Computational analysis of the effect of SARS-CoV-2 Omicron variant spike protein mutations

By Dr. Ramya Dwivedi, Ph.D.Reviewed by Aimee MolineuxDec 20 2021

In a recent study, researchers used computational structural biology methods to analyze the role of mutations in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant, Omicron, and the infectivity and immune escape properties.

The study published on the preprint server bioRxiv* evaluates different structures of the Omicron’s Spike protein and its binding with the host receptor angiotensin-converting enzyme (ACE-2), and several antibodies.

This news article was a review of a preliminary scientific report that had not undergone peer-review at the time of publication. Since its initial publication, the scientific report has now been peer reviewed and accepted for publication in a Scientific Journal. Links to the preliminary and peer-reviewed reports are available in the Sources section at the bottom of this article. View Sources

While most antibody epitopes and mutations are within the S-ACE2 interface, the results from this study suggest that these mutations within the RBD of Omicron may cause only partial immune escape, at the expense of reduced ACE2 binding affinity and bind strongly with most antibodies.

Background

The SARS-CoV-2 infection caused over 271.9 million confirmed cases of Coronavirus Disease 2019 (COVID-19), including over 5.3 million deaths. Despite mitigating efforts across the world, emerging variants continue to threaten the health of individuals, burden healthcare support, and destabilize the economy.

The recent SARS-CoV-2 variant (B.1.1.529), named Omicron, has again raised serious concerns as it rapidly spreads worldwide, despite vaccination rollouts and other non-pharmaceutical interventions.

It was first sequenced by the Botswana Harvard HIV Reference Laboratory in South Africa on the 22nd November 2021 (GISAID: EPI_ISL_6752027) and was declared as a variant of concern with the designation Omicron on 26th November 2021, by the World Health Organization (WHO).

Compared to Wuhan-Hu-1, the omicron variant had high mutations - particularly, 32 mutations in the Spike protein, which binds to the host ACE-2 to gain entry into human cells. Importantly, 15 of these mutations occur in the receptor-binding domain (RBD) - a site critical to ACE-2 interaction and epitope for most antibodies. Therefore, these mutations in the omicron variant also raise major concerns of immune escape.

Further, like Alpha and Delta variants, omicron has similar mutations at the furin cleavage site outside the RBD. This causes higher fusogenic potential, increasing the virus’s infectivity.

Therefore, based on the knowledge of the mutations in omicron, it is expected to be a stronger variant of concern. While immune escape studies are extensively undertaken, the present study computationally investigates the mutations on the Spike protein, focusing on understanding how individual amino acid changes contribute to both immune escapes and increased viral infectivity.

This study attempts to,

provide a robust interpretation of the dangers of new variants based on the amino acid changes and the roles played by the residues, as opposed to concerns due to total numbers of non-synonymous changes alone.”

Findings

As of November 25, the researchers defined a consensus set of mutations from 77 sequences assigned as Omicron in GISAID.

The mutations employed in the present study are the following (part of the definition of the Omicron S protein): A67V, T95I, G142D, L212I, G339D, S371L, S373P, S375F, K417N, N440K, G446S, S477N, T478K, E484A, Q493R, G496S, Q498R, N501Y, Y505H, T547K, D614G, H655Y, N679K, P681H, N764K, D796Y, N856K, Q954H, N969K, L981F. The researchers reported that the structure of the open and closed states of the trimeric S Omicron protein as well as Omicron S in complex with ACE2 and the antibodies was as described in a previous study.

They created structural models of the Omicron S protein in open and closed states, interacting with ACE-2 and for each of 77 complexes of S bound to different antibodies with known structures.

Employing Dynamical Signatures (DS) and Vibrational Difference Scores (VDS), the researchers evaluated the propensity of S variants to favor the open state. The researchers calculated the Dynamical Signature of the Omicron S protein presenting a large rigidification of the open state and some increase of flexibility of the closed state, with a Vibrational Difference Score of 7.66x10^-1 J.K^-1. Compared with previous studies, this is the largest score of all variants, indicating favorable interactions with ACE2.

Compared to the interactions in the wild-type, the researchers observed that the interactions in the omicron S with ACE-2 or with the antibodies were favorable and non-favorable interactions gained and lost, affecting the entire interface and not just the mutated region.

Thus, to understand the effect of mutation on binding affinity based on these interactions, the researchers introduced the Binding Influence Score (BIS), which combines the net change in interactions of a residue and those of its neighbors, except for the neighbor residues that are themselves mutating.

The researchers reported that the BIS shows excellent correlation with experimental data (Pearson correlation coefficient of 0.87) on individual mutations in the ACE2 interface for the Alpha, Beta, Gamma, Delta, and Omicron variants combined. Interestingly, the BIS showed that all mutations apart from N501Y in the protein-protein interface reduced ACE2 binding affinity.

Further, the majority of the antibodies interact with the SARS-CoV-2 S protein through the same interface as that of binding to ACE2. To evaluate the propensity for immune escape, the researchers calculated the net change of interactions and found that in only 28% of the S-antibody complexes some level of immune escape is possible.

Notably, the researchers hinted that SARS-CoV-2 is evolving selective residues such that it,

facilitates immune escape at the expense of ACE2 binding affinity.”

Conclusion

This study highlights the potential evolutionary trade-off observed in the omicron variant, detailing the dynamics of the protein structure, its interactions, and subsequent effects.

Although the mutations in the Omicron S-ACE2 interface decrease the ACE2 interaction affinity, and may negatively affect the spike-antibody binding, the calculations suggested immune escape. However, the interactions with the majority of the antibodies tested here appear stronger.

This news article was a review of a preliminary scientific report that had not undergone peer-review at the time of publication. Since its initial publication, the scientific report has now been peer reviewed and accepted for publication in a Scientific Journal. Links to the preliminary and peer-reviewed reports are available in the Sources section at the bottom of this article. View Sources