Upon entering the body, nerve agents can bind active amino acid residues to form phosphonylated adducts. Tabun derivatives (O-alkyl-N,N-dialkyl phosphoroamidocyanidates) have strikingly different structural features from other G-series nerve agents, such as sarin and soman. Here, we investigate the binding mechanism for the phosphonylated adducts of nerve agents of tabun derivatives. Binding sites for three tabun derivatives, O-ethyl-N,N- dimethyl phosphoramidocyanidate (GA), O-ethyl-N,N-ethyl(methyl) phosphoramidocyanidate, and O-ethyl-N,N-diethylphosphoramidocyanidate were studied. Quadrupole-orbitrap mass spectrometry (Q-Orbitrap-MS) coupled to proteomics was used to screen adducts between tabun derivatives and albumin, immunoglobulin, and hemoglobin. The results reveal that all three tabun derivatives exhibit robust selectivity to lysine residues, rather than other amino acid residue types. A set of 10 lysine residues on human serum albumin are labeled by tabun derivatives in vitro, with K525 (K*QTALVELVK) and K199 (LK*CASLQK) peptides displaying the most reactivity. Tabun derivatives formed stable adducts on K525 and K414 (K*VPQVSTPTLVEVSR) for at least 7 days and on K351 (LAK*TYETTLEK) for at least 5 days in a rabbit model. Three of these peptides-K525, K414, and K351-have the highest homology with human serum albumin of all 5 lysine residues that bound to examined rabbit blood proteins in vivo. Molecular simulation of the tabun-albumin interaction using structural analysis and molecular docking provided theoretical evidence supporting lysine residue reactivity to phosphonylation by tabun derivatives. K525 has the lowest free binding energy and the strongest hydrogen bonding to human albumin. In summary, these findings identify unique binding properties for tabun derivatives to blood proteins.

中文翻译：

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Tabun 亚型神经毒剂在体外和体内暴露后的蛋白质加合物结合特性

进入体内后，神经毒剂可以结合活性氨基酸残基形成膦酰化加合物。Tabun 衍生物（O-烷基-N,N-二烷基磷酰氨基氰化物）与其他 G 系列神经毒剂（如沙林和梭曼）具有显着不同的结构特征。在这里，我们研究了塔崩衍生物神经毒剂的膦酰化加合物的结合机制。研究了三种塔崩衍生物的结合位点，即 O-乙基-N,N-二甲基氨基氰化磷 (GA)、O-乙基-N,N-乙基（甲基）氨基氰化磷和 O-乙基-N,N-二乙基氨基氰化磷。四极杆轨道阱质谱 (Q-Orbitrap-MS) 与蛋白质组学结合用于筛选 Tabun 衍生物与白蛋白、免疫球蛋白和血红蛋白之间的加合物。结果表明，所有三种 Tabun 衍生物都对赖氨酸残基而非其他氨基酸残基类型表现出强大的选择性。人血清白蛋白上的一组 10 个赖氨酸残基在体外被 Tabun 衍生物标记，其中 K525 (K*QTALVELVK) 和 K199 (LK*CASLQK) 肽显示出最大的反应性。在兔子模型中，Tabun 衍生物在 K525 和 K414 (K*VPQVSTPTLVEVSR) 上形成稳定加合物至少 7 天，在 K351 (LAK*TYETTLEK) 上形成至少 5 天。这些肽中的三种-K525、K414 和 K351-在与体内检测的兔血蛋白结合的所有 5 个赖氨酸残基中与人血清白蛋白具有最高的同源性。使用结构分析和分子对接对 Tabun-白蛋白相互作用的分子模拟提供了支持赖氨酸残基对 Tabun 衍生物磷酸化反应的理论证据。K525 对人白蛋白具有最低的自由结合能和最强的氢键。总之，这些发现确定了塔崩衍生物与血液蛋白质的独特结合特性。