Dynamic allostery highlights the evolutionary differences between the CoV-1 and CoV-2 main proteases

Area of Science:

• Biophysics
• Structural Biology
• Virology

Background:

• SARS-CoV-2 emerged globally from 2019-2022, necessitating research into its molecular mechanisms.
• Comparative studies of SARS-CoV-1 and SARS-CoV-2 proteins are crucial for understanding viral evolution and biophysical changes.
• The main protease (mPro) is a key target for antiviral drug development due to its essential role in viral replication.

Purpose of the Study:

• To investigate the long-range dynamic coupling of SARS-CoV-1 and SARS-CoV-2 main proteases (mPro).
• To compare the effects of mutations and inhibitor binding on the dynamic flexibility of CoV-1 and CoV-2 mPro.
• To elucidate the allosteric mechanisms underlying the observed dynamic differences between the two viral proteases.

Main Methods:

• Utilized the Dynamic Coupling Index (DCI) to analyze inter- and intrachain dynamic coupling of catalytic site residues.
• Employed the dynamic flexibility index (DFI) to compare flexibility changes upon inhibitor binding in CoV-1 and CoV-2 mPro.
• Performed comparative analysis of residue substitutions and their impact on overall protein flexibility.

Main Results:

• Identified significant cross-chain dynamic coupling between active sites and distal residues in SARS-CoV-2 mPro, absent in SARS-CoV-1 mPro.
• Observed enhanced cooperativity in SARS-CoV-2 mPro due to these long-distance interactions.
• Demonstrated opposing flexibility changes in a distal protein region upon inhibitor binding: increased in CoV-1 mPro, decreased in CoV-2 mPro.
• Found that substituted residues in CoV-2 mPro exhibited less flexibility change than average, indicating allosteric modulation.

Conclusions:

• SARS-CoV-2 mPro exhibits enhanced cooperativity and distinct allosteric regulation compared to SARS-CoV-1 mPro.
• Mutations in SARS-CoV-2 likely induce allosteric effects, altering protein dynamics and flexibility.
• Understanding these dynamic differences is vital for developing targeted antiviral therapies against SARS-CoV-2.