Barozi Victor, Edkins Adrienne L, Tastan Bishop Özlem
Research Unit in Bioinformatics (RUBi), Department of Biochemistry and Microbiology, Rhodes University, Makhanda/Grahamstown 6139, South Africa.
The Biomedical Biotechnology Research Unit (BioBRU), Department of Biochemistry and Microbiology, Rhodes University, Makhanda/Grahamstown 6139, South Africa.
Comput Struct Biotechnol J. 2022;20:4562-4578. doi: 10.1016/j.csbj.2022.08.015. Epub 2022 Aug 17.
The interaction between the Spike (S) protein of SARS-CoV-2 and the human angiotensin converting enzyme 2 (hACE2) is essential for infection, and is a target for neutralizing antibodies. Consequently, selection of mutations in the S protein is expected to be driven by the impact on the interaction with hACE2 and antibody escape. Here, for the first time, we systematically characterized the collective effects of mutations in each of the Omicron sub-lineages (BA.1, BA.2, BA.3 and BA.4) on both the viral S protein receptor binding domain (RBD) and the hACE2 protein using post molecular dynamics studies and dynamic residue network (DRN) analysis. Our analysis suggested that Omicron sub-lineage mutations result in altered physicochemical properties that change conformational flexibility compared to the reference structure, and may contribute to antibody escape. We also observed changes in the hACE2 substrate binding groove in some sub-lineages. Notably, we identified unique allosteric communication paths in the reference protein complex formed by the DRN metrics and hubs, originating from the RBD core traversing the receptor binding motif of the S protein and the N-terminal domain of the hACE2 to the active site. We showed allosteric changes in residue network paths in both the RBD and hACE2 proteins due to Omicron sub-lineage mutations. Taken together, these data suggest progressive evolution of the Omicron S protein RBD in sub-lineages towards a more efficient interaction with the hACE2 receptor which may account for the increased transmissibility of Omicron variants.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的刺突（S）蛋白与人血管紧张素转换酶2（hACE2）之间的相互作用是感染所必需的，并且是中和抗体的作用靶点。因此，预计S蛋白中突变的选择将受到对与hACE2相互作用的影响以及抗体逃逸的驱动。在此，我们首次使用分子动力学后研究和动态残基网络（DRN）分析，系统地表征了奥密克戎各亚谱系（BA.1、BA.2、BA.3和BA.4）中突变对病毒S蛋白受体结合域（RBD）和hACE2蛋白的集体影响。我们的分析表明，与参考结构相比，奥密克戎亚谱系突变导致理化性质改变，从而改变构象灵活性，并可能导致抗体逃逸。我们还观察到一些亚谱系中hACE2底物结合凹槽的变化。值得注意的是，我们通过DRN指标和枢纽在由RBD核心、S蛋白的受体结合基序以及hACE2的N端结构域到活性位点形成的参考蛋白复合物中确定了独特的变构通讯路径。我们展示了由于奥密克戎亚谱系突变导致RBD和hACE2蛋白中残基网络路径的变构变化。综上所述，这些数据表明奥密克戎S蛋白RBD在亚谱系中朝着与hACE2受体更有效的相互作用方向逐步进化，这可能解释了奥密克戎变体传播性增加的原因。
