Molecular mechanisms underlying enhanced ACE-2-RBD stability in SARS-CoV-2 variants: The impact of key SARS-CoV-2 RBD...

Viruses undergo mutations over time, most of which have little to no impact. However, certain changes can significantly influence viral traits such as transmissibility and disease severity. Newer SARS-CoV-2 variants, including XBB.1.5, XBB.1.16, EG.5, and BA.2.86, have emerged with key mutations-D405N, G446S, N460K, and R408S-altering their biological behavior. This study explores how mutations in the receptor-binding domain (RBD) of various SARS-CoV-2 variants affect their molecular interactions, structural stability, and binding affinity with the human ACE-2 receptor (hACE-2), offering insights valuable for drug discovery. Using computational methods, binding free energy calculations revealed that variants such as BQ.1.1, CH.1.1, EG.5, EG.5.1, XBB.1, XBB.1.5, XBB.1.9.1, XBB.2.3, and BA.2.75 demonstrate stronger binding to hACE-2 than the wild-type (WT), which exhibited a binding energy of -35.24 ± 8.97 kcal/mol. This enhanced binding is linked to increased hydrogen bonds (H-bonds) and electrostatic interactions, with correlation coefficients of 0.51 and 0.28, respectively. Structural stability analyses, based on average RMSD values, showed that most mutations did not compromise the RBD-hACE-2 complex's integrity, except in variants XBB.1.5, XBB.1.9.1, and XBB.1.9.2. These findings suggest that specific mutations enhance interactions through H-bonds, hydrophobic effects, and electrostatic forces, contributing to overall stability. In summary, this study highlights that several SARS-CoV-2 variants bind more effectively to hACE-2 than the WT and earlier variants like BA.5 and BQ.1. These stronger interactions may underlie their higher transmission rates. The molecular insights provided here improve understanding of how specific mutations influence the virus's behavior, aiding future therapeutic development.