Structural basis of Omicron immune evasion: A comparative computational study

Abstract

Background: The vaccines used against SARS-CoV-2 by now have been able to develop some neutralising antibodies in the vaccinated population and their effectiveness has been challenged by the emergence of the new strains with numerous mutations in the spike protein of SARS-CoV-2. Since S protein is the major immunogenic protein of the virus which contains Receptor Binding Domain (RBD) that interacts with the human Angiotensin-Converting Enzyme 2 (ACE2) receptors, any mutations in this region should affect the neutralisation potential of the antibodies leading to the immune evasion. Several variants of concern of the virus have emerged so far, amongst which the most critical are Delta and recently reported Omicron. In this study, we have mapped and reported mutations on the modelled RBD and evaluated binding affinities of various human antibodies with it.

Method: Docking and molecular dynamics simulation studies have been used to explore the effect of mutations on the structure of RBD and RBD-antibody interaction.

Results: These analyses show that the mutations mostly at the interface of a nearby region lower the binding affinity of the antibody by ten to forty percent, with a downfall in the number of interactions formed as a whole. It implies the generation of immune escape variants.

Conclusions: Notable mutations and their effect was characterised that explain the structural basis of antibody efficacy in Delta and a compromised neutralisation effect for the Omicron variant. Thus, our results pave the way for robust vaccine design that can be effective for many variants.

Keywords: Compromised neutralisation; Molecular docking; Molecular dynamics simulations; Omicron; SARS-CoV-2 variants.

Graphical abstract

Fig. 1

Surface plots showing crystal structure of the spike protein RBD (wild type) in complex with five antibodies binding at their respective binding sites (epitopes) (A) Front view and (B) Rear view for the wild type strain. Surface plot showing mutated residues highlighted in green colour, for Delta (C. Front and D. Rear view) and Omicron (E. Front and F. Rear view). Scientific names of the antibodies along with PDB IDs are annotated.

Fig. 2

Superposed structures of spike RBD before (orange) and after (cyan) MD simulations in the strains (A) Wild Type (B) Delta (C) Omicron. Location of mutated residues are depicted by green colour spheres. (D) Superposed structure of the wild type, delta and omicron spike RBD depicting impact of mutations on the protein structure (Magenta = Wild Type, Grey = Delta and Blue = Omicron variant. C-alpha atoms of mutated residues are shown in red (for delta) and green (for omicron) colour spheres.).

Fig. 3

Ribbon and surface diagrams showing the interface region of interaction between the spike RBD (tan) and the neutralising antibody with its heavy and light chain (violet) complex (for antibody CC12.1) for (A) Wild Type (B) Delta and (C) Omicron variant. Interacting residues of the spike RBD, the mutated residues and the antibody interacting residues are displayed in red, green and cyan colour respectively. RBD residues which are mutated and interact with antibodies are shown in blue. Interacting residues present in the vicinity (6 Å) of the mutated residues of the spike RBD are shown in orange.

Fig. 4

2D plot showing the interface region of interaction between the spike RBD and the neutralising antibody CC12.1 for (A) Delta and (B) Omicron variant. RBD residues which are mutated and interact with antibodies are highlighted by a blue circle. Interacting residues present in the vicinity (6 Å) of the mutated residues of the spike RBD are encircled in orange.

Fig. 5

(A) RMSD profile of RBD domain in the holo state (C-alpha atoms of RBD-domain in the holo complex after fitting to them), distributions of (B) SASA from RBD interface, (C) SASA from antibody interface and (D) number of contacts. WT, Delta and Omicron strains are displayed in blue, green and orange colour respectively.

Fig. 6

Residue wise contacts and their stabilities during last 75% simulation time for (A) RBD interface and (B) antibody interface. WT, Delta and Omicron strains are displayed in blue, green and orange colour respectively. Data for all three sets of simulations are displayed separately.