The Omicron variant BA.2.86.1 of SARS- CoV-2 demonstrates an altered interaction network and dynamic features to enhance the interaction with the hACE2

Abstract

The SARS-CoV-2 variant BA.2.86 (Omicron) has emerged with unique mutations that may increase its transmission and infectivity. This study investigates how these mutations alter the interaction network and dynamic properties of the Omicron receptor-binding domain (RBD) compared to the wild-type virus, focusing on its binding affinity to the human ACE2 (hACE2) receptor. Protein-protein docking and all-atom molecular dynamics simulations were used to analyze structural and dynamic differences. Despite the structural similarity, the Omicron variant exhibits a distinct interaction network with new residues such as Lys353 and Arg498 that significantly enhance its binding capacity. The dynamic analysis reveals increased flexibility in the RBD, particularly in loop regions crucial for hACE2 interaction. Mutations significantly alter the secondary structure, leading to greater flexibility and conformational adaptability compared to the wild type. Binding free energy calculations confirm that the Omicron RBD has a higher binding affinity (- 70.47 kcal/mol) to hACE2 than the wild-type RBD (- 61.38 kcal/mol). These results suggest that the altered interaction network and enhanced dynamics of the Omicron variant contribute to its increased infectivity, providing insights for the development of targeted therapeutics and vaccines.

Keywords: Molecular Dynamic Simulation; Mutation; Receptor binding domain; SARS-CoV-2; Vaccine.

Fig. 1

Workflow of structural modeling and molecular dynamics simulation analysis for the Omicron BA.2.86.1 variant and Wuhan spike-RBD comparison.

Fig. 2

Structural and dynamic features of the BA.2.86 (Omicron) variant of SARS-CoV-2. (a) 3D structure of the spike glycoprotein, highlighting key domains. (b) Schematic showing the location of RBD and mutations. (c) Interaction of hACE2 with the Omicron RBD. (d) Superimposition of wild-type and BA.2.86 RBD, illustrating structural deviation (RMSD = 0.420 Å).

Fig. 3

Comparative interaction networks between the wild-type (a) and Omicron BA.2.86.1 variant (b) RBDs with hACE2, showing key alterations in hydrogen bonds and contact points that may enhance receptor binding and affect transmissibility.

Fig. 4

(A) RMSD plot comparing the wild-type (cyan) and BA.2.86.1 (red) RBD-hACE2 complexes show greater structural fluctuations in the variant, particularly in key binding residues, indicating enhanced flexibility. (B) RMSD plot of unbound wild-type (black) and BA.2.86.1 (orange) RBDs reveals increased fluctuations in the variant, suggesting a broader conformational range that may enhance adaptability and binding to hACE2. These findings suggest that the BA.2.86.1 variant may exhibit increased transmissibility and immune evasion.

Fig. 5

RMSF analysis of wild-type and variant SARS-CoV-2 RBD in complex with ACE2 and the Apo state. (A) RMSF plot comparing wild-type RBD-ACE2 (blue) and variant RBD-ACE2 (red) showing lower fluctuations in the variant complex, indicating reduced flexibility. (B) RMSF plot of unbound (Apo) wild-type RBD (black) and variant RBD (orange) with the variant displaying higher fluctuations across multiple regions, suggesting increased flexibility in the Apo state.

Fig. 6

Radius of gyration (Rg) analysis of RBD in complex with ACE2 and the Apo form (A) The variant BA.2.86.1 RBD-ACE2 complex (red) exhibits higher Rg values compared to the wild type (cyan), indicating greater conformational flexibility. (B) The Apo BA.2.86.1 RBD (orange) shows increasing Rg values over time, reflecting reduced compactness compared to the wild-type RBD (black).

Fig. 7

Structural superposition of RBD snapshots at various time intervals during the molecular dynamic simulation. (a) Structural comparison of RBD at 0 ns (green), 25 ns (cyan), and 50 ns (orange), highlighting regions of increased flexibility. (b) Superposition of RBD at 0 ns (green), 60 ns (yellow), and 100 ns (orange), showing significant deviations in the highlighted regions over time.

Fig. 8

Hydrogen bond analysis of wild-type SARS-CoV-2 and Omicron variant BA.2.86.1 RBD complexes with ACE2 receptor over a 100 ns molecular dynamics simulation. The wild-type RBDACE2 complex (blue) shows a higher and more stable number of H-bonds (8–14 on average), whereas the BA.2.86.1 variant (red) forms fewer hydrogen bonds (5–10 on average), indicating a more flexible binding interaction.