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Investigating the stability of dengue virus envelope protein dimer using well-tempered metadynamics simulations.
Proteins: Structure, Function, and Bioinformatics ( IF 3.2 ) Pub Date : 2019-11-25 , DOI: 10.1002/prot.25844
Haiping Zhang 1, 2 , Eric L J Kai 1 , Lanyuan Lu 1
Affiliation  

We explored the stability of the dengue virus envelope (E) protein dimer since it is widely assumed that the E protein dimer is stabilized by drug ligands or antibodies in an acidic environment, neutralizing the virus's ability to fuse with human cells. During this process, a large conformational change of the E protein dimer is required. We performed Molecular Dynamics simulations to mimic the conformational change and stability of the dimer in neutral and acidic conditions with the well-tempered metadynamics method. Furthermore, as a few neutralizing antibodies discovered from dengue patients were reported, we used the same simulation method to examine the influence of a selected antibody on the dimer stability in both neutral and acidic conditions. We also investigated the antibody's influence on a point-mutated E protein that had been reported to interrupt the protein-antibody interaction and result in more than 95% loss of the antibody's binding ability. Our simulation results are highly consistent with the experimental conclusion that binding of the antibody to the E protein dimer neutralizes the virus, especially in a low pH condition, while the mutation of W101A or N153A significantly reduces the antibody's ability in stabilizing the E protein dimer. We demonstrate that well-tempered metadynamics can be used to accurately explore the antibody's interaction on large protein complexes such as the E protein dimer, and the computational approach in this work is promising in future antibody development.

中文翻译:

使用完善的元动力学模拟研究登革热病毒包膜蛋白二聚体的稳定性。

我们广泛研究了登革热病毒病毒包膜(E)蛋白二聚体的稳定性,因为人们普遍认为E蛋白二聚体在酸性环境中被药物配体或抗体稳定,从而中和了病毒与人细胞融合的能力。在此过程中,E蛋白二聚体的构象变化很大。我们进行了分子动力学模拟,以通过良好的动力学方法模拟中性和酸性条件下二聚体的构象变化和稳定性。此外,由于报告了从登革热患者身上发现的一些中和抗体,我们使用相同的模拟方法来检查所选抗体对中性和酸性条件下二聚体稳定性的影响。我们还研究了抗体 据报道,它对点突变的E蛋白的影响会中断蛋白质与抗体的相互作用,并导致抗体结合能力损失超过95%。我们的模拟结果与实验结论高度一致,该结论是抗体与E蛋白二聚体的结合会中和病毒,尤其是在低pH条件下,而W101A或N153A的突变会大大降低抗体稳定E蛋白二聚体的能力。我们证明了良好的代谢动力学可以用来准确地探索抗体在大蛋白复合物(例如E蛋白二聚体)上的相互作用,并且这项工作中的计算方法在未来的抗体开发中很有希望。的结合能力。我们的模拟结果与实验结论高度一致,该结论是抗体与E蛋白二聚体的结合会中和病毒,尤其是在低pH条件下,而W101A或N153A的突变会大大降低抗体稳定E蛋白二聚体的能力。我们证明了良好的代谢动力学可以用来准确地探索抗体在大蛋白复合物(例如E蛋白二聚体)上的相互作用,并且这项工作中的计算方法在未来的抗体开发中很有希望。的结合能力。我们的模拟结果与实验结论高度一致,该结论是抗体与E蛋白二聚体的结合会中和病毒,尤其是在低pH条件下,而W101A或N153A的突变会大大降低抗体稳定E蛋白二聚体的能力。我们证明了良好的代谢动力学可以用来准确地探索抗体在大蛋白复合物(例如E蛋白二聚体)上的相互作用,并且这项工作中的计算方法在未来的抗体开发中很有希望。稳定E蛋白二聚体的能力。我们证明了良好的代谢动力学可以用来准确地探索抗体在大蛋白复合物(例如E蛋白二聚体)上的相互作用,并且这项工作中的计算方法在未来的抗体开发中很有希望。稳定E蛋白二聚体的能力。我们证明了良好的代谢动力学可以用来准确地探索抗体在大蛋白复合物(例如E蛋白二聚体)上的相互作用,并且这项工作中的计算方法在未来的抗体开发中很有希望。
更新日期:2019-11-25
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