Department of Chemistry, University of California, Irvine, California 92697-2025, United States.
Department of Molecular Biology and Biochemistry, University of California, Irvine, California 92697-3900, United States.
Biochemistry. 2020 Oct 6;59(39):3741-3756. doi: 10.1021/acs.biochem.0c00462. Epub 2020 Sep 24.
The SARS-CoV-2 main protease (M) is essential to viral replication and cleaves highly specific substrate sequences, making it an obvious target for inhibitor design. However, as for any virus, SARS-CoV-2 is subject to constant neutral drift and selection pressure, with new M mutations arising over time. Identification and structural characterization of M variants is thus critical for robust inhibitor design. Here we report sequence analysis, structure predictions, and molecular modeling for seventy-nine M variants, constituting all clinically observed mutations in this protein as of April 29, 2020. Residue substitution is widely distributed, with some tendency toward larger and more hydrophobic residues. Modeling and protein structure network analysis suggest differences in cohesion and active site flexibility, revealing patterns in viral evolution that have relevance for drug discovery.
SARS-CoV-2 主要蛋白酶（M）对病毒复制至关重要，它能特异性切割底物序列，因此成为抑制剂设计的明显靶点。然而，就像任何病毒一样，SARS-CoV-2 会持续受到中性漂变和选择压力的影响，从而不断产生新的 M 突变。因此，鉴定和结构表征 M 变体对于稳健的抑制剂设计至关重要。在此，我们报告了截至 2020 年 4 月 29 日共 79 种 M 变体的序列分析、结构预测和分子建模，涵盖了该蛋白中所有临床上观察到的突变。取代的残基分布广泛，倾向于较大和疏水性更强的残基。建模和蛋白质结构网络分析表明，在凝聚性和活性位点灵活性方面存在差异，揭示了病毒进化中的模式，这对药物发现具有重要意义。
