Issue 16, 2022

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

Abstract

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

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

Supplementary files

Article information

Article type
Communication
Submitted
12 Jan 2022
Accepted
01 Apr 2022
First published
01 Apr 2022

Phys. Chem. Chem. Phys., 2022,24, 9141-9145

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

A. K. Padhi and T. Tripathi, Phys. Chem. Chem. Phys., 2022, 24, 9141 DOI: 10.1039/D2CP00171C

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