A recent study posted to the bioRxiv* pre-print server analyzed the effects of the interaction between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron spike amino acid and the human angiotensin-converting enzyme 2 (ACE2) receptor or with human antibodies. 
Study: In Silico Analysis Of The Effects Of Omicron Spike Amino Acid Changes On The Interactions With Human ACE2 Receptor And Structurally Characterized Complexes With Human Antibodies. Image Credit: Kateryna Kon/Shutterstock
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
Introduction
The emergence of the SARS-CoV-2 Omicron variant of concern (VOC) has led various studies to understand the virus’s interaction with the human immune system. The knowledge of the effects of Omicron on human antibodies is important to understand the detectability, transmissibility, and epidemiology of Omicron and other SARS-CoV-2 variants.
About the study
The present study analyzed the effects of the SARS-CoV-2 Omicron spike amino acid changes on human ACE2 receptors and human antibodies.
A total of 877 sequences identified as Omicron sequences, provided by the global initiative on sharing all influenza data (GISAID), were studied to observe the amino acid changes caused by Omicron infection. Out of these, more than 30 structures of spike protein formed a complex with human ACE2. Two representative structures of these complexes were selected and characterized as being X-ray crystallography-solvable, having a resolution less than or equal to 2.50 Angstroms (Å), and having a wider coverage of the spike sequence.
Among the over 300 spike protein-antibody ensembles available in the protein data bank (PDB), 158 representative ensembles were selected based on the following criteria: i. Presence of one or more or a portion of non-redundant human antibodies in the ensemble; ii. Completeness of the spike protein; iii. Absence of mutations at the antibody interfaces; iv. RBD conformation; v. Resolution better than 4 Å.
The spike protein-antibody ensembles selected were analyzed to study the interfacial interactions between the amino acid residues belonging to each chain of spike and each antibody chain. For Omicron variant analysis, only missense mutations in the structure of the spike protein were modeled to understand the effect of these mutations on the protein. The amino acid substitutions belonging to the Omicron variant were then introduced on the structure of spike proteins, and the interface interactions were recalculated.
Results
The results show that 30 amino acid replacements were observed in the SARS-CoV-2 Omicron spike glycoprotein in the GISAID sequences studied. Among these 30 amino acids, 12 were characteristic of the Omicron samples, 15 were found within the receptor-binding domain (RBD), and ten were involved in human ACE2 receptor interactions.
The Omicron spike glycoprotein was identified to have four amino acid deletions, including a double deletion that was also detected in other SARS-CoV-2 VOCs, a triple deletion characteristic to the Omicron VOC, a single-base deletion characteristic to the Omicron VOC, and another single-base deletion detected in 20% of the Omicron samples. The study also reported an insertion which is the first insertion detected in any SARS-CoV-2 VOC.
The amino acid changes related to the Omicron variant gave rise to an increased charge of +3 in the spike region interacting with ACE2, which stabilized the interaction between ACE2-spike protein. Due to the amino acid replacements, a reduction in the number of H-bond interactions was observed between the ACE2 receptor and Omicron Spike protein.
Among the 158 representative ensembles selected from the PDB, 114 included only one antibody, 20 included two antibodies, and only one included three antibodies. The original interface interactions in 135 ensembles were affected by the amino acid replacements. The ensembles with two or three antibodies were split up to form a total of 157 spike-single antibody complexes.
Out of the 157 complexes, 134 antibodies interacted with the RBD while 23 interacted with other spike regions. A loss of interactions between the spike protein and the antibody was observed in 68 of the 157 complexes, while an increase in interactions was found in 70 out of the 157 complexes. An equal number of decreased and increased interactions were detected in 19 out of the 157 complexes.
Conclusion
The study results show that the SARS-CoV-2 Omicron spike glycoprotein underwent ten amino acid changes in residues with ACE2 interactions, out of which seven were not detected in any other VOC. The increased positive net charge of the spike protein may improve spike-ACE2 interaction, which then increases Omicron transmissibility. When compared to the protein spike-ACE2 complexes of the previous VOCs, an equilibrium of loss of existing interactions and gain of new interactions in the complexes were observed in the Omicron spike-ACE2 complexes. Therefore, the study concluded that the Omicron variant had a moderate impact on the spike-ACE2 interactions.
The researchers suggest that this approach to analyzing amino acid interactions can be further extended to study other SARS-CoV-2 proteins like the nucleocapsid protein targeted by antibodies. Enabling the availability of more 3D data structures of protein-antibody complexes can easily detect newly emerging VOCs using immuno-based tests and devices available.
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
Article Revisions
- May 10 2023 - The preprint preliminary research paper that this article was based upon was accepted for publication in a peer-reviewed Scientific Journal. This article was edited accordingly to include a link to the final peer-reviewed paper, now shown in the sources section.
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