The inhibition of glycerol permeation via human aquaporin-10 (hAQP10) by organometallic gold complexes has been studied by stopped-flow fluorescence spectroscopy, and its mechanism has been described using molecular modelling and atomistic simulations. The most effective hAQP10 inhibitors are cyclometalated Au(III) C^N compounds known to efficiently react with cysteine residues leading to the formation of irreversible C-S bonds. Functional assays also demonstrate the irreversibility of the binding to hAQP10 by the organometallic complexes. The obtained computational results by metadynamics show that the local arylation of Cys209 in hAQP10 by one of the gold inhibitors is mapped into a global change of the overall free energy of glycerol translocation across the channel. Our study further pinpoints the need to understand the mechanism of glycerol and small molecule permeation as a combination of local structural motifs and global pore conformational changes, which are taking place on the scale of the translocation process and whose study, therefore, require sophisticated molecular dynamics strategies.

中文翻译：

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通过结合生物物理方法和原子模拟研究的有机金化合物对水通道蛋白 10 的不可逆抑制机制。

已通过停流荧光光谱研究了有机金属金配合物通过人水通道蛋白-10 (hAQP10) 抑制甘油渗透，并使用分子建模和原子模拟描述了其机制。最有效的 hAQP10 抑制剂是环金属化的 Au(III) C^N 化合物，已知可与半胱氨酸残基有效反应，从而形成不可逆的 CS 键。功能测定还证明了有机金属配合物与 hAQP10 结合的不可逆性。通过元动力学获得的计算结果表明，一种金抑制剂对 hAQP10 中 Cys209 的局部芳基化映射为甘油跨通道易位的总自由能的全局变化。