Self-assembled Cage Research Articles

Encapsulation of Azaphosphatranes and Proazaphosphatranes in Confined Spaces.

Proazaphosphatranes (also named Verkade's superbases) and their azaphosphatrane conjugated acids have been recently been shown to be confined in either covalent or self-assembled molecular cages, or immobilized in nanopores of hybrid materials. The encapsulation of these phosphorus moieties turns out to strongly affect both their acid-base, catalytic, and recognition properties. The thermodynamics and kinetics of the proton transfer as well as the selectivity and catalytic activities of Verkade's superbases were strongly changed upon their confinement in a hemicryptophane cavity. Moreover, self-assembled cages, including azaphosphatrane moieties, were found to display remarkable anion recognition properties in water. In this Minireview, these new aspects of the chemistry of aza- and proaza-phosphatranes are presented, in order to highlight the great potential of such an approach.

Enhanced reactivity of twisted amides inside a molecular cage.

When an amide group is distorted from its planar conformation, the conjugation between the nitrogen lone pair and the π* orbital of the carbonyl is disrupted and the reactivity towards nucleophiles is enhanced. Although there are several reports on the synthesis of activated twisted amides, amide activation through mechanical twisting is much less common. Here, we report twisted amides that are stabilized through their inclusion in a self-assembled coordination cage. When secondary aromatic amides are included in a Td-symmetric cage, the cis-twisted conformation is favoured over the trans-planar one-as evidenced by single-crystal X-ray diffraction analysis-revealing that the amide can twist by up to 34°. As a consequence of this distortion, the hydrolysis of amides is significantly accelerated upon inclusion.

Multicomponent Self-Assembly of PdII /PtII Interlocked Molecular Cages: Cage-to-Cage Conversion and Self-Sorting in Aqueous Medium.

Coordination-driven self-assembly is an efficient approach for constructing complicated molecules with the aid of reversible bond formation. However, constructing topologically complicated interlocked systems and their formation studies remain challenging tasks. The formation of two water-soluble hexanuclear interlocked cages by multicomponent self-assembly of a flexible triimidazole donor (L1) and a rigid tripyridyl donor (L2) based on a triazine core in combination with 90° cis-blocked PdII and PtII acceptors is reported here. Formation of interlocked systems having a composition of M6 (L1)2 (L2)2 (M=Pd or Pt) becomes feasible through cavity-induced self-recognition of two similar units having a composition of M3 (L1)(L2). Self-sorting of two independently prepared cages of [M3 (L1)2 ] and [M6 (L2)4 ] in aqueous medium leads to the formation of interlocked systems, and their formation was monitored by time-dependent 1 H NMR spectroscopy. Self-recognition of L1 by [M6 (L2)4 ] or L2 by [M3 (L1)2 ] leads to the formation of interlocked systems, as confirmed from 1 H NMR spectroscopic titrations of L1 with cages {M6 (L2)4 } and L2 with {M3 (L1)2 }, respectively. Both the interlocked cages of Pd and Pt are highly stable, and formation of either system is equally probable as observed from the treatments of Pd3 (L1)2 with Pt6 (L2)4 or Pt3 (L1)2 with Pd6 (L2)4 , which lead to the formation of two different self-assembled homometallic interlocked cages [Pt6 (L1)2 (L2)2 +Pd6 (L1)2 (L2)2 ] instead of forming any other heterometallic assemblies. Formation of interlocked cages is dependent on the steric bulk of the diamine ligand bound to the metal acceptors. A N-alkyl-substituted blocking amine prefers the non-interlocked cage instead of the interlocked analogue.

Self-assembled conjoined-cages

A self-assembled coordination cage usually possesses one well-defined three-dimensional (3D) cavity whereas infinite number of 3D-cavities are crafted in a designer metal-organic framework. Construction of a discrete coordination cage possessing multiple number of 3D-cavities is a challenging task. Here we report the peripheral decoration of a trinuclear [Pd3L6] core with one, two and three units of a [Pd2L4] entity for the preparation of multi-3D-cavity conjoined-cages of [Pd4(La)2(Lb)4], [Pd5(Lb)4(Lc)2] and [Pd6(Lc)6] formulations, respectively. Formation of the tetranuclear and pentanuclear complexes is attributed to the favorable integrative self-sorting of the participating components. Cage-fusion reactions and ligand-displacement-induced cage-to-cage transformation reactions are carried out using appropriately chosen ligand components and cages prepared in this work. The smaller [Pd2L4] cavity selectively binds one unit of NO3−, F−, Cl− or Br− while the larger [Pd3L6] cavity accommodates up to four DMSO molecules. Designing aspects of our conjoined-cages possess enough potential to inspire construction of exotic molecular architectures.

