systems. This study presents a comparative analysis of two remarkably small semiconductors utilizing diketopyrrolopyrrole functionalized with urea units as hydrogen-bonding motifs, strategically positioned at opposing ends of the conjugated core. We show how the subtle distinction in functionalization not only influences morphology and self-assembly dynamics via hydrogen-bonding and π-π stacking formation, but also holds significant consequences for ultimate charge transport properties. Our observations into the interplay of noncovalent interactions provide valuable insights and strategic pathways for the design of novel materials with enhanced electronic characteristics.

Luminescent Supramolecular Ionic Frameworks based on Organic Fluorescent Polycations and Polyanionic Phosphorescent Metal Clusters.

Emissive ionic supramolecular frameworks are designed by associating tetraphenylethylene-based tetra-cationic units and di-anionic molybdenum or tetra-anionic rhenium octahedral clusters. Obtained structures were characterized by single-crystal X-ray diffraction. The emission properties of the hybrids were investigated as dry powders or in various solvents by one photon and two photon absorption leading to a O2 concentration dependent luminescence color for the Mo based hybrid.

Investigating Recurrent Matere Bonds in Pertechnetate Compounds.

In this manuscript we evaluate the X-ray structure of five new pertechnetate derivatives of general formula [M(H2O)4(TcO4)2], M=Mg, Co, Ni, Cu, Zn (compounds 1-5) and one perrhenate compound Zn(H2O)4(ReO4)2 (6). In these complexes the metal center exhibits an octahedral coordination with the pertechnetate units as axial ligands. All compounds exhibit the formation of directional Tc⋅⋅⋅O Matere bonds (MaBs) that propagate the [M(H2O)4(TcO4)2], into 1D supramolecular polymers in the solid state. Such 1D polymers are linked, generating 2D layers, by combining additional MaBs and hydrogen bonds (HBs). Such concurrent motifs have been analyzed theoretically, suggesting the noncovalent σ-hole nature of the MaBs. The interaction energies range from weak (~ -2 kcal/mol) for the MaBs to strong (~ -30 kcal/mol) for the MaB+HB assemblies, where HB dominates. In case of M=Zn, the corresponding perrhenate Zn(H2O)4(ReO4)2 complex, has been also synthesized for comparison purposes, resulting in the formation of an isostructural X-ray structure, corroborating the structure-directing role of Matere bonds.