4.6 Article

High-throughput design of symmetrical dimeric SARS-CoV-2 main protease: structural and physical insights into hotspots for adaptation and therapeutics

Journal

PHYSICAL CHEMISTRY CHEMICAL PHYSICS
Volume 24, Issue 16, Pages 9141-9145

Publisher

ROYAL SOC CHEMISTRY
DOI: 10.1039/d2cp00171c

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Dimerization of SARS-CoV-2 main protease is essential for its activity, and mutations in the dimeric interface may further stabilize it. Through protein design strategies, potential mutations that can stabilize the protein have been identified in the circulating SARS-CoV-2 genomes, providing insights into viral adaptation and mutational surveillance.
Dimerization of SARS-CoV-2 main protease (M-pro) is a prerequisite for its processing activity. With >2000 mutations already reported in M-pro, SARS-CoV-2 may accumulate mutations in the M-pro dimeric interface to stabilize it further. We employed high-throughput protein design strategies to design the symmetrical dimeric interface of M-pro (300 000 designs) to identify mutational hotspots that render the M-pro more stable. We found that similar to 22% of designed mutations that yield stable M-pro dimers already exist in SARS-CoV-2 genomes and are currently circulating. Our multi-parametric analyses highlight potential M-pro mutations that SARS-CoV-2 may develop, providing a foundation for assessing viral adaptation and mutational surveillance.

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