Keck Center for Science and Engineering, Graduate Program in Computational and Data Sciences, Schmid College of Science and Technology, Chapman University, Orange, CA 92866, USA.
Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Irvine, CA 92618, USA.
Viruses. 2023 May 10;15(5):1143. doi: 10.3390/v15051143.
Evolutionary and functional studies suggested that the emergence of the Omicron variants can be determined by multiple fitness trade-offs including the immune escape, binding affinity for ACE2, conformational plasticity, protein stability and allosteric modulation. In this study, we systematically characterize conformational dynamics, structural stability and binding affinities of the SARS-CoV-2 Spike Omicron complexes with the host receptor ACE2 for BA.2, BA.2.75, XBB.1 and XBB.1.5 variants. We combined multiscale molecular simulations and dynamic analysis of allosteric interactions together with the ensemble-based mutational scanning of the protein residues and network modeling of epistatic interactions. This multifaceted computational study characterized molecular mechanisms and identified energetic hotspots that can mediate the predicted increased stability and the enhanced binding affinity of the BA.2.75 and XBB.1.5 complexes. The results suggested a mechanism driven by the stability hotspots and a spatially localized group of the Omicron binding affinity centers, while allowing for functionally beneficial neutral Omicron mutations in other binding interface positions. A network-based community model for the analysis of epistatic contributions in the Omicron complexes is proposed revealing the key role of the binding hotspots R498 and Y501 in mediating community-based epistatic couplings with other Omicron sites and allowing for compensatory dynamics and binding energetic changes. The results also showed that mutations in the convergent evolutionary hotspot F486 can modulate not only local interactions but also rewire the global network of local communities in this region allowing the F486P mutation to restore both the stability and binding affinity of the XBB.1.5 variant which may explain the growth advantages over the XBB.1 variant. The results of this study are consistent with a broad range of functional studies rationalizing functional roles of the Omicron mutation sites that form a coordinated network of hotspots enabling a balance of multiple fitness tradeoffs and shaping up a complex functional landscape of virus transmissibility.
进化和功能研究表明，奥密克戎变体的出现可以通过多种适应性权衡来决定，包括免疫逃逸、与 ACE2 的结合亲和力、构象灵活性、蛋白质稳定性和变构调节。在这项研究中，我们系统地描述了 SARS-CoV-2 Spike 奥密克戎与宿主受体 ACE2 结合的构象动力学、结构稳定性和结合亲和力，用于 BA.2、BA.2.75、XBB.1 和 XBB.1.5 变体。我们结合多尺度分子模拟和变构相互作用的动态分析，以及蛋白质残基的基于集合的突变扫描和上位性相互作用的网络建模。这项多方面的计算研究描述了分子机制，并确定了能量热点，这些热点可以介导 BA.2.75 和 XBB.1.5 复合物预测的稳定性增加和结合亲和力增强。结果表明，一种由稳定性热点和奥密克戎结合亲和力中心的局部空间群驱动的机制，同时允许在其他结合界面位置进行功能有益的奥密克戎中性突变。提出了一种基于网络的奥密克戎复合物上位性贡献分析的社区模型，揭示了结合热点 R498 和 Y501 在介导与其他奥密克戎位点的基于社区的上位性耦合以及允许补偿动力学和结合能量变化中的关键作用。结果还表明，在趋同进化热点 F486 中的突变不仅可以调节局部相互作用，还可以重新布线该区域的局部社区全局网络，从而允许 F486P 突变恢复 XBB.1.5 变体的稳定性和结合亲和力，这可能解释了其相对于 XBB.1 变体的生长优势。这项研究的结果与广泛的功能研究一致，这些研究合理化了奥密克戎突变位点的功能作用，这些突变位点形成了一个热点的协调网络，实现了多种适应性权衡的平衡，并形成了病毒传染性的复杂功能景观。
