Molecular dynamics simulations of the SARS-CoV-2 Spike protein and variants of concern: structural evidence for convergent adaptive evolution

The Spike protein's structure of the SARS-CoV-2 provides a unique opportunity to consider perturbations at the atomic level. We used the cryo-electron microscopy structure of the open conformation of the Spike protein to assess the impact of the mutations observed in the variants of concern at the molecular level. Molecular dynamics were subsequently performed with both the wt and the mutated forms to compare the flexibility and variation data for each residue of the three-dimensional fluctuations in the region associated with each alpha carbon. Additionally, protein-protein docking was used to investigate the interaction of each mutated profile with the ACE-2 receptor. After the molecular dynamics, the results show that the mutations increased the stability of the trimeric protein, with greater stability observed in the Gamma variant harboring the 10 characteristic mutations. The results of molecular dynamics, as shown by RMSF demonstrated for the residues that comprise the binding domain receptor (RBD), exhibited a reduction in flexibility, which was more pronounced in the Gamma variant. Finally, protein-protein docking experiments revealed an increase in the number of hydrophobic interactions and hydrogen bonds in the Gamma variant against the ACE-2 receptor, as opposed to the other variants. Taken together, these <i>in silico</i> experiments suggest that the evolution of the mutations favored the increased stability of Spike protein while potentially improving its interaction with the ACE-2 receptor, which in turn may indicate putative structural outcomes of the selection of these mutations in the convergent adaptive evolution as it has been observed for SARS-CoV-2. Communicated by Ramaswamy H. Sarma

新冠病毒（SARS-CoV-2）刺突蛋白（Spike protein）的结构为在原子层面探究其结构扰动提供了独特契机。本研究利用刺突蛋白开放构象的冷冻电镜（cryo-electron microscopy）结构，在分子层面评估各关切变异株（variants of concern）所携带突变的影响。随后我们对野生型（wild-type，wt）及突变型刺突蛋白分别开展分子动力学（molecular dynamics）模拟，以对比各残基在对应α碳原子（alpha carbon）相关区域的三维涨落柔性与变化数据。此外，本研究通过蛋白-蛋白对接（protein-protein docking）技术，探究每种突变特征组合与ACE-2受体（ACE-2 receptor）的相互作用情况。分子动力学模拟结果显示，各类突变均提升了三聚体刺突蛋白的稳定性，其中携带10个特征突变的伽马变异株（Gamma variant）稳定性提升最为显著。通过均方根波动（Root Mean Square Fluctuation, RMSF）对构成受体结合域（Receptor Binding Domain, RBD）的残基进行分析，结果可见该区域的柔性有所降低，且这一现象在伽马变异株中更为突出。最后，蛋白-蛋白对接实验结果表明，相较于其他变异株，伽马变异株与ACE-2受体之间的疏水相互作用与氢键数量均有所增加。综合来看，这些计算机模拟（in silico）实验表明，突变的演化倾向于提升刺突蛋白的稳定性，同时可能增强其与ACE-2受体的结合能力。这一结果也暗示，在新冠病毒（SARS-CoV-2）中观测到的趋同适应性进化过程中，这类突变的选择可能带来相应的结构层面变化。本文由Ramaswamy H. Sarma转交刊发。