Design and Characterization of an Icosahedral Protein Cage Formed by a Double-Fusion Protein Containing Three Distinct Symmetry Elements.

Exploiting simple types of symmetry common to many natural protein oligomers as a starting point, several recent studies have succeeded in engineering complex self-assembling protein architectures reminiscent but distinct from those evolved in the natural world. Designing symmetric protein cages with a wide range of properties has been of particular interest for potential applications in the fields of medicine, energy, imaging, and more. In this study we genetically fused three naturally symmetric protein components together-a pentamer, trimer, and dimer-in a fashion designed to create a self-assembling icosahedral protein cage built from 60 copies of the protein subunit. The connection between the pentamer and dimer was based on a continuous shared α helix in order to control the relative orientation of those components. Following selection of suitable components by computational methods, a construct with favorable design properties was tested experimentally. Negative stain electron microscopy and solution-state methods indicated successful formation of a 60-subunit icosahedral cage, 2.5 MDa in mass and 30 nm in diameter. Diverse experimental studies also suggested substantial degrees of flexibility and asymmetric deformation of the assembled particle in solution. The results add further examples of successes and challenges in designing atomically precise protein materials.

Selective, cofactor-mediated catalytic oxidation of alkanethiols in a self-assembled cage host.

A spacious Fe(ii)-iminopyridine self-assembled cage complex can catalyze the oxidative dimerization of alkanethiols, with air as stoichiometric oxidant. The reaction is aided by selective molecular recognition of the reactants, and the active catalyst is derived from the Fe(ii) centers that provide the structural vertices of the host. The host is even capable of size-selective oxidation and can discriminate between alkanethiols of identical reactivity, based solely on size.

Design and structure of two new protein cages illustrate successes and ongoing challenges in protein engineering.

In recent years, new protein engineering methods have produced more than a dozen symmetric, self-assembling protein cages whose structures have been validated to match their design models with near-atomic accuracy. However, many protein cage designs that are tested in the lab do not form the desired assembly, and improving the success rate of design has been a point of recent emphasis. Here we present two protein structures solved by X-ray crystallography of designed protein oligomers that form two-component cages with tetrahedral symmetry. To improve on the past tendency toward poorly soluble protein, we used a computational protocol that favors the formation of hydrogen-bonding networks over exclusively hydrophobic interactions to stabilize the designed protein-protein interfaces. Preliminary characterization showed highly soluble expression, and solution studies indicated successful cage formation by both designed proteins. For one of the designs, a crystal structure confirmed at high resolution that the intended tetrahedral cage was formed, though several flipped amino acid side chain rotamers resulted in an interface that deviates from the precise hydrogen-bonding pattern that was intended. A structure of the other designed cage showed that, under the conditions where crystals were obtained, a noncage structure was formed wherein a porous 3D protein network in space group I21 3 is generated by an off-target twofold homomeric interface. These results illustrate some of the ongoing challenges of developing computational methods for polar interface design, and add two potentially valuable new entries to the growing list of engineered protein materials for downstream applications.

Rationalizing the Activity of an "Artificial Diels-Alderase": Establishing Efficient and Accurate Protocols for Calculating Supramolecular Catalysis.

Self-assembled cages have emerged as novel platforms to explore bioinspired catalysis. While many different size and shape supramolecular structures are now readily accessible, only a few are known to accelerate chemical reactions under substoichiometric conditions. These limited examples point to a poor understanding of cage catalysis in general, limiting the ability to design new systems. Here we show that a simple and efficient density-functional-theory-based methodology, informed by explicitly solvated molecular dynamics and coupled cluster calculations, is sufficient to accurately reproduce experimental guest binding affinities (MAD = 1.9 kcal mol-1) and identify the catalytic Diels-Alder proficiencies (>80% accuracy) of two homologous Pd2L4 metallocages with a variety of substrates. This analysis reveals how subtle structural differences in the cage framework affect binding and catalysis. These effects manifest in a smaller distortion and more favorable interaction energy for the catalytic cage compared to the inactive structure. This study gives detailed insight that would otherwise be difficult to obtain from experiments, providing new opportunities in the design of catalytically active supramolecular cages.

