ELUCIDATION OF PERSISTENT MUTATIONAL LANDSCAPE IN SARS-CoV-2 MAIN PROTEASE: A STRUCTURAL BIOINFORMATICS ANALYSIS

Mkandawire, Winnie

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ELUCIDATION OF PERSISTENT MUTATIONAL LANDSCAPE IN SARS-CoV-2 MAIN PROTEASE: A STRUCTURAL BIOINFORMATICS ANALYSIS

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SARS-CoV-2 is a major public health burden whose spread and severity has dramatically increased causing overwhelming rise in morbidity and mortality alongside economic crisis worldwide. The virus’s Main protease (Mpro) enzyme is one of the drug targets that has been widely studied to combat coronaviruses. This protease plays a crucial role in the process of viral maturation and replication, therefore, inhibiting it would reduce viral load and thus alleviate symptom intensity. The design of robust inhibitors against the Mpro requires characterization of the fixed viral genomic mutational landscape and the populations of conformations it engenders. Studies suggest that fixed or pervasive mutations indicate evolution or adaptation of virus to its niche. Thus, central to the success of drug design efforts is developing an understanding of structural and functional variations in the enzyme, particularly as mutations become persistent and new strains emerge. In this work, we attempted to detect if the human SARS-CoV-2 Mpro is undergoing selective pressure due to pervasive mutations and tried to infer the collective effects of fixed positively selected mutations on protease functionality. We analyzed global population isolates of human SARS-CoV-2, downloaded from the GISAID database as of February 9th 2021. Overall, mutations were seen at 169 sites with each enzyme having 1-6 changes – with 16 positions showing significant persistent variations subjected to selection pressure and 11 variants having positive selection. Interestingly, these mutations showed a trend towards substitution for larger and more hydrophobic residues when compared with the wild type SARS-CoV-2 sequence. Additionally, when mapped onto the 3D structure of the reference protein, 3 of the 11 positively selected significant variations were located closer to the active site. Using in silico approaches, we speculate that these mutations may have beneficial effects to the protease functionality and hence signify adaptation of SARS-CoV-2 to the human niche. This study will help uncover evolutionary mechanisms of adaptation and resistance in SARS-CoV-2 Mpro that can be targeted with inhibitors designed to be robust to the resistance and in turn help treat this deadly infection.

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