Cavity-Directed Synthesis of Labile Polyoxometalates for Catalysis in Confined Spaces.

The artificial microenvironments inside coordination cages have gained significant attention for performing enzyme-like catalytic reactions by facilitating the formation of labile and complex molecules through a "ship-in-a-bottle" approach. Despite many fascinating examples, this approach remains scarcely explored in the context of synthesizing metallic clusters such as polyoxometalates (POMs). The development of innovative approaches to control and influence the speciation of POMs in aqueous solutions would greatly advance their applicability and could ultimately lead to the formation of elusive clusters that cannot be synthesized by using traditional methods. In this study, we employ host-guest stabilization within a coordination cage to enable a novel cavity-directed synthesis of labile POMs in aqueous solutions under mild conditions. The elusive Lindqvist [M6O19]2- (M=Mo or W) POMs were successfully synthesized at room temperature via the condensation of molybdate or tungstate building blocks within the confined cavity of a robust and water-soluble Pt6L4(NO3)12 coordination cage. Importantly, the encapsulation of these POMs enhances their stability in water, rendering them efficient catalysts for environmentally friendly and selective sulfoxidation reactions using H2O2 as a green oxidant in a pure aqueous medium. The approach developed in this paper offers a means to synthesize and stabilize the otherwise unstable metal-oxo clusters in water, which can broaden the scope of their applications.

Supramolecular Self-Assembly of Proteins Promoted by Hybrid Polyoxometalates.

Controlling the formation of supramolecular protein assemblies and endowing them with new properties that can lead to novel functional materials is an important but challenging task. In this work, a new hybrid polyoxometalate is designed to induce controlled intermolecular bridging between biotin-binding proteins. Such bridging interactions lead to the formation of supramolecular protein assemblies incorporating metal-oxo clusters that go from several nanometers in diameter up to the micron range. Insights into the self-assembly process and the nature of the resulting biohybrid materials are obtained by a combination of Small Angle X-ray Scattering (SAXS), Transmission Electron Microscopy (TEM), and Dynamic Light Scattering (DLS), along with fluorescence, UV-vis, and Circular Dichroism (CD) spectroscopy. The formation of hybrid supramolecular assemblies is determined to be driven by biotin binding to the protein and electrostatic interactions between the anionic metal-oxo cluster and the protein, both of which also influence the stability of the resulting assemblies. As a result, the rate of formation, size, and stability of the supramolecular assemblies can be tuned by controlling the electrostatic interactions between the cluster and the protein (e.g., through varying the ionic strength of the solution), thereby paving the way toward biomaterials with tunable assembly and disassembly properties.

Reactivity of metal-oxo clusters towards biomolecules: from discrete polyoxometalates to metal-organic frameworks.

Metal-oxo clusters hold great potential in several fields such as catalysis, materials science, energy storage, medicine, and biotechnology. These nanoclusters of transition metals with oxygen-based ligands have also shown promising reactivity towards several classes of biomolecules, including proteins, nucleic acids, nucleotides, sugars, and lipids. This reactivity can be leveraged to address some of the most pressing challenges we face today, from fighting various diseases, such as cancer and viral infections, to the development of sustainable and environmentally friendly energy sources. For instance, metal-oxo clusters and related materials have been shown to be effective catalysts for biomass conversion into renewable fuels and platform chemicals. Furthermore, their reactivity towards biomolecules has also attracted interest in the development of inorganic drugs and bioanalytical tools. Additionally, the structural versatility of metal-oxo clusters allows for the efficiency and selectivity of the biomolecular reactions they promote to be readily tuned, thereby providing a pathway towards reaction optimization. The properties of the catalyst can also be improved through incorporation into solid supports or by linking metal-oxo clusters together to form Metal-Organic Frameworks (MOFs), which have been demonstrated to be powerful heterogeneous catalysts. Therefore, this review aims to provide a comprehensive and critical analysis of the state of the art on biomolecular transformations promoted by metal-oxo clusters and their applications, with a particular focus on structure-activity relationships.

Exploring the Reactivity of Polyoxometalates toward Proteins: From Interactions to Mechanistic Insights.

The latest advances in the study of the reactivity of metal-oxo clusters toward proteins showcase how fundamental insights obtained so far open new opportunities in biotechnology and medicine. In this Perspective, these studies are discussed through the lens of the reactivity of a family of soluble anionic metal-oxo nanoclusters known as polyoxometalates (POMs). POMs act as catalysts in a wide range of reactions with several different types of biomolecules and have promising therapeutic applications due to their antiviral, antibacterial, and antitumor activities. However, the lack of a detailed understanding of the mechanisms behind biochemically relevant reactions-particularly with complex biological systems such as proteins-still hinders further developments. Hence, in this Perspective, special attention is given to reactions of POMs with peptides and proteins showcasing a molecular-level understanding of the reaction mechanism. In doing so, we aim to highlight both existing limitations and promising directions of future research on the reactivity of metal-oxo clusters toward proteins and beyond.

