在这项研究中,我们对SARS-CoV-2尖峰OmicronXBB谱系与宿主细胞受体ACE2和一组不同的一类抗体的结合机制进行了计算研究。这项研究的中心目的是检查汇聚进化热点之间的上位耦合潜在的分子因素,这些因素能够使Omicron变体BA.1,BA2,BA.3,BA.4/BA.5,BQ.1.1,XBB.1,XBB.1.5和XBB.1.5L455F/F456L的ACE2结合和抗体规避最佳平衡。通过结合进化分析,分子动力学模拟,通过对ACE2复合物中的刺突蛋白残基进行基于集合的突变扫描,我们确定了与生化研究结果一致的结构稳定性和结合亲和力热点。与深度突变扫描实验的结果一致,我们的定量分析正确地再现了XBB.1.5和BA.2变体中的强和变体特异性上位效应.显示Y453W和F456L突变当与XBB.1.5中的Q493偶联时可以增强ACE2结合,而这些突变当与BA.2变体中的R493位置偶联时变得不稳定。结果提供了Omicron变体中上位机制的分子原理,显示Q493/R493热点在调节XBB谱系中会聚突变位点L455F和F456L之间的上位耦合中的核心作用。OmicronXBB刺突变体与ACE2受体和一组一类抗体的突变扫描和结合分析的结果为实验证据提供了定量的理论基础,即物理近端结合热点Y501,R498,Q493,L455F,和F456L可以确定强ACE2结合,而趋同突变位点F456L和F486P则有助于介导广泛的抗体抗性。该研究支持一种机制,其中对ACE2结合亲和力的影响是通过一小组通用结合热点来介导的,而免疫逃避的作用可能更依赖于变异,并受到构象适应性刺突区域中的趋同突变位点的调节。
In this study, we performed a computational study of binding mechanisms for the SARS-CoV-2 spike Omicron XBB lineages with the host cell receptor ACE2 and a panel of diverse class one antibodies. The central objective of this investigation was to examine the molecular factors underlying epistatic couplings among convergent evolution hotspots that enable optimal balancing of ACE2 binding and antibody evasion for Omicron variants BA.1, BA2, BA.3, BA.4/BA.5, BQ.1.1, XBB.1, XBB.1.5, and XBB.1.5 + L455F/F456L. By combining evolutionary analysis, molecular dynamics simulations, and ensemble-based mutational scanning of spike protein residues in complexes with ACE2, we identified structural stability and binding affinity hotspots that are consistent with the results of biochemical studies. In agreement with the results of deep mutational scanning experiments, our quantitative analysis correctly reproduced strong and variant-specific epistatic effects in the XBB.1.5 and BA.2 variants. It was shown that Y453W and F456L mutations can enhance ACE2 binding when coupled with Q493 in XBB.1.5, while these mutations become destabilized when coupled with the R493 position in the BA.2 variant. The results provided a molecular rationale of the epistatic mechanism in Omicron variants, showing a central role of the Q493/R493 hotspot in modulating epistatic couplings between convergent mutational sites L455F and F456L in XBB lineages. The results of mutational scanning and binding analysis of the Omicron XBB spike variants with ACE2 receptors and a panel of class one antibodies provide a quantitative rationale for the experimental evidence that epistatic interactions of the physically proximal binding hotspots Y501, R498, Q493, L455F, and F456L can determine strong ACE2 binding, while convergent mutational sites F456L and F486P are instrumental in mediating broad antibody resistance. The study supports a mechanism in which the impact on ACE2 binding affinity is mediated through a small group of universal binding hotspots, while the effect of immune evasion could be more variant-dependent and modulated by convergent mutational sites in the conformationally adaptable spike regions.