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

Abstract

The SARS-CoV-2 coronavirus has become one of the most immediate and widely studied systems since its identification and subsequent global outbreak from 2019 to 2022. In an effort to understand the biophysical changes as a result of mutations, the mechanistic details of multiple different proteins within the SARS-CoV-2 virus have been studied and compared with SARS-CoV-1. Focusing on the main protease (mPro), we explored the long-range dynamics using the Dynamic Coupling Index (DCI) to investigate the dynamic coupling between the catalytic site residues and the rest of the protein, both inter- and intrachain, for the CoV-1 and CoV-2 mPro. We found that there is significant cross-chain coupling between these active sites and specific distal residues in the CoV-2 mPro not present in CoV-1. The enhanced long-distance interactions, particularly between the two chains, suggest subsequently enhanced cooperativity for CoV-2. A further comparative analysis of the dynamic flexibility using the dynamic flexibility index (DFI) between the CoV-1 and CoV-2 mPros shows that the inhibitor binding near active sites induces change in flexibility to a distal region of the protein, opposite in behavior between the two systems; this region becomes more flexible upon inhibitor binding in CoV-1, while it becomes less flexible in the CoV-2 mPro. Upon inspection, we show that, on average, the dynamic flexibility of the sites substituted from CoV-1 to CoV-2 changes significantly less than the average calculated across all residues within the structure, indicating that the differences in behaviors between the two systems is likely the result of allosteric influence, in which the new substitutions in CoV-2 induce flexibility and dynamic changes elsewhere in the structure.