Rational synthesis of elusive organic-inorganic hybrid metal-oxo clusters: formation and post-functionalization of hexavanadates.

Paving the way towards new functional materials relies increasingly on the challenging task of forming organic-inorganic hybrid compounds. In that regard, discrete atomically-precise metal-oxo nanoclusters have received increasing attention due to the wide range of organic moieties that can be grafted onto them through functionalization reactions. The Lindqvist hexavanadate family of clusters, such as [V6O13{(OCH2)3C-R}2]2- (V6-R), is particularly interesting due to the magnetic, redox, and catalytic properties of these clusters. However, compared to other metal-oxo cluster types, V6-R clusters have been less extensively explored, which is mainly due to poorly understood synthetic challenges and the limited number of viable post-functionalization strategies. In this work, we present an in-depth investigation of the factors that influence the formation of hybrid hexavanadates (V6-R HPOMs) and leverage this knowledge to develop [V6O13{(OCH2)3CNHCOCH2Cl}2]2- (V6-Cl) as a new and tunable platform for the facile formation of discrete hybrid structures based on metal-oxo clusters in relatively high yields. Moreover, we showcase the versatility of the V6-Cl platform through its post-functionalization via nucleophilic substitution with various carboxylic acids of differing complexity and with functionalities that are relevant in multiple disciplines, such as supramolecular chemistry and biochemistry. Hence, V6-Cl was shown to be a straightforward and versatile starting point for the formation of functional supramolecular structures or other hybrid materials, thereby enabling their exploration in various fields.

Fine-tuning non-covalent interactions between hybrid metal-oxo clusters and proteins.

Interactions between the protein Hen Egg White Lysozyme (HEWL) and three different hybrid Anderson-Evans polyoxometalate clusters - AE-NH2 (δ-[MnMo6O18{(OCH2)3CNH2}2]3-), AE-CH3 (δ-[MnMo6O18{(OCH2)3CCH3}2]3-) and AE-Biot (δ-[MnMo6O18{(OCH2)3CNHCOC9H15N2OS}2]3-) - were studied via tryptophan fluorescence spectroscopy and single crystal X-ray diffraction. Quenching of tryptophan fluorescence was observed in the presence of all three hybrid polyoxometalate clusters (HPOMs), but the extent of quenching and the binding affinity were greatly dependent on the nature of the organic groups attached to the cluster. Control experiments further revealed the synergistic effect of the anionic polyoxometalate core and organic ligands towards enhanced protein interactions. Furthermore, the protein was co-crystallised with each of the three HPOMs, resulting in four different crystal structures, thus allowing for the binding modes of HPOM-protein interactions to be investigated with near-atomic precision. All crystal structures displayed a unique mode of binding of the HPOMs to the protein, with both functionalisation and the pH of the crystallisation conditions influencing the interactions. From the crystal structures, it was determined that HPOM-protein non-covalent complexes formed through a combination of electrostatic attraction between the polyoxometalate cluster and positively charged surface regions of HEWL, and direct and water-mediated hydrogen bonds with both the metal-oxo inorganic core and the functional groups of the ligand, where possible. Hence, functionalisation of metal-oxo clusters shows great potential in tuning their interactions with proteins, which is of interest for several biomedical applications.

Exploiting Interactions between Polyoxometalates and Proteins for Applications in (Bio)chemistry and Medicine.

The specific interactions of anionic metal-oxo clusters, known as polyoxometalates (POMs), with proteins can be leveraged for a wide range of analytical and biomedical applications. For example, POMs have been developed as selective catalysts that can induce protein modifications and have also been shown to facilitate protein crystallization, both of which are instrumental in the structural characterization of proteins. POMs can also be used for selective protein separation and enzyme inhibition, which makes them promising therapeutic agents. Hence, understanding POM-protein interactions is essential for the development of POM-based materials and their implementation in several fields. In this Review we summarize in detail the key insights that have been gained so far on POM-protein interactions. Emphasis is also given to hybrid POMs functionalized with organic ligands to prompt further research in this direction owing to the promising recent results on tuning POM-protein interactions through POM functionalization.

Versatile post-functionalisation strategy for the formation of modular organic-inorganic polyoxometalate hybrids.

