Ebola virus (EBOV) is highly lethal due to virally encoded immune antagonists, and the combination of EBOV VP24 with karyopherin alpha (KPNA) will trigger anti-interferon (IFN) signaling. The crystal structure of VP24-KPNA5 has been proposed in recent studies, but the precise binding mechanisms are still unclear. In order to explore the VP24-KPNA5 protein binding micro-mechanisms, Molecular Dynamic (MD) simulations and Molecular Mechanics Generalized Born Surface Area (MM-GB/SA) energy calculation are performed. The obtained results show that EBOV VP24 binding to KPNA5 will rigidify their binding-face, and both proteins will be compacted during binding. According to the analyses of binding free energies of WT and the eight mutant systems, MUT3 makes the most effective contributions to the interaction; additionally MUT4, R398A and the double mutant have the second most effective influence. Hydrogen bond analysis demonstrates that inhibitors which can interfere with the formation of hydrogen bonds D480-T138, E483-R137 and D205-R396 will prevent the anti-IFN effect. Meanwhile, by combining the decomposition of binding free energies (DC) with computational alanine scanning (CAS) results, it is shown that VP24 residues R137 and T138 will be potential targets for EBOV VP24 inhibitors, and KPNA5 residues R396, R398, R480, Y477 and F484 will be potential targets to prevent KPNA5 binding to VP24, which will ultimately block anti-IFN signaling. Our investigations provide theoretical data to understand the binding modes of VP24-KPNA5. The precise binding mechanisms of the complex may shed light on the development of potential novel inhibitors against EBOV infection.

中文翻译：

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埃博拉病毒抗干扰素信号转导的全原子分子动力学研究：EBOV VP24与核转运蛋白α5结合的相互作用机制。

埃博拉病毒（EBOV）由于病毒编码的免疫拮抗剂而具有极高的致死性，并且EBOV VP24与核蛋白（α）组合将触发抗干扰素（IFN）信号传导。VP24-KPNA5的晶体结构已在最近的研究中提出，但确切的结合机制仍不清楚。为了探索VP24-KPNA5蛋白结合的微观机制，进行了分子动力学（MD）模拟和分子力学广义生表面积（MM-GB / SA）能量计算。获得的结果表明，EBOV VP24与KPNA5的结合将使它们的结合面变硬，并且在结合过程中两种蛋白都将被压紧。根据野生型和八个突变体系统的结合自由能的分析，MUT3是最有效的相互作用。另外是MUT4，R398A和双突变体具有第二个最有效的影响。氢键分析表明，可能干扰氢键D480-T138，E483-R137和D205-R396形成的抑制剂将阻止抗IFN作用。同时，结合结合自由能（DC）的分解和计算丙氨酸扫描（CAS）结果，表明VP24残基R137和T138将成为EBOV VP24抑制剂的潜在靶标，而KPNA5残基R396，R398，R480，Y477 F484和F484将成为潜在的靶标，以防止KPNA5与VP24结合，从而最终阻止抗IFN信号传导。我们的研究提供理论数据，以了解VP24-KPNA5的绑定模式。该复合物的精确结合机制可能会为潜在的针对EBOV感染的新型抑制剂的开发提供启示。