The omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) characterized by 30 mutations in its spike protein, has rapidly spread worldwide since November 2021, significantly exacerbating the ongoing COVID-19 pandemic. In order to investigate the relationship between these mutations and the variant's high transmissibility, we conducted a systematic analysis of the mutational effect on spike–angiotensin-converting enzyme-2 (ACE2) interactions and explored the structural/energy correlation of key mutations, utilizing a reliable coarse-grained model. Our study extended beyond the receptor-binding domain (RBD) of spike trimer through comprehensive modeling of the full-length spike trimer rather than just the RBD. Our free-energy calculation revealed that the enhanced binding affinity between the spike protein and the ACE2 receptor is correlated with the increased structural stability of the isolated spike protein, thus explaining the omicron variant's heightened transmissibility. The conclusion was supported by our experimental analyses involving the expression and purification of the full-length spike trimer. Furthermore, the energy decomposition analysis established those electrostatic interactions make major contributions to this effect. We categorized the mutations into four groups and established an analytical framework that can be employed in studying future mutations. Additionally, our calculations rationalized the reduced affinity of the omicron variant towards most available therapeutic neutralizing antibodies, when compared with the wild type. By providing concrete experimental data and offering a solid explanation, this study contributes to a better understanding of the relationship between theories and observations and lays the foundation for future investigations.

中文翻译：

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SARS-CoV-2 omicron 变种传播模式的机制研究

严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 的 omicron 变体的特点是其刺突蛋白有 30 个突变，自 2021 年 11 月以来已在全球范围内迅速传播，显着加剧了正在进行的 COVID-19 大流行。为了研究这些突变与变异体高遗传性之间的关系，我们对突变对尖峰-血管紧张素转换酶-2 (ACE2)相互作用的影响进行了系统分析，并利用可靠的粗粒度模型。我们的研究通过对全长刺突三聚体而不仅仅是 RBD 进行全面建模，扩展到刺突三聚体的受体结合域 (RBD) 之外。我们的自由能计算表明，刺突蛋白和 ACE2 受体之间增强的结合亲和力与分离的刺突蛋白结构稳定性的增加相关，从而解释了 omicron 变体的更高的传递性。我们的实验分析涉及全长刺突三聚体的表达和纯化，支持了该结论。此外，能量分解分析表明，静电相互作用对这种效应做出了重大贡献。我们将突变分为四组，并建立了一个可用于研究未来突变的分析框架。此外，我们的计算合理地证明了与野生型相比，omicron 变体对大多数可用的治疗性中和抗体的亲和力降低。通过提供具体的实验数据和可靠的解释，这项研究有助于更好地理解理论和观察之间的关系，并为未来的研究奠定基础。