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.

SARS-CoV-2 S 蛋白是病毒与人类免疫系统之间相互作用的主要点。因此，S 蛋白不是静态靶标，而是经历快速的分子进化。为了更全面地了解进化过程中的选择压力，我们检查了 S 蛋白中的残基位置，这些残基位置在密切相关的病毒中差异很大，但在感染人类的​​病毒子集中是保守的。这些“进化上重要”的残基并不是均匀分布在S蛋白上，而是集中在两个结构域：N端结构域和受体结合结构域，这两个结构域在许多相关病毒的宿主细胞结合中都发挥着作用。除了位于这两个结构域之外，进化重要性还与结构灵活性相关，并与距已知或预测的宿主受体结合残基的距离成反比。最后，我们观察到构成此类残基的氨基酸组成存在偏向于更像人类而非病毒的序列基序。