Synthetic Hosts Research Articles

Multicomponent, Multicavity Metallacages That Contain Different Binding Sites for Allosteric Recognition.

The encapsulation of different guest molecules by their different recognition domains of proteins leads to selective binding, catalysis, and transportation. Synthetic hosts capable of selectively binding different guests in their different cavities to mimic the function of proteins are highly desirable but challenging. Here, we report three ladder-shaped, triple-cavity metallacages prepared by multicomponent coordination-driven self-assembly. Interestingly, the porphyrin-based metallacage is capable of heteroleptic encapsulation of fullerenes (C60 or C70) and coronene using its different cavities, allowing distinct allosteric recognition of coronene upon the addition of C60 or C70. Owing to the different binding affinities of the cavities, the metallacage hosts one C60 molecule in the central cavity and two coronene units in the side cavities, while encapsulating two C70 molecules in the side cavities and one coronene molecule in the central cavity. The rational design of multicavity assemblies that enable heteroleptic encapsulation and allosteric recognition will guide the further design of advanced supramolecular constructs with tunable recognition properties.

Enantioselective Recognition of Functional Organic Molecules in Water by Biomimetic Macrocyclic Hosts.

Enantioselective recognition of functional organic molecules in water is routine in nature but remains a formidable challenge for synthetic hosts. Here, we reported two pairs of chiral naphthotubes with chiral centers located in the neighborhood of the inward-directing amide groups. These naphthotubes, with a chiral twisted cavity, show highly enantioselective recognition in water to a wide scope of organic molecules (90 chiral guests). The highest enantioselectivity of 34 was achieved with neotame. Small differences between all of the noncovalent interactions shielded in the hydrophobic cavity were revealed to be responsible for the enantioselective recognition in water, which is different from the traditional views. Moreover, these hosts can differentiate the analogues of aspartame using fluorescence spectroscopy. These chiral naphthotubes have made unprecedented achievements in enantioselective recognition, providing the basis for their applications in chiral analysis and separations.

Discovery of selective monosaccharide receptors via dynamic combinatorial chemistry.

The molecular recognition of saccharides by synthetic hosts has become an appealing but elusive task in the last decades. Herein, we combine Dynamic Combinatorial Chemistry (DCC) for the rapid self-assembly and screening of virtual libraries of receptors, with the use of ITC and NMR to validate the hits and molecular modelling to understand the binding mechanisms. We discovered a minimalistic receptor, 1F (N-benzyl-L-phenylalanine), with considerable affinity for fructose (Ka = 1762 M-1) and remarkable selectivity (>50-fold) over other common monosaccharides. The approach accelerates the discovery process of receptors for saccharides.

Precise Recognition in Water by an Endo-Functionalized Cavity: Tuning the Complementarity of Binding Sites.

Precise binding towards structurally similar substrates is a common feature of biomolecular recognition. However, achieving such selectivity-especially in distinguishing subtle differences in substrates-with synthetic hosts can be quite challenging. Herein, we report a novel design strategy involving the combination of different rigid skeletons to adjust the distance between recognition sites within the cavity, which allows for the highly selective recognition of hydrogen-bonding complementary substrates, such as 4-chromanone. X-ray single-crystal structures and density functional theory calculations confirmed that the distance of endo-functionalized groups within the rigid cavity is crucial for achieving high binding selectivity through hydrogen bonding. The thermodynamic data and molecular dynamics simulations revealed a significant influence of the hydrophobic cavity on the binding affinity. The new receptor possesses both high selectivity and high affinity, which provide valuable insights for the design of customized receptors.

