Sequence Characterization and Molecular Modeling of Clinically Relevant Variants of the SARS-CoV‑2 Main Protease

• Published in: Biochemistry (Easton) Vol. 59; no. 39; pp. 3741 - 3756
• Main Authors: Cross, Thomas J, Takahashi, Gemma R, Diessner, Elizabeth M, Crosby, Marquise G, Farahmand, Vesta, Zhuang, Shannon, Butts, Carter T, Martin, Rachel W
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 06.10.2020
• Subjects: active sites; Betacoronavirus - enzymology; Betacoronavirus - genetics; Catalytic Domain; cohesion; design; Drug Discovery; drugs; Evolution, Molecular; Humans; hydrophobicity; Models, Molecular; molecular models; Molecular Structure; Mutation; Phylogeny; prediction; Protease Inhibitors - chemistry; protein structure; proteinases; SARS-CoV-2; selection pressure; sequence analysis; Sequence Analysis, Protein; Viral Nonstructural Proteins - antagonists & inhibitors; Viral Nonstructural Proteins - genetics; virus replication; viruses
• ISSN: 0006-2960; 1520-4995; 1520-4995
• DOI: 10.1021/acs.biochem.0c00462

The SARS-CoV-2 main protease (M pro ) 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 pro mutations arising over time. Identification and structural characterization of M pro variants is thus critical for robust inhibitor design. Here we report sequence analysis, structure predictions, and molecular modeling for seventy-nine M pro 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.