Variability in SARS-CoV-2 Spike Protein Sequences: Impact on Receptor Binding and Immunotherapeutic Strategies

Background: The emergence of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, notably Omicron and Delta, necessitates a detailed analysis of the amino acid substitutions occurring within the spike (S) protein. The substitutions mentioned above are crucial in regulating the interactions between the virus and its host receptor angiotensin-converting enzyme 2 (ACE2), in addition to impacting the effectiveness of monoclonal antibodies (mAbs) used in therapy. Methods: In this paper, we employed computational mutational analysis using PremPS to predict the stability scores of the S protein. Our analysis highlighted several key mutations, including G181V and A222V, which exhibited significant alterations in stability, particularly within the N-terminal domain (NTD), and were notably prevalent in the Omicron variant. To further elucidate the impact of these mutations, we conducted docking simulations employing HADDOCK 2.4 to assess the binding affinity between the Omicron receptor-binding domain (RBD) and ACE2. Results: Our outcomes emerged that the Omicron RBD has a stronger attraction to ACE2, driven by mutations such as Q493R, Q498R, S477N, T478K, G496S and L452R, which significantly influenced the RBD-ACE2 complex dynamics. Additionally, we ascertained the potential for immune evasion by these mutations through docking simulations with mAbs. Our findings identified specific interactions between mutations like L452R, E484Q/A and Q493R with mAbs, suggesting their potential to evade immune recognition. Conclusions: In summary, our paper provides insight into the complex connection between the fluctuation of the SARS-CoV-2 S protein, receptor binding dynamics, and immunotherapeutic efficacy. These insights are essential for guiding the development of novel therapeutics and informing public health strategies aimed at combating the ongoing COVID-19 pandemic.