Precise Recognition in Water by an Endo‐Functionalized Cavity: Tuning the Complementarity of Binding Sites

AbstractPrecise binding towards structurally similar substrates is a common feature of biomolecular recognition. However, achieving such selectivity—especially in distinguishing subtle differences in substrates—with synthetic hosts can be quite challenging. Herein, we report a novel design strategy involving the combination of different rigid skeletons to adjust the distance between recognition sites within the cavity, which allows for the highly selective recognition of hydrogen‐bonding complementary substrates, such as 4‐chromanone. X‐ray single‐crystal structures and density functional theory calculations confirmed that the distance of endo‐functionalized groups within the rigid cavity is crucial for achieving high binding selectivity through hydrogen bonding. The thermodynamic data and molecular dynamics simulations revealed a significant influence of the hydrophobic cavity on the binding affinity. The new receptor possesses both high selectivity and high affinity, which provide valuable insights for the design of customized receptors.

Rationally Tailored Mesoporous Hosts for Optimal Protein Encapsulation.

Proteins play important roles in the therapeutic, medical diagnostic, and chemical catalysis industries. However, their potential is often limited by their fragile and dynamic nature outside cellular environments. The encapsulation of proteins in solid materials has been widely pursued as a route to enhance their stability and ease of handling. Nevertheless, the experimental investigation of protein interactions with rationally designed synthetic hosts still represents an area in need of improvement. In this work, we leveraged the tunability and crystallinity of metal-organic frameworks (MOFs) and developed a series of crystallographically defined protein hosts with varying chemical properties. Through systematic studies, we identified the dominating mechanisms for protein encapsulation and developed a host material with well-tailored properties to effectively encapsulate the protein ubiquitin. Specifically, in our mesoporous hosts, we found that ubiquitin encapsulation is thermodynamically favored. A more hydrophilic encapsulation environment with favorable electrostatic interactions induces enthalpically favored ubiquitin-MOF interactions, and a higher pH condition reduces the intraparticle diffusion barrier, both leading to a higher protein loading. Our findings provide a fundamental understanding of host-guest interactions between proteins and solid matrices and offer new insights to guide the design of future protein host materials to achieve optimal protein loading. The MOF modification technique used in this work also demonstrates a facile method to develop materials easily customizable for encapsulating proteins with different surface properties.

A Diverse Array of Large Capsules Transform in Response to Stimuli.

The allosteric regulation of biomolecules, such as enzymes, enables them to adapt and alter their conformation to fit specific substrates, expressing different functionalities in response to stimuli. Different stimuli can also trigger synthetic coordination cages to change their shape, size, and nuclearity by reconfiguring the dynamic metal-ligand bonds that hold them together. Here we demonstrate an abiological system consisting of different organic subcomponents and ZnII metal ions, which can respond to simple stimuli in complex ways. A ZnII20L12 dodecahedron transforms to give a larger ZnII30L12 icosidodecahedron through subcomponent exchange, as an aldehyde that forms bidentate ligands is displaced in favor of one that forms tridentate ligands together with a penta-amine subcomponent. In the presence of a chiral template guest, the same system that produced the icosidodecahedron instead gives a ZnII15L6 truncated rhombohedral architecture through enantioselective self-assembly. Under specific crystallization conditions, a guest induces a further reconfiguration of either the ZnII30L12 or ZnII15L6 cages to yield an unprecedented ZnII20L8 pseudo-truncated octahedral structure. The transformation network of these cages shows how large synthetic hosts can undergo structural adaptation through the application of chemical stimuli, opening pathways to broader applications.

Rational Design of the β‐Bulge Gate in a Green Fluorescent Protein Accelerates the Kinetics of Sulfate Sensing**

AbstractDetection of anions in complex aqueous media is a fundamental challenge with practical utility that can be addressed by supramolecular chemistry. Biomolecular hosts such as proteins can be used and adapted as an alternative to synthetic hosts. Here, we report how the mutagenesis of the β‐bulge residues (D137 and W138) in mNeonGreen, a bright, monomeric fluorescent protein, unlocks and tunes the anion preference at physiological pH for sulfate, resulting in the turn‐off sensor SulfOFF‐1. This unprecedented sensing arises from an enhancement in the kinetics of binding, largely driven by position 138. In line with these data, molecular dynamics (MD) simulations capture how the coordinated entry and gating of sulfate into the β‐barrel is eliminated upon mutagenesis to facilitate binding and fluorescence quenching.

