Intensive selection pressure constrains the evolutionary trajectory of SARS-CoV-2 genomes and results in various novel variants with distinct mutation profiles. Point mutations, particularly those within the receptor binding domain (RBD) of SARS-CoV-2 spike (S) protein, lead to the functional alteration in both receptor engagement and monoclonal antibody (mAb) recognition. Here, we review the data of the RBD point mutations possessed by major SARS-CoV-2 variants and discuss their individual effects on ACE2 affinity and immune evasion. Many single amino acid substitutions within RBD epitopes crucial for the antibody evasion capacity may conversely weaken ACE2 binding affinity. However, this weakened effect could be largely compensated by specific epistatic mutations, such as N501Y, thus maintaining the overall ACE2 affinity for the spike protein of all major variants. The predominant direction of SARS-CoV-2 evolution lies neither in promoting ACE2 affinity nor evading mAb neutralization but in maintaining a delicate balance between these two dimensions. Together, this review interprets how RBD mutations efficiently resist antibody neutralization and meanwhile how the affinity between ACE2 and spike protein is maintained, emphasizing the significance of comprehensive assessment of spike mutations.

中文翻译：

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SARS-CoV-2 刺突受体结合域的突变及其 ACE2 亲和力与抗体逃避之间的微妙平衡。


强烈的选择压力限制了 SARS-CoV-2 基因组的进化轨迹，并导致产生具有不同突变谱的各种新变体。点突变，特别是 SARS-CoV-2 刺突 (S) 蛋白受体结合域 (RBD) 内的点突变，会导致受体结合和单克隆抗体 (mAb) 识别的功能改变。在这里，我们回顾了主要 SARS-CoV-2 变体所具有的 RBD 点突变的数据，并讨论了它们对 ACE2 亲和力和免疫逃避的个体影响。 RBD 表位内的许多对抗体逃避能力至关重要的单个氨基酸取代可能会反过来削弱 ACE2 结合亲和力。然而，这种减弱的效果可以在很大程度上通过特定的上位突变（例如 N501Y）来补偿，从而保持 ACE2 对所有主要变体的刺突蛋白的总体亲和力。 SARS-CoV-2进化的主要方向既不在于促进ACE2亲和力也不在于逃避mAb中和，而是在于维持这两个维度之间的微妙平衡。本文共同解释了 RBD 突变如何有效抵抗抗体中和，同时如何维持 ACE2 与刺突蛋白之间的亲和力，强调了全面评估刺突突变的意义。