The experimental data collected over the past 15 years on the interaction of decavanadate(V) (V₁₀O₂₈^6–; V₁₀), 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) (Nb₁₀O₂₈^6–; Nb₁₀) 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 V₁₀, whereas Nb₁₀ 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 V₁₀ than Nb₁₀. Moreover, the binding mode of oxidovanadium(IV) ion, V^IVO²⁺, 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 V₁₀ and its reduction product V^IVO²⁺ with ATP, as previously observed by EPR spectroscopy. Finally, the competition with ATP was rationalized: since decavanadate prefers the nucleotide site α, Ca²⁺-ATP displaces V₁₀ from this site, while the competition is less important for Nb₁₀ 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.

中文翻译：

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合理化十钒酸盐（V）和氧化钒（IV）与G-肌动蛋白的结合以及与十价铌酸盐（V）和ATP的竞争

过去15年中收集的关于十钒酸盐（V）（V ₁₀ O ₂₈ ^6– ; V ₁₀），具有良好抗癌和抗菌作用的多金属氧酸盐（POM）与G-肌动蛋白的相互作用的实验数据通过几种计算方法（对接，密度泛函理论（DFT）和分子动力学（MD））。此外，与同构且更稳定的癸二酸盐（V）（Nb ₁₀ O ₂₈ ^6– ; Nb ₁₀）进行。鉴定出四个结合位点，命名为α，β，γ和δ，位点α是位于亚结构域II和IV的界面处的酶的裂口中的催化核苷酸位点。观察到，V ₁₀优选α_位，而β10 Nb ₁₀更稳定。这表明，与其他蛋白质不同，G-肌动蛋白可以同时结合两个POM，它们的作用是协同的。十vanadate和decaniobate均可在G-肌动蛋白中诱导构象重排，对于V _{10而言，它}比Nb _10大。此外，oxidovanadium（IV）离子的结合模式，V ^IV ö ²⁺，在可触及的半胱氨酸残基的–SH基团将十烷钒酸盐（V）还原后形成的，也发现在具有（His161，Asp154）配位的催化位点α中；该加合物与结合ATP的区域显着重叠，这说明了V ₁₀及其还原产物V ^IV O ²⁺与ATP之间的竞争，如先前通过EPR光谱观察到的。最终，与ATP的竞争得以合理化：由于十钒酸盐偏爱核苷酸位点α，因此Ca ²⁺ -ATP取代了该位点上的V ₁₀，而竞争对Nb _10的重要性则降低了因为该POM对β的亲和力高于对位α的亲和力。本文的一个相关结果是，在没有或存在最终抑制剂和/或与生物分子竞争的情况下，其他金属药物-蛋白质系统也可以用相同的方法进行研究，为解释生物学数据提供了重要的提示和合理的药物设计。