College of Life and Health Sciences, Northeastern University, Shenyang, Liaoning, China.
Key Laboratory of Data Analytics and Optimization for Smart Industry (Ministry of Education), Northeastern University, Shenyang, Liaoning, China.
J Med Virol. 2021 Apr;93(4):2132-2140. doi: 10.1002/jmv.26597. Epub 2020 Nov 1.
Since 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease 2019 (COVID-19) has infected 10 millions of people across the globe, and massive mutations in virus genome have occurred during the rapid spread of this novel coronavirus. Variance in protein sequence might lead to a change in protein structure and interaction, then further affect the viral physiological characteristics, which could bring tremendous influence on the pandemic. In this study, we investigated 20 nonsynonymous mutations in the SARS-CoV-2 genome in which incidence rates were all ≥ 1% as of September 1st, 2020, and then modeled and analyzed the mutant protein structures. The results showed that four types of mutations caused dramatic changes in protein structures (RMSD ≥ 5.0 Å), which were Q57H and G251V in open-reading frames 3a (ORF3a), S194L, and R203K/G204R in nucleocapsid (N). Next, we found that these mutations also affected the binding affinity of intraviral protein interactions. In addition, the hot spots within these docking mutant complexes were altered, among which the mutation Q57H was involved in both Orf3a-S and Orf3a-Orf8 protein interactions. Besides, these mutations were widely distributed all over the world, and their occurrences fluctuated as time went on. Notably, the incidences of R203K/G204R in N and Q57H in Orf3a were both over 50% in some countries. Overall, our findings suggest that SARS-CoV-2 mutations could change viral protein structure, binding affinity, and hot spots of the interface, thereby might have impacts on SARS-CoV-2 transmission, diagnosis, and treatment of COVID-19.
自 2019 年以来，严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）导致的 2019 年冠状病毒病（COVID-19）已在全球感染了 1000 万人，这种新型冠状病毒在迅速传播过程中发生了大量病毒基因组突变。蛋白质序列的差异可能导致蛋白质结构和相互作用的改变，进而进一步影响病毒的生理特性，这可能对大流行产生巨大影响。在这项研究中，我们研究了截至 2020 年 9 月 1 日 SARS-CoV-2 基因组中发生率均≥1%的 20 个非同义突变，并对突变蛋白结构进行了建模和分析。结果表明，有 4 种类型的突变导致蛋白质结构发生了剧烈变化（RMSD≥5.0Å），分别是开放阅读框 3a（ORF3a）中的 Q57H 和 G251V、核衣壳（N）中的 S194L 和 R203K/G204R。接下来，我们发现这些突变也影响了病毒内蛋白相互作用的结合亲和力。此外，这些对接突变复合物的热点发生了改变，其中突变 Q57H 涉及 Orf3a-S 和 Orf3a-Orf8 蛋白相互作用。此外，这些突变在世界各地广泛分布，并且随着时间的推移其发生率不断波动。值得注意的是，N 中的 R203K/G204R 和 Orf3a 中的 Q57H 在一些国家的发生率均超过 50%。总的来说，我们的研究结果表明，SARS-CoV-2 突变可能改变病毒蛋白结构、结合亲和力和界面热点，从而可能对 SARS-CoV-2 的传播、COVID-19 的诊断和治疗产生影响。