Hybrid structures incorporating different organic and inorganic constituents are emerging as a very promising class of materials since they synergistically combine the complementary and diverse properties of the individual components. Hybrid materials based on polyoxometalate clusters (POMs) are particularly interesting due to their versatile catalytic, redox, electronic, and magnetic properties, yet the controlled incorporation of different clusters into a hybrid structure is challenging and has been scarcely reported. Herein we propose a novel and general strategy for combining multiple types of metal-oxo clusters in a single hybrid molecule. Two novel hybrid POM structures (HPOMs) bis-functionalised with dipentaerythritol (R-POM1-R; R = (OCH2)3CCH2OCH2C(CH2OH)) were synthesised as building-blocks for the formation of heterometallic hybrid triads (POM2-R-POM1-R-POM2). Such a modular approach resulted in the formation of four novel heterometallic hybrids combing the Lindqvist {V6}, Anderson-Evans {XMo6} (X = Cr or Al) and trisubstituted Wells-Dawson {P2V3W15} POM structures. Their formation was confirmed by multinuclear Nuclear Magnetic Resonance (NMR), infrared (IR) and UV-Vis spectroscopy, as well as Mass Spectrometry, Diffusion Ordered Spectroscopy (DOSY) and elemental analysis. The thermal stability of the hybrids was also examined by Thermogravimetric Analysis (TGA), which showed that the HPOM triads exhibit higher thermal stability than comparable hybrid structures containing only one type of POM. The one-pot synthesis of these novel compounds was achieved in high yields in aqueous and organic media under simple reflux conditions, without the need of any additives, and could be translated to create other hybrid materials based on a variety of metal-oxo cluster building-blocks.

Expanding the Scope of Polyoxometalates as Artificial Proteases towards Hydrolysis of Insoluble Proteins.

Despite the enormous importance of insoluble proteins in biological processes, their structural investigation remains a challenging task. The development of artificial enzyme-like catalysts would greatly facilitate the elucidation of their structure since currently used enzymes in proteomics largely lose activity in the presence of surfactants, which are necessary to solubilize insoluble proteins. In this study, the hydrolysis of a fully insoluble protein by polyoxometalate complexes as artificial proteases in surfactant solutions is reported for the first time. The hydrolysis of zein as a model protein was investigated in the presence of Zr(IV) and Hf(IV) substituted Keggin-type polyoxometalates (POMs), (Et2 NH2 )10 [M(α-PW11 O39 )2 ] (M = Zr or Hf), and different concentrations of the anionic surfactant sodium dodecyl sulfate (SDS). Selective hydrolysis of the protein upon incubation with the catalyst was observed, and the results indicate that the hydrolytic selectivity and activity of the POM catalysts strongly depends on the concentration of surfactant. The molecular interactions between the POM catalyst and zein in the presence of SDS were explored using a combination of spectroscopic techniques which indicated competitive binding between POM and SDS towards the protein. Furthermore, the formation of micellar superstructures in ternary POM/surfactant/protein solutions has been confirmed by conductivity and Dynamic Light Scattering measurements.

Solution Dynamics of Hybrid Anderson-Evans Polyoxometalates.

Understanding the stability and speciation of metal-oxo clusters in solution is essential for many of their applications in different areas. In particular, hybrid organic-inorganic polyoxometalates (HPOMs) have been attracting increasing attention as they combine the complementary properties of organic ligands and metal-oxygen nanoclusters. Nevertheless, the speciation and solution behavior of HPOMs have been scarcely investigated. Hence, in this work, a series of HPOMs based on the archetypical Anderson-Evans structure, δ-[MnMo6O18{(OCH2)3C-R}2]3-, with different functional groups (R = -NH2, -CH3, -NHCOCH2Cl, -N═CH(2-C5H4N) {pyridine; -Pyr}, and -NHCOC9H15N2OS {biotin; -Biot}) and countercations (tetrabutylammonium {TBA}, Li, Na, and K) were synthesized, and their solution behavior was studied in detail. In aqueous solutions, decomposition of HPOMs into the free organic ligand, [MoO4]2-, and free Mn3+ was observed over time and was shown to be highly dependent on the pH, temperature, and nature of the ligand functional group but largely independent of ionic strength or the nature of the countercation. Furthermore, hydrolysis of the amide and imine bonds often present in postfunctionalized HPOMs was also observed. Hence, HPOMs were shown to exhibit highly dynamic behavior in solution, which needs to be carefully considered when designing HPOMs, particularly for biological applications.

Preservation of Nuclear Spin Order by Precipitation.

We demonstrate that non-equilibrium nuclear spin order survives precipitation from solution and redissolution. The effect is demonstrated on 13 C- and 2 H-labeled sodium fumarate, with precipitation and dissolution achieved by altering the pH. The lifetime of the spin magnetization in the precipitate suspension is found to be much longer than in solution. Our preliminary results show an extension of the effective relaxation time T1 for the metabolite fumarate by a factor of ≈6. We show that when the free radical agent TEMPO is present in the solution, it is not incorporated into the precipitate, suggesting that this procedure may provide a means to store and transport agents polarized by dynamic nuclear polarization. Although the relaxation time, T1 , of the precipitate suspension is longer than that of the same molecules in solution, it is significantly shorter than that observed in the immobilized solid state.