Expression, purification, and characterisation of recombinant ferritin in insect cells using the baculovirus expression system.

Ferritin is an attractive vector for the delivery of drug molecules and antigen proteins because of its unique structural and biochemical features. In this study, recombinant ferritin from Helicobacter pylori was expressed in the soluble form employing the baculovirus expression system. The optimum conditions for producing recombinant ferritin comprised MOI 5 of rBV-ferritin for 96h of infection. The recombinant ferritin was purified by Ni Sepharose™ 6 Fast Flow, with a purity and yield of 92.5% and 11.25mg/L, respectively. In addition, the recombinant ferritin showed a multimeric structure under non-denaturing conditions, as well as self-assembled spherical cage architecture with a diameter of approximately 12nm. Dot-ELISA results suggested that the His-tag at the N-terminus likely existed on the surface of the recombinant ferritin. Recombinant ferritin was produced by the baculovirus expression system, which has the potential to display exogenous proteins, and may aid in the delivery of drugs for disease prevention and treatment.

Bifurcation of self-assembly pathways to sheet or cage controlled by kinetic template effect

The template effect is a key feature to control the arrangement of building blocks in assemblies, but its kinetic nature remains elusive compared to the thermodynamic aspects, with the exception of very simple reactions. Here we report a kinetic template effect in a self-assembled cage composed of flexible ditopic ligands and Pd(II) ions. Without template anion, a micrometer-sized sheet is kinetically trapped (off-pathway), which is converted into the thermodynamically most stable cage by the template anion. When the template anion is present from the start, the cage is selectively produced by the preferential cyclization of a dinuclear intermediate (on-pathway). Quantitative and numerical analyses of the self-assembly of the cage on the on-pathway revealed that the accelerating effect of the template is stronger for the early stage reactions of the self-assembly than for the final cage formation step itself, indicating the kinetic template effect.

An antiaromatic-walled nanospace.

Over the past few decades, several molecular cages, hosts and nanoporous materials enclosing nanometre-sized cavities have been reported1-5, including coordination-driven nanocages6. Such nanocages have found widespread use in molecular recognition, separation, stabilization and the promotion of unusual chemical reactions, among other applications3-10. Most of the reported nanospaces within molecular hosts are confined by aromatic walls, the properties of which help to determine the host-guest behaviour. However, cages with nanospaces surrounded by antiaromatic walls have not yet been developed, owing to the instability of antiaromatic compounds; as such, the effect of antiaromatic walls on the properties of nanospaces remains unknown. Here we demonstrate the construction of an antiaromatic-walled nanospace within a self-assembled cage composed of four metal ions with six identical antiaromatic walls. Calculations indicate that the magnetic effects of the antiaromatic moieties surrounding this nanospace reinforce each other. This prediction is confirmed by 1H nuclear magnetic resonance (NMR) signals of bound guest molecules, which are observed at chemical shift values of up to 24 parts per million(ppm), owing to the combined antiaromatic deshielding effect of the surrounding rings. This value, shifted 15 ppm from that of the free guest, is the largest 1H NMR chemical shift displacement resulting from an antiaromatic environment observed so far. This cage may thus be considered as a type of NMR shift reagent, moving guest signals well beyond the usual NMR frequency range and opening the way to further probing the effects of an antiaromatic environment on a nanospace.

Reversible switching of arylazopyrazole within a metal-organic cage.

Arylazopyrazoles represent a new family of molecular photoswitches characterized by a near-quantitative conversion between two states and long thermal half-lives of the metastable state. Here, we investigated the behavior of a model arylazopyrazole in the presence of a self-assembled cage based on Pd–imidazole coordination. Owing to its high water solubility, the cage can solubilize the E isomer of arylazopyrazole, which, by itself, is not soluble in water. NMR spectroscopy and X-ray crystallography have independently demonstrated that each cage can encapsulate two molecules of E-arylazopyrazole. UV-induced switching to the Z isomer was accompanied by the release of one of the two guests from the cage and the formation of a 1:1 cage/Z-arylazopyrazole inclusion complex. DFT calculations suggest that this process involves a dramatic change in the conformation of the cage. Back-isomerization was induced with green light and resulted in the initial 1:2 cage/E-arylazopyrazole complex. This back-isomerization reaction also proceeded in the dark, with a rate significantly higher than in the absence of the cage.

