Structural analysis of spike proteins from SARS-CoV-2 variants of concern highlighting their functional alterations

Abstract

Aim: Mutations in the SARS-CoV-2 spike (S) protein have dramatically changed the transmissibility and pathogenicity of the virus. Therefore, we studied the binding affinity of Omicron spike-receptor binding domain (S-RBD) with human ACE2 receptor. Materials & methods: We used pyDockWEB and HADDOCK 2.4 docking for our study. Results: Computational docking indicated higher binding affinity of Omicron S-RBD as compared with wild-type SARS-CoV-2 and Delta S-RBD with ACE2. Interface analysis suggested four mutated residues of Omicron S-RBD for its enhanced binding. We also showed decreased binding affinity of Omicron and Delta S-RBDs with monoclonal antibodies. Conclusion: Compared with wild-type SARS-CoV-2, Omicron S-RBD exhibit higher binding with ACE2 and lower affinity against monoclonal antibodies.

Keywords: ACE2; Delta; Omicron; RBD; SARS-CoV-2; monoclonal antibodies; mutations; spike.

Figure 1.. Docking of SARS-CoV-2, Delta and Omicron Spike receptor binding domain with ACE2 receptor.

(A) Interface residues between docked complex of SARS-CoV-2 Spike RBD and ACE2 receptor. (B) Interface residues between docked complex of Delta Spike RBD and ACE2 receptor. (C) Interface residues between docked complex of Omicron Spike RBD and ACE2 receptor. SARS-CoV-2 Spike RBD is shown in light blue; Delta Spike RBD is shown in orange; Omicron Spike RBD is shown in dark blue; ACE2 is shown in pink. Interface residues between docked complex of Spike RBD and ACE2 are highlighted in green. RBD: Receptor binding domain.

Figure 2.. Docking of Spike receptor binding domain of SARS-CoV-2, Delta and Omicron with mAbs.

(A) pyDockWEB analysis of Bamlanivimab Fab (HC&LC) against S-RBD of (Ai) SARS-CoV-2, (Aii) Delta and (Aiii) Omicron. (B) pyDockWEB analysis of Casirivimab Fab (HC&LC) against S-RBD of (Bi) SARS-CoV-2, (Bii) Delta and (Biii) Omicron. (C) pyDockWEB analysis of Etesevimab Fab (HC&LC) against S-RBD of (Ci) SARS-CoV-2, (Cii) Delta and (Ciii) Omicron. SARS-CoV-2 Spike RBD is shown in light blue; Delta Spike RBD is shown in orange; Omicron spike RBD is shown in dark blue; bamlanivimab Fab heavy chain is shown in dark green; light chain is shown in light red; Casirivimab Fab heavy chain is shown in light green; light chain is shown in maroon; etesevimab Fab heavy chain is shown in violet; light chain is shown in dark yellow. Fab: Fragment antigen-binding region; HC: Heavy chain; LC: Light chain; RBD: Receptor binding domain.