Rational Design of the β-Bulge Gate in a Green Fluorescent Protein Accelerates the Kinetics of Sulfate Sensing.

Detection of anions in complex aqueous media is a fundamental challenge with practical utility that can be addressed by supramolecular chemistry. Biomolecular hosts such as proteins can be used and adapted as an alternative to synthetic hosts. Here, we report how the mutagenesis of the β-bulge residues (D137 and W138) in mNeonGreen, a bright, monomeric fluorescent protein, unlocks and tunes the anion preference at physiological pH for sulfate, resulting in the turn-off sensor SulfOFF-1. This unprecedented sensing arises from an enhancement in the kinetics of binding, largely driven by position 138. In line with these data, molecular dynamics (MD) simulations capture how the coordinated entry and gating of sulfate into the β-barrel is eliminated upon mutagenesis to facilitate binding and fluorescence quenching.

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.

Limitations of non-polarizable force fields in describing anion binding poses in non-polar synthetic hosts.

Transmembrane anion transport by synthetic ionophores has received increasing interest not only because of its relevance for understanding endogenous anion transport, but also because of potential implications for therapeutic routes in disease states where chloride transport is impaired. Computational studies can shed light on the binding recognition process and can deepen our mechanistic understanding of them. However, the ability of molecular mechanics methods to properly capture solvation and binding properties of anions is known to be challenging. Consequently, polarizable models have been suggested to improve the accuracy of such calculations. In this study, we calculate binding free energies for different anions to the synthetic ionophore, biotin[6]uril hexamethyl ester in acetonitrile and to biotin[6]uril hexaacid in water by employing non-polarizable and polarizable force fields. Anion binding shows strong solvent dependency consistent with experimental studies. In water, the binding strengths are iodide > bromide > chloride, and reversed in acetonitrile. These trends are well captured by both classes of force fields. However, the free energy profiles obtained from potential of mean force calculations and preferred binding positions of anions depend on the treatment of electrostatics. Results from simulations using the AMOEBA force-field, which recapitulate the observed binding positions, suggest strong effects from multipoles dominate with a smaller contribution from polarization. The oxidation status of the macrocycle was also found to influence anion recognition in water. Overall, these results have implications for the understanding of anion host interactions not just in synthetic ionophores, but also in narrow cavities of biological ion channels.

Corralarenes: A Family of Conjugated Tubular Hosts.

Despite the advances in host-guest chemistry, macrocyclic hosts with deep cavities are far from abundant among the large number of wholly synthetic hosts described in the literature. Herein, we describe the design and synthesis of two new tubular hosts, namely, corral[4]arene and corral[5]arene. The former has been isolated and characterized as two conformational diastereoisomers, one is centrosymmetric and the other asymmetric. The latter, a fivefold symmetrical and flexible host, has also been investigated in detail. It is composed of five 4,4'-dimethoxybiphenyl units bridged by ethynylene linkers at their 2,2'-positions and adopts a pentagonal conformation with a tubular-shaped cavity in the presence of guests. This structure endows corral[5]arene not only with a conjugated backbone, capable of bright fluorescent emission (quantum yield, 56%), but also a deep π-electron-rich aromatic cavity with remarkable conformational flexibility. The adaptive cavity of corral[5]arene allows it to accommodate a wide range of neutral and positively charged electron-deficient guests with different molecular sizes and shapes. Binding constants between this host and these guests in three different nonpolar organic solvents lie in the range of 103 to 107 M-1. Moreover, corral[5]arene exhibits dynamic chirality on account of the axes of chirality associated with each of the five biphenyl units and displays first-order transformation as exhibited by circular dichroism in response to the addition of chiral guests. All these stereochemical features render corral[5]arene an attractive host for a variety of supramolecular and nanotechnological applications.

