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

Abstract

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.

Speciation atlas of polyoxometalates in aqueous solutions

“…Furthermore, it should be noted that the presence of biomolecules in solution can impact the stability and behavior of POMs (50,51). In particular, POM-protein and POM-peptide interactions are complex and important areas of research that must be considered in many biological applications (52)(53)(54). These interactions can influence the efficacy and specificity of POMs in various biological contexts, making their study of great importance in the field.…”

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

“…M-POMs with highly Lewis acidic metal centers, such as Ce 4 + , Zr 4 + and Hf 4 + , have been shown to effectively and selectively hydrolyze peptide bonds in a diverse range of proteins and, interestingly, the nature of embedded metal center has been observed to have an influence on the selectivity of the hydrolysis. [4,20,[57][58][59] The proposed mechanism involves activation of the carbonyl group in the peptide bond through coordination of the embedded Lewis acid metal center to the carbonyl oxygen. [20,60] This proposed mechanism is supported by the observed coordination of a Zr 4 + -substituted Keggin POM to the carbonyl group of an asparagine residue (Asn65) in a cocrystal of the POM with HEWL (Figure 3d).…”

“…Although crystallographic and computational studies have shown that the embedded metal center in M‐POMs most likely does not play a major role in POM‐protein interactions, further studies have revealed the importance of the nature of the incorporated metal centers on POM reactivity towards proteins. M‐POMs with highly Lewis acidic metal centers, such as Ce 4+ , Zr 4+ and Hf 4+ , have been shown to effectively and selectively hydrolyze peptide bonds in a diverse range of proteins and, interestingly, the nature of embedded metal center has been observed to have an influence on the selectivity of the hydrolysis [4, 20, 57–59] . The proposed mechanism involves activation of the carbonyl group in the peptide bond through coordination of the embedded Lewis acid metal center to the carbonyl oxygen [20, 60] .…”

“…However, breaking down proteins typically requires the use of a catalyst to promote the hydrolysis of the otherwise highly stable peptide bond, which links amino acids within the protein structure and has an estimated half‐life of around 200–600 years under physiological conditions [100] . Hence, in recent years, our group has investigated the reactivity of POMs towards proteins and demonstrated that the specificity of POM‐protein interactions can be exploited for the selective hydrolysis of a wide range of proteins, that differ in terms of their size, secondary structure, and isoelectric point (pI) [4, 7] . The negative charge of the POM provides a directing effect by favoring positively charged regions of the protein surface [57] .…”

“…By utilizing MoSto to compactly store Mo in the form of polyoxomolybdates, these bacteria have a competitive advantage during Mo‐deprivation periods in their growth phase [3] . Moreover, metallic clusters, particularly polyoxometalates (POMs), have gained significant attention in biochemistry owing to their unique physical, chemical and structural properties that enable interactions with biological molecules, especially proteins [4] . Recently, there has been a growing interest in exploring these interactions as they have the potential to lead to further developments of POMs as inorganic drugs, [5, 6] artificial enzymes, [7, 8] and innovative biomaterials [9, 10] …”