An outbreak of Zika virus (ZIKV) infections in 2015–16 that caused microcephaly and other congenital abnormalities in newborns prompted intense research across the globe. These studies have suggested that ZIKV can survive high temperatures and harsh physiological conditions, unlike the other flaviviruses such as dengue virus (DENV). In contrast, recent cryo-electron microscopy studies have shown very similar architecture of the ZIKV and DENV envelopes that constitute the primary level of viral protection. Encouraged by these findings, here we attempt to identify the crucial protein residues that make the ZIKV envelope so robust by employing coarse-grained and all-atomic molecular dynamics simulations and computational mutagenesis studies. In accordance with more recent cryo-electron microscopy findings, our simulation results exhibited stable ZIKV envelope protein shell both at 29^oC and 40°C, whereas the DENV2 shell loosened up significantly at 40°C. Subsequently, we simulated a series of ZIKV variants to identify the specific domain and residues involved in maintaining the structural integrity of the viral protein shell at high temperatures. Our results suggest that the DIII domain—more specifically, the CD- and FG-loop residues of the ZIKV protein shell—play a crucial role in making the virus envelope thermostable by inducing strong raft-raft interactions. These findings can accelerate the rational design of ZIKV therapeutics.

2015-16 年爆发的寨卡病毒 (ZIKV) 感染导致新生儿出现小头畸形和其他先天性异常，促使全球开展了深入研究。这些研究表明，与登革热病毒 (DENV) 等其他黄病毒不同，ZIKV 可以在高温和恶劣的生理条件下存活。相比之下，最近的低温电子显微镜研究表明，构成病毒保护主要水平的 ZIKV 和 DENV 包膜结构非常相似。受到这些发现的鼓舞，我们在这里尝试通过采用粗粒度和全原子分子动力学模拟和计算诱变研究来确定使 ZIKV 包膜如此坚固的关键蛋白质残基。根据最近的低温电子显微镜发现，^o C 和 40°C，而 DENV2 外壳在 40°C 时明显松动。随后，我们模拟了一系列 ZIKV 变体，以确定在高温下维持病毒蛋白壳结构完整性所涉及的特定结构域和残基。我们的研究结果表明，DIII 结构域——更具体地说，ZIKV 蛋白壳的 CD 和 FG 环残基——通过诱导强烈的筏-筏相互作用在使病毒包膜热稳定方面发挥着至关重要的作用。这些发现可以加速 ZIKV 疗法的合理设计。