Mutational screening and energetic landscape of the Spike protein in the SARS-CoV-2 and ACE2 binding process

We investigated the molecular mechanisms that enhance the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infectivity through adaptations of the Spike protein, particularly its interactions with the Angiotensin-Converting Enzyme 2 (ACE2). We focused on the free energy of binding during the pre-fusion phase by analyzing the 17,598,328 mutation sequences accumulated in GISAID over six years since the start of the COVID-19 pandemic. The aim was to identify specific mutations in the Spike protein that may contribute to an increase in infectivity. This work systematically explored the impact of these mutations on infectivity and identified a significant conformational change in the Spike protein. The role of codon frequency on mutation rates was also evaluated, highlighting the importance of the binding strength between the Spike protein and ACE2 for viral infectivity, and the impact of mutations targeting immune evasion in promoting viral adaptability. Additionally, crystallographic structures were analyzed using quantum mechanics calculations to unveil the energy relationships within the Spike-ACE2 complex. Finally, the Alpha (B.1.1.7), Beta (B.1.351), and Omicron (BA.2) variants were analyzed within the context of the proposed strategy. Our findings allow for a clear separation between mutations that arise from the binding process and those associated with immune evasion.