Mutational profile confers increased stability of SARS-CoV-2 spike protein in Brazilian isolates

Spike (S) protein has been recognized as a promising molecular target for diagnostic, vaccines and antiviral drugs development for COVID-19. In this study, we analyzed the most predominant mutations in the S protein of Brazilian isolates and predicted the effect of these amino acid alterations to protein conformation. A total of 25,924 sequences were obtained from GISAID for five regions of Brazilian territory (Midwest, North, Northeast, South, and Southeast), according to exclusion criteria. Most of the SARS-CoV-2 isolates belongs to the G clade and showed a large occurrence of D614G, N501Y and L18F substitutions. Prediction effects of these amino acid substitutions on the structure dynamics of the spike protein indicated a positive ΔΔG values and negative ΔΔSVib in most cases which is associated to structural stabilization and flexibility reduction of the S protein. Mutations E484K, N501Y and K417N belong to several SARS-CoV-2 variants of concern such as Alpha, Beta, Gamma and Delta, and showed high incidence among Brazilian isolates. These mutations have been described to increase RBD affinity to ACE-2 host and abolishment of RBD affinity to potent neutralizing ant-RBD. The increase in rates of infection and reinfection requires continuous genomic surveillance studies in order to characterize emerging mutations and monitor vaccine efficacy, and thus consideration structural data and dynamics in the observed phenotypes.
Communicated by Ramaswamy H. Sarma

刺突（S）蛋白已被认定为新型冠状病毒肺炎（COVID-19）诊断、疫苗及抗病毒药物研发的极具潜力的分子靶点。本研究针对巴西分离株S蛋白中最主要的突变展开分析，并预测了这些氨基酸变异对蛋白质构象的影响。依据排除标准，我们从全球共享所有流感数据倡议（GISAID）获取了巴西境内五个区域（中西部、北部、东北部、南部及东南部）的共计25924条序列。绝大多数严重急性呼吸综合征冠状病毒2（SARS-CoV-2）分离株属于G进化枝，且携带D614G、N501Y及L18F氨基酸替换的检出率较高。针对上述氨基酸替换对刺突蛋白结构动力学的影响进行预测后发现，多数情况下呈现正ΔΔG值与负ΔΔSVib值，该结果与S蛋白的结构稳定化及柔性降低密切相关。E484K、N501Y及K417N突变属于Alpha、Beta、Gamma、Delta等多种严重急性呼吸综合征冠状病毒2关切变异株（VOC），且在巴西分离株中具有较高的发生率。已有研究显示，此类突变可增强受体结合域（RBD）与宿主血管紧张素转换酶2（ACE-2）的结合能力，并削弱RBD与强效中和抗RBD抗体的结合活性。感染及再感染率的上升亟需开展持续性的基因组监测研究，以鉴定新发突变并监测疫苗效力，因此需将结构数据及动力学特征纳入所观察到的表型分析范畴。本文由Ramaswamy H. Sarma审阅刊发。