Outbreaks of the Ebola virus (EBOV) continue to occur and while a vaccine and treatment are now available, there remains a dearth of options for those who become sick with EBOV disease. An understanding at the atomic and molecular level of the various steps in the EBOV replication cycle can provide molecular targets for disrupting the virus. An important step in the EBOV replication cycle is the transport of EBOV structural matrix VP40 protein molecules to the plasma membrane inner leaflet, which involves VP40 binding to the host cell's Sec24c protein. Though some VP40 residues involved in the binding are known, the molecular details of VP40–Sec24c binding are not known. We use various molecular computational techniques to investigate the molecular details of how EBOV VP40 binds with the Sec24c complex of the ESCRT-I pathway. We employed different docking programs to identify the VP40-binding site on Sec24c and then performed molecular dynamics simulations to determine the atomic details and binding interactions of the complex. We also investigated how the inter-protein interactions of the complex are affected upon mutations of VP40 amino acids in the Sec24c-binding region. Our results provide a molecular basis for understanding previous coimmunoprecipitation experimental studies. In addition, we found that VP40 can bind to a site on Sec24c that can also bind Sec23 and suggests that VP40 may use the COPII transport mechanism in a manner that may not need the Sec23 protein in order for VP40 to be transported to the plasma membrane.

中文翻译：

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埃博拉病毒蛋白 VP40 与 Sec24c 结合以转运至质膜

埃博拉病毒 (EBOV) 的暴发继续发生，虽然现在可以使用疫苗和治疗方法，但对于那些感染 EBOV 疾病的人来说仍然缺乏选择。了解 EBOV 复制周期中各个步骤的原子和分子水平可以为破坏病毒提供分子靶点。EBOV 复制周期中的一个重要步骤是将 EBOV 结构基质 VP40 蛋白分子转运至质膜内叶，这涉及 VP40 与宿主细胞的 Sec24c 蛋白结合。虽然一些参与结合的 VP40 残基是已知的，但 VP40–Sec24c 结合的分子细节尚不清楚。我们使用各种分子计算技术来研究 EBOV VP40 如何与 ESCRT-I 通路的 Sec24c 复合物结合的分子细节。我们采用不同的对接程序来识别 Sec24c 上的 VP40 结合位点，然后进行分子动力学模拟以确定复合物的原子细节和结合相互作用。我们还研究了复合物的蛋白质间相互作用如何影响 Sec24c 结合区域中 VP40 氨基酸的突变。我们的结果为理解以前的免疫共沉淀实验研究提供了分子基础。此外，我们发现 VP40 可以与 Sec24c 上的一个位点结合，该位点也可以结合 Sec23，这表明 VP40 可能以一种不需要 Sec23 蛋白即可将 VP40 转运到质膜的方式使用 COPII 转运机制.