Abstract
The COVID-19 pandemic, triggered by the SARS-CoV-2 virus, has resulted in nearly 630 million cases and 6.60 million fatalities globally, as of November 2022. SARS-CoV-2, a species of the Coronaviridae family, has a single-stranded positive-sense RNA genome as well as four main structural proteins (S, E, M, and N) required for viral entrance into target cells. The spike protein (S) influences this entry through interactions with human angiotensin-converting enzyme 2 (hACE2) receptor. The World Health Organization (WHO) recognized numerous variants of concern (VOCs) that involve Alpha, Beta, Gamma, Delta, and Omicron, having multiple mutations within the spike protein, altering infection rates and immunity evasion. The Omicron variant, featuring 50 mutations, mainly within the spike protein's receptor-binding domain (RBD), has a higher transmission rate as compared to other variants. This study focused on two recent Omicron subvariants, XBB.1.5 and CH.1.1, which are known for their high affinity for the human ACE2 receptor. Utilizing an in silico strategy, a total of 1.65 μs molecular dynamics (MD) simulations were performed to assess the stability as well as binding details of these subvariants along with the wild-type Omicron variants. The comprehensive structural stability of the spike protein-hACE2 complexes was evaluated by using numerous parameters including root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), radius of gyration (R (g)), and principal component analysis (PCA). Moreover, the binding free energies have been determined using the MM-GBSA approach to provide insights into the binding affinities of these variants. Evaluation revealed that the unbound mutant frameworks (SM and TM) displayed higher degrees of instability in comparison to the wild-type (WT) Omicron variant. In contrast, the WT-hACE2 of the Omicron variant complex was less stable than the subvariants, SM-hACE2 and TM-hACE2 complexes. Binding free energy calculations employing MM-PBSA disclosed higher binding energy values for the SM-hACE2 and TM-hACE2 complexes, suggesting a more stable and ordered binding interaction. The observed increase in transmissibility of the new XBB.1.5 and CH.1.1 subvariants, in comparison to the wild-type Omicron, appears to be due to this greater stability and ordered binding.