Cofactor-Mediated Nucleophilic Substitution Catalyzed by a Self-Assembled Holoenzyme Mimic.

A self-assembled Fe4L6 cage is capable of co-encapsulating multiple carboxylic acid containing guests in its cavity, and these acids can act as cofactors for cage-catalyzed nucleophilic substitutions. The kinetics of the substitution reaction depend on the size, shape, and binding affinity of each of the components, and small structural changes in guest size can have large effects on the reaction. The host is quite promiscuous and is capable of binding multiple guests with micromolar binding affinities while retaining the ability to effect turnover and catalysis. Substrate binding modes vary widely, from simple 1:1 complexes to 1:2 complexes that can show either negative or positive cooperativity, depending on the guest. The molecularity of the dissociative substitution reaction varies, depending on the electrophile leaving group, acid cofactor, and nucleophile size: small changes in the nature of substrate can have large effects on reaction kinetics, all controlled by selective molecular recognition in the cage interior.

Tuning the Solubility of Self-Assembled Fluorescent Aromatic Cages Using Functionalized Amino Acid Building Blocks.

We previously reported novel fluorescent aromatic cages that are self-produced using a set of orthogonal dynamic covalent reactions, operating simultaneously in one-pot, to assemble up to 10 components through 12 reactions into a single cage-type structure. We now introduce N-functionalized amino acids as new building blocks that enable tuning the solubility and analysis of the resulting cages. A convenient divergent synthetic approach was developed to tether different side chains on the N-terminal of a cysteine-derived building block. Our studies show that this chemical functionalization does not prevent the subsequent self-assembly and effective formation of desired cages. While the originally described cages required 94% DMSO, the new ones bearing hydrophobic side chains were found soluble in organic solvents (up to 75% CHCl3), and those grafted with hydrophilic side chains were soluble in water (up to 75% H2O). Fluorescence studies confirmed that despite cage functionalization the aggregation-induced emission properties of those architectures are retained. Thus, this work significantly expands the range of solvents in which these self-assembled cage compounds can be generated, which in turn should enable new applications, possibly as fluorescent sensors.

Palladium(II)-Based Self-Assembled Heteroleptic Coordination Architectures: A Growing Family.

Metal-driven self-assembly is one of the most effective approaches to lucidly design a large range of discrete 2D and 3D coordination architectures/complexes. Palladium(II)-based self-assembled coordination architectures are usually prepared by using suitable metal components, in either a partially protected form (PdL') or typical form (Pd; charges are not shown), and designed ligand components. The self-assembled molecules prepared by using a metal component and only one type of bi- or polydentate ligand (L) can be classified in the homoleptic series of complexes. On the other hand, the less explored heteroleptic series of complexes are obtained by using a metal component and at least two different types of non-chelating bi- or polydentate ligands (such as La and Lb ). Methods that allow the controlled generation of single, discrete heteroleptic complexes are less understood. A survey of palladium(II)-based self-assembled coordination cages that are heteroleptic has been made. This review article illustrates a systematic collection of such architectures and credible justification of their formation, along with reported functional aspects of the complexes. The collected heteroleptic assemblies are classified here into three sections: 1) [(PdL')m (La )x (Lb )y ]-type complexes, in which the denticity of La and Lb is equal; 2) [(PdL')m (La )x (Lb )y ]-type complexes, in which the denticity of La and Lb is different; and 3) [Pdm (La )x (Lb )y ]-type complexes, in which the denticity of La and Lb is equal. Representative examples of some important homoleptic architectures are also provided, wherever possible, to set a background for a better understanding of the related heteroleptic versions. The purpose of this review is to pave the way for the construction of several unique heteroleptic coordination assemblies that might exhibit emergent supramolecular functions.

A Self-Assembled Cage with Endohedral Acid Groups both Catalyzes Substitution Reactions and Controls Their Molecularity.

