Unlocking the Genetic Mysteries of SARS-CoV-2: A Deep Dive into the Sequence, Structure, and Dynamics of Mpro Mutations

Abstract A global challenge is presented by the continuous surge in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), leading to the COVID-19 pandemic. A major concern arises as SARS-CoV-2 undergoes mutations, potentially increasing its lethality for humans. Mutations in crucial replication enzymes, particularly the main protease (Mpro), add complexity to disease progression and impact the effectiveness of existing COVID-19 treatments. In this study, the thermodynamic stability of Mpro mutants was predicted using nine structure-based methods. Gibbs free energy for 109 Mpro mutants was predicted, and the top three recurrently destabilizing mutants (I106T, F140L, and A173S) across multiple methods were discovered. Analysis of secondary structure changes revealed diverse alterations and a dynamics study highlighted increased rigidity in A173S and heightened flexibility in I106T and F140L. This study sheds light on the evolving SARS-CoV-2 landscape and emphasises the potential functional consequences of specific mutants