Open AccessSequence Characterization and Molecular Modeling of Clinically Relevant Variants of the SARS-CoV-2 Main Protease
Author(s) -
Thomas J. Cross,
Gemma R. Takahashi,
Elizabeth M. Diessner,
Marquise G. Crosby,
Vesta Farahmand,
Shan Zhuang,
Carter T. Butts,
Rachel W. Martin
Publication year - 2020
Publication title -
biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.43
H-Index - 253
eISSN - 1520-4995
pISSN - 0006-2960
DOI - 10.1021/acs.biochem.0c00462
Subject(s) - computational biology , protease , biology , viral replication , sequence analysis , covid-19 , proteases , drug discovery , virus , genetics , chemistry , biochemistry , enzyme , gene , medicine , disease , pathology , infectious disease (medical specialty)
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.
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