The blood protein von Willebrand factor (VWF) is a key link between inflammation and pathological thrombus formation. In particular, oxidation of methionine residues in specific domains of VWF due to the release of oxidants in inflammatory conditions has been linked to an increased platelet‐binding activity. However, the atomistic details of how methionine oxidation activates VWF have not been elucidated to date. Yet understanding the activation mechanism of VWF under oxidizing conditions can lead to the development of novel therapeutics that target VWF selectively under inflammatory conditions in order to reduce its thrombotic activity while maintaining its haemostatic function. In this manuscript, we used a combination of a dynamic flow assay and molecular dynamics (MD) simulations to investigate how methionine oxidation removes an auto‐inhibitory mechanism of VWF. Results from the dynamic flow assay revealed that oxidation does not directly activate the A1 domain, which is the domain in VWF that contains the binding site to the platelet surface receptor glycoprotein Ibα (GpIbα), but rather removes the inhibitory function of the neighboring A2 and A3 domains. Furthermore, the MD simulations combined with free energy perturbation calculations suggested that methionine oxidation may destabilize the binding interface between the A1 and A2 domains leading to unmasking of the GpIbα‐binding site in the A1 domain.

中文翻译：

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氧化关闭了血管性血友病因子的自动抑制机制

血液蛋白血管性血友病因子 (VWF) 是炎症和病理性血栓形成之间的关键环节。特别是，由于炎症状态下氧化剂的释放，VWF 特定结构域中蛋氨酸残基的氧化与血小板结合活性增加有关。然而，迄今为止尚未阐明蛋氨酸氧化如何激活 VWF 的原子细节。然而，了解 VWF 在氧化条件下的激活机制可以导致开发在炎症条件下选择性靶向 VWF 的新疗法，以降低其血栓形成活性，同时保持其止血功能。在这份手稿中，我们结合使用动态流动分析和分子动力学 (MD) 模拟来研究蛋氨酸氧化如何消除 VWF 的自动抑制机制。动态流动分析的结果表明，氧化不会直接激活 A1 结构域，它是 VWF 中包含与血小板表面受体糖蛋白 Ibα (GpIbα) 结合位点的结构域，而是消除了相邻 A2 的抑制功能和A3 域。此外，MD 模拟与自由能扰动计算相结合表明，甲硫氨酸氧化可能会破坏 A1 和 A2 结构域之间的结合界面，从而导致 A1 结构域中 GpIbα 结合位点的暴露。它是 VWF 中的结构域，包含与血小板表面受体糖蛋白 Ibα (GpIbα) 的结合位点，但消除了相邻 A2 和 A3 结构域的抑制功能。此外，MD 模拟与自由能扰动计算相结合表明，甲硫氨酸氧化可能会破坏 A1 和 A2 结构域之间的结合界面，导致 A1 结构域中 GpIbα 结合位点的暴露。它是 VWF 中的结构域，包含与血小板表面受体糖蛋白 Ibα (GpIbα) 的结合位点，但消除了相邻 A2 和 A3 结构域的抑制功能。此外，MD 模拟与自由能扰动计算相结合表明，甲硫氨酸氧化可能会破坏 A1 和 A2 结构域之间的结合界面，导致 A1 结构域中 GpIbα 结合位点的暴露。