Rationalizing the Decavanadate(V) and Oxidovanadium(IV) Binding to G-Actin and the Competition with Decaniobate(V) and ATP

Abstract

The experimental data collected over the past 15 years on the interaction of decavanadate(V) (V 10 O 28 6– ; V 10 ), a polyoxometalate (POM) with promising anticancer and antibacterial action, with G-actin, were rationalized by using several computational approaches (docking, density functional theory (DFT), and molecular dynamics (MD)). Moreover, a comparison with the isostructural and more stable decaniobate(V) (Nb 10 O 28 6– ; Nb 10 ) was carried out. Four binding sites were identified, named α, β, γ, and δ, the site α being the catalytic nucleotide site located in the cleft of the enzyme at the interface of the subdomains II and IV. It was observed that the site α is preferred by V 10 , whereas Nb 10 is more stable at the site β; this indicates that, differently from other proteins, G-actin could contemporaneously bind the two POMs, whose action would be synergistic. Both decavanadate and decaniobate induce conformational rearrangements in G-actin, larger for V 10 than Nb 10 . Moreover, the binding mode of oxidovanadium(IV) ion, V IV O 2+ , formed upon the reduction of decavanadate(V) by the –SH groups of accessible cysteine residues, is also found in the catalytic site α with (His161, Asp154) coordination; this adduct overlaps significantly with the region where ATP is bound, accounting for the competition between V 10 and its reduction product V IV O 2+ with ATP, as previously observed by EPR spectroscopy. Finally, the competition with ATP was rationalized: since decavanadate prefers the nucleotide site α, Ca 2+ -ATP displaces V 10 from this site, while the competition is less important for Nb 10 because this POM shows a higher affinity for β than for site α. A relevant consequence of this paper is that other metallodrug–protein systems, in the absence or presence of eventual inhibitors and/or competition with molecules of the organism, could be studied with the same approach, suggesting important elements for an explanation of the biological data and a rational drug design.

Computational Modelling of the Interactions Between Polyoxometalates and Biological Systems

“…More recently, computational studies based on MD simulations have also analysed the interaction of polyoxoniobates and polyoxovanadates with different proteins. ( Sciortino et al, 2021 ), ( Chaudhary et al, 2021 ) The nature of the characterised interactions are similar to those of tungstates and transition metal-substituted tungstates with the POM···protein binding dominated by electrostatic and hydrogen bonding forces. Experimentally, the analysis of X-ray polyoxovanadate-protein structures show that the binding sites include a variety of positively charged amino acids such as Arg, His and Lys.…”

“…( Narasimhan et al, 2011 ; Prudent et al, 2010 ; Prudent et al, 2008 ; Hu et al, 2007 ; Tiago et al, 2007 ; Pezza et al, 2002 ; Judd et al, 2001 ; Sarafianos et al, 1996 ). Owing to the intrinsic limitations of docking methods, atomistic molecular dynamics (MD) simulations have been more recently performed to reveal the driving forces that are responsible for the specific interactions ( Figure 1A )[ ( Solé-Daura et al, 2016 ; Paul et al, 2018 ; Solé-Daura et al, 2020a ; Sciortino et al, 2021 ; Chaudhary et al, 2021 )] Pioneer MD simulations analysed the interaction between model protein hen egg-white lysoszyme (HEWL) and three different POMs, the Ce-substituted Keggin-type anion [PW 11 O 39 Ce(OH 2 ) 4 ] 3− the corresponding 1:2 dimer [Ce(PW 11 O 39 ) 2 ] 10− and the Zr-substituted Lindqvist-type anion [W 5 O 18 Zr(OH 2 ) (OH)] 3− , which differ in the overall charge, the size, the shape and the type of substituted metal. ( Solé-Daura et al, 2016 ).…”

Gold Compounds Inhibit the Ca2+-ATPase Activity of Brain PMCA and Human Neuroblastoma SH-SY5Y Cells and Decrease Cell Viability

“…The model used was previously applied to several inorganic compounds, including vanadate. In fact, several studies were described about the interaction of organic and inorganic compounds and their effects on P-type ATPases [23,[36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51]. Therefore, several experiments with several vanadium compounds [45,47,48] at the same experimental conditions for comparison were performed, and the potencies of inhibition are compared in Table 2.…”

“…However, for the majority of the inorganic compounds described to inhibit P-type ATPases, the protein conformations and binding sites are still to be determined [17,18,23,25]. In the near future, protein structural models would help explain such enzymatic results [25,36]. For some drugs, such as thapsigargin (TG) and cyclopiazonic acid (CPA), the mechanisms of action and ATPases binding sites are clearly established [24].…”

Unlocking Phase Diagrams for Molybdenum and Tungsten Nanoclusters and Prediction of their Formation Constants

“…This chemical variety has been accompanied by a broad range of topologies: molybdenum blue wheels 6,7 , keplerates, 8,9 and polyperoxouranates 10,11 . Metal-oxo compounds also present different applications in relevant fields such as biochemistry [12][13][14][15] , catalysis [16][17][18][19][20][21] and nuclear reprocessing 22,23 .…”