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A Fluorogenic Peptide Cleavage Assay to Screen for Proteolytic Activity: Applications for coronavirus spike protein activation
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Mutation Effects on Structure and Dynamics: Adaptive Evolution of the SARS-CoV-2 Main Protease
Elizabeth M Diessner1, Gemma R Takahashi2, Thomas J Cross3
1Department of Chemistry, University of California, Irvine, Irvine, California 92697, United States.
Biochemistry
|January 19, 2023
Summary
The SARS-CoV-2 main protease (Mpro) has evolved during the COVID-19 pandemic. Molecular dynamics reveal mutations favor increased hydrophobicity and a less constrained active site, suggesting host adaptation.
Area of Science:
- Virology
- Structural Biology
- Computational Biology
Background:
- The SARS-CoV-2 main protease (Mpro) is essential for viral replication.
- Mpro is a conserved but evolving target throughout the COVID-19 pandemic.
Purpose of the Study:
- To investigate phenotypic changes in clinically observed SARS-CoV-2 Mpro variants.
- To analyze the structural and dynamic effects of Mpro mutations using molecular simulations.
Main Methods:
- Atomistic molecular dynamics simulations.
- Analysis of protein structure networks and active site networks.
- Substitution and phylogenetic analyses of Mpro variants.
Main Results:
- Mutations in Mpro show a trend towards increased hydrophobicity across all structural levels.
- Analysis indicates reduced active site constraint and altered global cohesion in variants.
- Phylogenetic data supports evolutionary adaptation driven by selective pressures.
Conclusions:
- SARS-CoV-2 Mpro is adapting to its host environment by increasing hydrophobicity.
- These evolutionary changes may impact Mpro function and viral replication dynamics.
- Understanding Mpro evolution is crucial for developing effective antiviral strategies.
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