Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein is the prime target for vaccines, diagnostics, and therapeutic antibodies against the virus. While anchored in the viral envelope, for effective virulence, the spike needs to maintain structural flexibility to recognize the host cell surface receptors and bind to them, a property that can heavily depend upon the dynamics of the unresolved domains, most prominently the stalk. Construction of the complete, membrane-bound spike model and the description of its dynamics are critical steps in understanding the inner working of this key element of the viral infection by SARS-CoV-2. Combining homology modeling, protein–protein docking, and molecular dynamics (MD) simulations, we have developed a full spike structure in a native membrane. Multimicrosecond MD simulations of this model, the longest known single trajectory of the full spike, reveal conformational dynamics employed by the protein to explore the surface of the host cell. In agreement with cryogenic electron microscopy (cryo-EM), three flexible hinges in the stalk allow for global conformational heterogeneity of spike in the fully glycosylated system mediated by glycan–glycan and glycan–lipid interactions. The dynamical range of the spike is considerably reduced in its nonglycosylated form, confining the area explored by the spike on the host cell surface. Furthermore, palmitoylation of the membrane domain amplifies the local curvature that may prime the fusion. We show that the identified hinge regions are highly conserved in SARS coronaviruses, highlighting their functional importance in enhancing viral infection, and thereby, provide points for discovery of alternative therapeutics against the virus.

中文翻译：

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翻译后修饰优化了 SARS-CoV-2 刺突与宿主细胞受体有效相互作用的能力

严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 刺突糖蛋白是针对该病毒的疫苗、诊断和治疗抗体的主要靶标。虽然锚定在病毒包膜中，但为了获得有效的毒力，刺突需要保持结构灵活性，以识别宿主细胞表面受体并与其结合，这一特性在很大程度上取决于未解析结构域（最突出的是茎）的动态。构建完整的膜结合刺突模型并描述其动力学是了解 SARS-CoV-2 病毒感染这一关键要素的内部工作原理的关键步骤。结合同源建模、蛋白质-蛋白质对接和分子动力学（MD）模拟，我们在天然膜中开发了完整的刺突结构。该模型的多微秒 MD 模拟是已知最长的全尖峰单轨迹，揭示了蛋白质探索宿主细胞表面的构象动力学。与低温电子显微镜（cryo-EM）一致，茎中的三个柔性铰链允许由聚糖-聚糖和聚糖-脂质相互作用介导的完全糖基化系统中刺突的整体构象异质性。非糖基化形式的刺突动态范围显着减小，限制了宿主细胞表面刺突探索的区域。此外，膜域的棕榈酰化放大了可能引发融合的局部曲率。我们发现，所鉴定的铰链区在 SARS 冠状病毒中高度保守，突出了它们在增强病毒感染方面的功能重要性，从而为发现针对该病毒的替代疗法提供了依据。