Unraveling the Chemistry of High Valent Arylcopper Compounds and Their Roles in Copper-Catalyzed Arene C-H Bond Transformations Using Synthetic Macrocycles.

Recent decades have witnessed a resurgence of the study of copper-catalyzed organic reactions. As the surrogate of noble metal catalysts, copper salts have been shown to exhibit remarkable versatility in activating various C-H bonds enabling the construction of diverse carbon-carbon and carbon-heteroatom bonds. Advantageously, copper salts are also naturally abundant, inexpensive, and less toxic in comparison to precious metals. Despite significant developments in synthesis, the mechanism of copper catalysis remains elusive. Hypothetical pathways such as the two-electron Cu(III)/Cu(I) and Cu(II)/Cu(0) catalytic cycles and the one-electron Cu(II)/Cu(I) catalytic cycle have been invoked to diagram C-H bond transformations because of the formidable challenges to isolate and characterize transient high valent organocopper intermediates. In fact, organocopper chemistry has been dominated for a long time by the acknowledged nucleophilic organocopper(I) compounds. Since the beginning of the new millennium, we have been systematically studying the supramolecular chemistry of heteracalix[n]aromatics. Owing to the ease of their synthesis and selective functionalizations, self-tunable conformation and cavity structures resulting from the interplay of heteroatoms with aromatic subunits, and outstanding properties in molecular recognition and self-assembly, heteracalix[n]aromatics have become a class of privileged synthetic macrocyclic hosts. Our journey to the chemistry of high valent organocopper compounds started with a serendipitous discovery of the facile formation of a stable organocopper compound, which contains astonishingly a Ph-Cu(III) σ-bond under very mild aerobic conditions. When we examined routinely the effect of the macrocyclic structures on noncovalent complexation properties, titration of tetraazacalix[1]arene[3]pyridine with Cu(ClO4)2·6H2O resulted in the precipitation of dark-purple crystals of phenylcopper(III) diperchlorate. Our curiosity about the transformation of an arene C-H bond into an Ar-Cu(III) bond prompted us to conduct an in-depth investigation of the reaction of macrocyclic arenes with copper(II) salts, leading to the isolation of arylcopper(II) compounds which are unprecedented and the missing link in organocopper chemistry. With structurally well-defined organometallics in hand, we have explored extensively the reactivities of both arylcopper(II) and arylcopper(III) compounds, demonstrating their versatility and uniqueness in chemical synthesis. Novel and fascinating arene C-H transformations under copper catalysis have been developed. Using acquired high valent arylcopper compounds as molecular probes, and employing the functionalizations of tetraazacalix[1]arene[3]pyridines as model reactions, we have revealed the diverse mechanisms of copper-promoted arene C-H bond reactions. Elusive reaction pathways of some copper-catalyzed C-X bond activations have also been unraveled. In the meantime, we have also witnessed pleasingly the rapid development of field with the advent of new high valent organocopper compounds. Without any doubt, studies of the synthesis, reactivity, and catalysis of high valent organocopper compounds have been reshaping the field of organocopper chemistry. This Account summarizes our endeavors to explore the chemistry of structurally well-defined arylcopper(II) and arylcopper(III) compounds and the mechanisms of copper-catalyzed arene C-H and C-X bond transformations. We hope this Account will inspire chemists to study thoroughly the fundamentals and the cutting-edge catalysis of high valent organocopper compounds advancing and redefining the discipline of organocopper chemistry.

Switchable bifunctional molecular recognition in water using a pH-responsive Endo-functionalized cavity

The construction of water-soluble synthetic hosts with a stimuli-responsive endo-functionalized cavity is challenging. These hosts feature a switchable cavity and may bring new properties to the fields of self-assembly, molecular machines, and biomedical sciences. Herein, we report a pair of water-soluble naphthotubes with a pH-responsive endo-functionalized cavity. The inward-directing secondary amine group of the hosts can be protonated and deprotonated. Thus, the hosts have different cavity features at the two states and show drastically different binding preference and selectivity in water. We reveal that the binding difference of the two host states is originated from the differences in charge repulsion, hydrogen bonding and the hydrophobic effects. Moreover, the guest binding can be easily switched in a ternary mixture with two guest molecules by adjusting the pH value of the solution. These pH-responsive hosts may be used for the construction of smart self-assembly systems and water-soluble molecular machines.

