登革病毒包膜蛋白胞外域二聚体在不同pH和温度梯度下的机械稳定性和解离动力学的计算研究
Computational Insights into Mechanostability and Dissociation Dynamics of the Dengue Virus Envelope Protein Ectodomain Dimer Across pH and Temperature Gradients
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中文总结 AI 辅助
通过定向分子动力学模拟，研究了登革病毒E蛋白胞外域二聚体在不同pH和温度下的解离机制，发现高稳定性界面、亚稳态中间态及pH敏感接触，为抗病毒药物设计提供靶点。
中文摘要 AI 辅助
登革病毒（DENV）是一种具有包膜的黄病毒，具有重要的公共卫生意义。其包膜（E）蛋白通过同源二聚体解离及随后的膜融合介导病毒进入宿主细胞，使其成为抗病毒策略的主要靶点之一。为探究该过程的分子决定因素，我们在不同pH和温度条件下，对来自DENV-2和DENV-3的E蛋白胞外域（ecE）二聚体进行了定向分子动力学（SMD）模拟。力-延伸分析显示，两种血清型的界面均高度稳定，断裂力超过1000 pN。pH和温度对整体机械抗性影响较小。然而，与DENV-2相比，DENV-3对热应激表现出独特的敏感性。我们在所有条件下均识别出一条稳健的不对称解离路径，其特征是存在一个亚稳态中间态，涉及部分二聚体打开和融合环（FL）暴露。该中间态暴露一个免疫优势表位，并在生理条件下持续存在，提示其可作为治疗干预的可行靶点。界面相互作用网络的主要贡献来自范德华相互作用，其次是氢键、盐桥和π-阳离子相互作用。DENV-3在涉及结构域EDI、EDII和EDIII的极性相互作用中贡献略大。此外，配对占有率分析识别出在酸性条件下被破坏的pH敏感接触，尤其在DENV-3中，为ecE解离早期阶段提供了机制性见解。综合这些发现，我们为解离机制提供了结构见解，识别出关键的亚稳态和pH敏感相互作用，这些可用于开发稳定二聚体并阻止病毒融合的抗病毒药物。
英文摘要
Dengue virus (DENV) is an enveloped flavivirus of major public health importance. Its envelope (E) protein mediates viral entry through homodimer dissociation and subsequent membrane fusion, making it one of the principal targets for antiviral strategies. To investigate the molecular determinants of this process, we performed steered molecular dynamics (SMD) simulations of the E protein ectodomain (ecE) dimer from DENV-2 and DENV-3 under variable pH and temperature conditions. Force-extension analyses revealed a highly stable interface for both serotypes, with rupture forces exceeding 1000 pN. pH and temperature had modest effects on overall mechanical resistance. However, DENV-3 displayed a distinct sensitivity to thermal stress compared to DENV-2. We identified a robust, asymmetric dissociation pathway across all conditions, characterized by a metastable intermediate state involving partial dimer opening and exposure of the fusion loop (FL). This intermediate exposes an immunodominant epitope and persists under physiological conditions, suggesting it as a viable target for therapeutic intervention. The primary contributions to the interfacial interaction network were found to arise from van der Waals interactions, followed by hydrogen bonds, salt bridges, and pi-cation interactions. DENV-3 exhibited a slightly greater contribution from polar interactions involving domains EDI, EDII, and EDIII. Furthermore, pairwise occupancy analysis identified pH-sensitive contacts that are disrupted under acidic conditions, particularly in DENV-3, providing mechanistic insight into the early stages of ecE dissociation. Together, these findings provide structural insights into the dissociation mechanism, identifying key metastable states and pH-sensitive interactions that could be exploited to develop antivirals that stabilize the dimer and prevent viral fusion.
发表机构
- São Paulo State University (UNESP)（圣保罗州立大学）
- Nicolaus Copernicus University in Torun（托伦哥白尼大学）
- Istituto Italiano di Tecnologia (IIT)（意大利理工学院）
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