The Japanese encephalitis virus (JEV) is one of the vector borne causes of encephalitis found in southeastern Asia. This positive single-stranded RNA virus is a member of the Flaviviridae family, which notably includes dengue, tick-borne, West Nile, Zika as well as yellow fever, and transmits to humans by infected mosquitos. The main site of interactions for antibodies against this virus is the envelope protein domain III (ED3). The present report investigates the time-dependent structural and conformational changes of JEV ED3 functional epitopes and escape mutants by computer simulations. The results indicate the presence of significant structural differences between the functional epitopes and the escape mutants. Mutation-induced structural/conformational instabilities of this type can decrease the antibody neutralization activity. Among the different escape mutants studied here, Ser40Lys/Asp41Arg appear to be most unstable, while Ser40Glu/Asp41Leu exhibit the lowest structural variations. The highest level of escape mutation observed in Ser40Lys is linked to the relatively higher values of root mean square deviation/fluctuation found in the molecular dynamics simulation of this protein. Secondary-structure deviations and depletion of H bonding are other contributing factors to the protein's increased instability. Overall, the proteins with residue 41 mutations are found to be structurally more ordered than those with residue 40 mutations. The detailed time-based structural assessment of the mutant epitopes described here may contribute to the development of novel vaccines and antiviral drugs necessary to defend against future outbreaks of JEV escape mutants.

中文翻译：

---

日本脑炎病毒包膜蛋白结构域 III 功能表位和逃逸突变体的结构和分子分析。

日本脑炎病毒 (JEV) 是在东南亚发现的脑炎病媒传播原因之一。这种阳性单链 RNA 病毒是黄病毒科的成员，主要包括登革热、蜱传、西尼罗河病毒、寨卡病毒以及黄热病，并通过受感染的蚊子传播给人类。针对这种病毒的抗体相互作用的主要位点是包膜蛋白结构域 III (ED3)。本报告通过计算机模拟研究了 JEV ED3 功能表位和逃逸突变体的时间依赖性结构和构象变化。结果表明功能表位和逃逸突变体之间存在显着的结构差异。这种类型的突变诱导的结构/构象不稳定性会降低抗体中和活性。在这里研究的不同逃逸突变体中，Ser40Lys/Asp41Arg 似乎最不稳定，而 Ser40Glu/Asp41Leu 表现出最低的结构变化。在 Ser40Lys 中观察到的最高水平的逃逸突变与在该蛋白质的分子动力学模拟中发现的相对较高的均方根偏差/波动值有关。二级结构偏差和 H 键的消耗是导致蛋白质不稳定性增加的其他因素。总体而言，发现具有残基 41 突变的蛋白质在结构上比具有残基 40 突变的蛋白质更有序。此处描述的突变表位的基于时间的详细结构评估可能有助于开发新的疫苗和抗病毒药物，以防止未来爆发 JEV 逃逸突变体。