Laboratory for Structural Bioinformatics, Center for Biosystems Dynamics Research, RIKEN, Yokohama, Kanagawa 230-0045, Japan.
Molecular and Structural Biophysics Laboratory, Department of Biochemistry, North-Eastern Hill University, Shillong - 793022, India.
Phys Chem Chem Phys. 2022 Apr 20;24(16):9141-9145. doi: 10.1039/d2cp00171c.
Dimerization of SARS-CoV-2 main protease (M) is a prerequisite for its processing activity. With >2000 mutations already reported in M, SARS-CoV-2 may accumulate mutations in the M dimeric interface to stabilize it further. We employed high-throughput protein design strategies to design the symmetrical dimeric interface of M (300 000 designs) to identify mutational hotspots that render the M more stable. We found that ∼22% of designed mutations that yield stable M dimers already exist in SARS-CoV-2 genomes and are currently circulating. Our multi-parametric analyses highlight potential M mutations that SARS-CoV-2 may develop, providing a foundation for assessing viral adaptation and mutational surveillance.
SARS-CoV-2 主蛋白酶 (M) 的二聚化是其加工活性的前提。在 M 中已经报告了超过 2000 种突变，SARS-CoV-2 可能会在 M 的二聚体界面积累突变，以进一步稳定它。我们采用高通量蛋白质设计策略来设计 M 的对称二聚体界面（30 万个设计），以识别使 M 更稳定的突变热点。我们发现，在 SARS-CoV-2 基因组中已经存在并正在传播的，能够产生稳定 M 二聚体的设计突变约有 22%。我们的多参数分析强调了 SARS-CoV-2 可能发展的潜在 M 突变，为评估病毒适应性和突变监测提供了基础。