A self-assembled Fe4 L6 cage complex internally decorated with acid functions is capable of accelerating the thioetherification of activated alcohols, ethers and amines by up to 1000-fold. No product inhibition is seen, and effective supramolecular catalysis can occur with as little as 5 % cage. The substrates are bound in the host with up to micromolar affinities, whereas the products show binding that is an order of magnitude weaker. Most importantly, the cage host alters the molecularity of the reaction: whereas the reaction catalyzed by simple acids is a unimolecular, SN 1-type substitution process, the rate of the host-mediated process is dependent on the concentration of nucleophile. The molecularity of the cage-catalyzed reaction is substrate-dependent, and can be up to bimolecular. In addition, the catalysis can be prevented by a large excess of nucleophile, where substrate inhibition dominates, and the use of tritylated anilines as substrates causes a negative feedback loop, whereby the liberated product destroys the catalyst and stops the reaction.

Fine-Tuned Visible and Near-Infrared Luminescence on Self-Assembled Lanthanide-Organic Tetrahedral Cages with Triazole-Based Chelates.

The construction of well-defined lanthanide complexes emitting in both the visible and near-infrared regions is of great importance due to their widespread applications in phosphors, light-emitting diodes, biosensors/probes, optical communications, etc. In comparison to the well-known mononuclear and dinuclear lanthanide complexes, multinuclear lanthanide supramolecular edifices with bright luminescence are still scarce. Herein, we report the coordination self-assembly of strongly luminescent lanthanide-organic tetrahedral Ln4L4 cages with a series of tris(tridentate) ligands based on the triazole chelates. Among them, the new ligand L3 with triazole-pyridine-triazole (TPT) chelates manifests an excellent sensitization toward all of the lanthanide ions (Ln = Pr, Nd, Sm, Eu, Tb, Dy, Ho, Er, Tm, Yb) that emit in both the visible and near-infrared regions, with a record luminescent quantum yield for Tb4(L3)4 (Φ = 82%) being obtained. In contrast, ligands with amido-pyridine-triazole (APT) or TPA chelates show much weaker sensitization ability. Energy levels for all ligands were measured, and TD-DFT calculations were employed to shed light on the sensitization mechanism. Finally, white-light emission systems formed by combining the desired luminescent compounds have been demonstrated. Our strongly luminescent LOPs provide new candidates for photochemical supramolecular devices.

Correction to Modifying Self-Assembled Peptide Cages To Control Internalization into Mammalian Cells.

Correction to Modifying Self-Assembled Peptide Cages To Control Internalization into Mammalian Cells.

Recent progresses in the accumulation of metal ions into the apo-ferritin cage: Experimental and theoretical perspectives

Ferritin is a self-assembled 24-mer protein cage which is naturally designed for iron storage. Other than iron, the apo-ferritin cage template can accommodate various non-natural metal substrates such as metal ions, metal complexes, and organic molecules. Because of this property, the apo-ferritin template is utilized for preparing inorganic nanomaterials which include quantum dot, metal nanoparticle, metal oxide etc. Although current studies are largely focusing on preparation, the basis of nanomaterial formations such as metal ion deposition, translocation, core formation etc. are not clarified. Therefore, studying the process of metal ions immobilization in ferritin cage with detailed coordination structures is an important topic in the area of material chemistry to develop bioinspired nanomaterials with a fundamental understanding of specific metal–protein interaction. Until now, there are only a limited number of reports except iron, which describes the metal ions accumulation with details characterization by X-ray crystallography. In addition, theoretical calculations are providing important information, particularly the dynamics of the accumulation process of metal ions as well as conformational changes in the amino acid side chains. Under this background, the current review highlights the recent and significant progress on the metal ion accumulation process in order to design and construct novel ferritin-based bionanomaterials.

Self-assembled Pd3L2 cages having flexible tri-imidazole donors

Four new M3L2 molecular cages (CA1–CA4) have been synthesized in excellent yield via coordination driven self –assembly of flexible tri-imidazole donors based on triazine (L1) and tri-phenyl benzene (L2) core with 90° cis-blocked metal acceptors of Pd(II). Two of them CA1 and CA2 are highly soluble in water. All the cages were characterized by spectroscopic studies and ESI-MS; CA3 and CA4 also by X-ray diffraction. Selective formation of two separate cages CA3 and CA4 was noticed instead of a hetero-ligand cage, when the metal acceptor (dppf)Pd(OTf)2 was treated with a mixture of ligands L1 and L2.