Table_1_Flexible, Functional, and Familiar: Characteristics of SARS-CoV-2 Spike Protein Evolution.DOCX

The SARS-CoV-2 S protein is a major point of interaction between the virus and the human immune system. As a consequence, the S protein is not a static target but undergoes rapid molecular evolution. In order to more fully understand the selection pressure during evolution, we examined residue positions in the S protein that vary greatly across closely related viruses but are conserved in the subset of viruses that infect humans. These “evolutionarily important” residues were not distributed evenly across the S protein but were concentrated in two domains: the N-terminal domain and the receptor-binding domain, both of which play a role in host cell binding in a number of related viruses. In addition to being localized in these two domains, evolutionary importance correlated with structural flexibility and inversely correlated with distance from known or predicted host receptor-binding residues. Finally, we observed a bias in the composition of the amino acids that make up such residues toward more human-like, rather than virus-like, sequence motifs.

严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）刺突（S）蛋白是该病毒与人类免疫系统相互作用的核心位点。因此，该刺突蛋白并非静态靶标，而是处于快速的分子进化过程中。为更全面地解析进化过程中的选择压力，我们对刺突蛋白上的残基位点开展了分析：这些位点在近缘病毒中存在显著序列差异，但在感染人类的病毒亚群中却呈现保守性。这类被称为‘进化关键残基’的位点并非均匀分布于刺突蛋白全序列，而是集中在两个结构域中：N端结构域（N-terminal domain）与受体结合结构域（receptor-binding domain）；二者在多种近缘病毒的宿主细胞结合过程中均发挥功能。除定位于上述两个结构域外，进化关键残基的重要性还与结构柔性呈正相关，与已知或预测的宿主受体结合残基的空间距离呈负相关。最后，我们发现构成这类残基的氨基酸组成存在偏好性：其序列基序更趋近于人类宿主的序列特征，而非病毒本身的序列模式。