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 in silico 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

严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）的刺突蛋白（Spike protein）结构，为在原子尺度下探究其扰动效应提供了独特契机。本研究采用冷冻电镜（cryo-electron microscopy）解析的刺突蛋白开放构象结构，在分子层面评估了各关切变异株中观测到的突变所产生的影响。随后分别针对野生型（wild type, wt）与突变型刺突蛋白开展分子动力学（molecular dynamics）模拟，对比各残基在与各α碳原子相关区域的三维波动中的柔韧性与波动变异数据。此外，本研究还采用蛋白质-蛋白质对接（protein-protein docking）技术，探究各突变型刺突蛋白与血管紧张素转换酶2（ACE-2）受体的相互作用情况。分子动力学模拟结果显示，突变可提升三聚体刺突蛋白的稳定性，其中携带10种特征突变的伽马变异株稳定性提升最为显著。针对受体结合域（Receptor Binding Domain, RBD）残基的均方根波动（RMSF）分析结果表明，该区域的柔韧性出现下降，且这一现象在伽马变异株中表现得更为突出。最后，蛋白质-蛋白质对接实验结果显示，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）实验结果表明，相关突变的演化提升了刺突蛋白的稳定性，同时可能增强其与ACE-2受体的结合能力，这也提示了SARS-CoV-2趋同适应性进化过程中，这类突变的选择可能带来上述结构性变化。由Ramaswamy H. Sarma转交。