Drug repurposing and sequence analysis in S-glycoprotein variants reveals critical signature patterns and destabilization of receptor-binding domain in omicron variant

The evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus since its emergence in 2019 has yielded several new viral variants with varied infectivity, disease severity, and antigenicity. Although most mutations are expected to be relatively neutral, mutations at the Spike region of the genome have shown to have a major impact on the viral transmission and infection in humans. Therefore, it is crucial to survey the structures of spike protein across the global virus population to contextualize the rate of therapeutic success against these variants. In this study, high-frequency mutational variants from different geographic regions were pooled in order to study the structural evolution of the spike protein through drug docking and MD simulations. We investigated the mutational burden in the spike subregions and have observed that the different variants harbour unique signature patterns in the spike subregions, with certain domains being highly prone to mutations. Further, the MD simulations and docking study revealed that different variants show differential stability when docked for the same set of drug targets. This work sheds light on the mutational burden and the stability landscape of the spike protein across the variants from different geographical regions. Communicated by Ramaswamy H. Sarma

自2019年首次出现以来，严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）的演化已产生多种新型病毒变异株，这些变异株在感染性、疾病严重程度及抗原性方面存在显著差异。尽管大多数突变相对呈中性，但病毒基因组刺突（Spike）区域的突变已被证实对病毒在人群中的传播与感染具有重大影响。因此，对全球病毒种群中刺突蛋白的结构进行系统调研，以解析针对这些变异株的治疗成功率的相关背景，具有重要意义。本研究收集了来自不同地理区域的高频突变变异株，旨在通过药物对接及分子动力学（MD）模拟，探究刺突蛋白的结构演化规律。我们对刺突亚区的突变负荷开展了分析，观察到不同变异株在刺突亚区存在独特的特征模式，且部分结构域极易发生突变。此外，分子动力学模拟与药物对接研究显示，当针对同一组药物靶点进行对接实验时，不同变异株展现出差异化的稳定性。本研究阐明了不同地理区域来源的变异株中刺突蛋白的突变负荷与稳定性图谱。本文由Ramaswamy H. Sarma转交。