Combining Excellent Selectivity with Broad Target Scope: Biosensing with Arrayed Deep Cavitand Hosts.

Simple macrocyclic water-soluble hosts such as cucurbiturils, cyclophanes, and calixarenes have long been used for biosensing via indicator displacement assays. Using multiple hosts and dyes in an arrayed format allows pattern recognition-based "chemical nose" sensing, which confers exquisite selectivity, even rivaling the abilities of biological recognition tools such as antibodies. However, a challenge in indicator displacement-based biosensing with macrocyclic hosts is that selectivity and scope are often inversely correlated: strong selectivity for a specific target can limit wide application, and broad scope sensing can suffer from a lack of selectivity between similar targets. This problem can be addressed by using water-soluble, self-folding deep cavitands as hosts. These flexible bowl-shaped receptors can be easily functionalized with different motifs at the upper and lower rim, and the large cavities can bind many different fluorescent dyes, causing either fluorescence enhancement or quenching upon binding.Cavity-based affinity is strongest for NMe3+ groups such as trimethyl-lysine, and we have exploited this for the site-selective recognition of post-translational lysine methylations in oligopeptides. The host recognizes the NMe3+ group, and by applying differently functionalized hosts in an arrayed format, discrimination between identical modifications at different positions on the oligopeptide is possible. Multiple recognition elements can be exploited for selectivity, including a defined, yet "breathable" cavity, and variable upper rim functions oriented toward the target.While the performance of the host/guest sensing system is impressive for lysine methylations, the most important advance is the use of multiple different sensing mechanisms that can target a broad range of different biorelevant species. The amphiphilic deep cavitands can both bind fluorescent dyes and interact with charged biomolecules. These non-cavity-based interactions, when paired with additives such as heavy metal ions, modulate fluorescence response in an indirect manner, and these different mechanisms allow selective recognition of serine phosphorylation, lysine acetylation, and arginine citrullination. Other targets include heavy metals, drugs of abuse, and protein isoforms. Furthermore, the hosts can be applied in supramolecular tandem assays of enzyme function: the broad scope allows analysis of such different enzymes as chromatin writers/erasers, kinases, and phosphatases, all from a single host scaffold. Finally, the indirect sensing concept allows application in sensing different oligonucleotide secondary structures, including G-quadruplexes, hairpins, triplexes, and i-motifs. Discrimination between DNA strands with highly similar structures such as G-quadruplex strands with bulges and vacancies can be achieved. Instead of relying on a single highly specific fluorescent probe, the synthetic hosts tune the fluorophore-DNA interaction, introducing multiple recognition equilibria that modulate the fluorescence signal. By applying machine learning algorithms, a classification model can be established that can accurately predict the folding state of unknown sequences. Overall, the unique recognition profile of self-folded deep cavitands provides a powerful, yet simple sensing platform, one that can be easily tuned for a wide scope of biorelevant targets, in complex biological media, without sacrificing selectivity in the recognition.

Selective recognition of methyl viologen by an endo-functionalized naphthobox

Highly selective binding of structurally similar substrates is common for biomolecular recognition, but is often challenging to realize in synthetic hosts. Herein, we report highly selective binding of methyl viologen over other analogues by an endo-functionalized naphthobox. X-ray single crystal structure and Density Functional Theory (DFT) calculations revealed that the endo-functionalized groups in the cavity of the naphthobox is important for the high binding selectivity through the formation of multiple CH⋅⋅⋅N, CH⋅⋅⋅π, and π⋅⋅⋅π interactions with methyl viologen.

Dynamic optimization of guest binding in a library of diastereomeric heteroleptic coordination cages

<h2>Summary</h2> Biological receptors, such as enzymes, are highly flexible and alter their conformation to fit target substrates. Synthetic supramolecular hosts, such as coordination cages, also exhibit some ability to adapt their cavity shape and size in response to guest molecules due to the dynamic nature of the linkages that hold them together. Here, we report the preparation of a new trigonal-prismatic coordination cage that forms selectively, incorporating two different ligands. The cage exhibits up to four diastereomeric configurations, differing in the "portrait" or "landscape" orientation of tetratopic pyrene-based ligands on its rectangular faces. Three diastereomeric forms of the cage have been structurally characterized, and NMR spectroscopy confirmed the formation of a mixture of diastereomers in solution. Although the cage panels are rigid, the different orientations that each panel can adopt enable the cage cavity to dynamically adapt to optimize the binding of guests, including elongated adamantane derivatives and toxic organochlorine pesticides.

Biomimetic Recognition of Quinones in Water by an Endo-Functionalized Cavity with Anthracene Sidewalls.

Selective molecular recognition in water is the foundation of numerous biological functions but is a challenge for most synthetic hosts. We employ the concept of endo-functionalized cavity and the strategy of simultaneous construction to address this issue. The concept and the strategy were demonstrated in the construction of a biomimetic host for selectively recognizing quinones in water. The host was synthesized by joining two pieces of bent anthracene dimer through amide bond formation, affording a deep hydrophobic cavity and inward-directing hydrogen bonding sites. The host can recognize quinones over their close analogues in water, and its association affinity to p-benzoquinone is the highest among all the known hosts and is even comparable to that of the bioreceptor. The binding with an anthraquinone reaches nanomolar affinity. Shielded hydrogen bonding, C-H⋅⋅⋅π, and charge transfer interactions, and the hydrophobic effect are responsible for the high binding affinity and selectivity.

Biomimetic Recognition of Quinones in Water by an Endo‐Functionalized Cavity with Anthracene Sidewalls

AbstractSelective molecular recognition in water is the foundation of numerous biological functions but is a challenge for most synthetic hosts. We employ the concept of endo‐functionalized cavity and the strategy of simultaneous construction to address this issue. The concept and the strategy were demonstrated in the construction of a biomimetic host for selectively recognizing quinones in water. The host was synthesized by joining two pieces of bent anthracene dimer through amide bond formation, affording a deep hydrophobic cavity and inward‐directing hydrogen bonding sites. The host can recognize quinones over their close analogues in water, and its association affinity to p‐benzoquinone is the highest among all the known hosts and is even comparable to that of the bioreceptor. The binding with an anthraquinone reaches nanomolar affinity. Shielded hydrogen bonding, C−H⋅⋅⋅π, and charge transfer interactions, and the hydrophobic effect are responsible for the high binding affinity and selectivity.

Water and the Cation-π Interaction.

The cation-π interaction and the hydrophobic effect are important intermolecular forces in chemistry and play major roles in controlling recognition in biological systems. We compared their relative contributions to the binding of molecular "dumbbell" guests in synthetic container hosts in water. The guests offered direct, intramolecular competition between trimethylammonium groups, -N+(CH3)3, and tert-butyl groups, -C(CH3)3, for the internal surfaces (aromatic panels) of the containers. In contrast with previous studies, the container molecules consistently preferred binding to the uncharged tert-butyl groups, regardless of the presence of anionic, cationic, or zwitterionic groups on the container peripheries. This preference is determined by solvation of the polar trimethylammonium group in water, which outcompetes the attraction between the positive charge and the π-surfaces in the container. The synthetic container complexes provide a direct measure of the relative strengths of cation-π interactions and desolvation in water. Interactions with the uncharged tert-butyl group are more than 12 kJ mol-1 more favorable than the cation-π interactions with the trimethylammonium group in these cavitand complexes.