The SARS-CoV-2-Omicron variant can bind more efficiently to the ACE2 receptor


Although scientists around the world have made efforts to develop and manufacture safe and effective vaccines against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the pathogen that causes the ongoing 2019 coronavirus disease (COVID) pandemic 19) caused. , this virus continues to mutate. Shortly after the launch of the first Pfizer and Moderna vaccines, both based on the messenger ribonucleic acid (mRNA) platform, the advent of the Delta variant took the world by storm, driving cases, deaths and hospital admissions to dire levels worldwide.

To learn: The Omicron variant increases the interactions of SARS-CoV-2 spike glycoprotein with ACE2. Image source: Kryptograf /

The last identified SARS-CoV-2 variant is the Omicron variant (B.1.1.529). This variant, which was quickly named Variant of Concern (VOC) by the World Health Organization (WHO), has the highest number of mutations of all known variants; however, their biological effects have yet to be revealed.

A new study published on the subject bioRxiv * preprint server discusses the effects of the mutations of the Omicron variant on its binding efficiency to the angiotensin converting enzyme 2 (ACE2) receptor, which mediates viral attachment and entry into host cells.


The rapid rate at which infections from the Omicron VOC of SARS-CoV-2 are increasing since its recent emergence has alarmed health officials and governments around the world. Almost as a reflex action, many countries immediately blacklisted flights and other entry routes from numerous countries in order to reduce the transmission of this new variant.

The Omicron VOC has 30 mutations on the spike glycoprotein, 14 of them on the receptor binding domain (RBD) of the spike protein. The RBD is crucial for virus-receptor binding through its interactions with the peptidase domain (PD) of the ACE2 receptor.

The numerous new and common mutations of the spike glycoprotein, particularly the RBD, the omicron variant, cause differences in the way it interacts with the ACE2-PD, thus affecting the rate and ease of virus entry. Spike protein’s RBD is the target of neutralizing antibodies produced by natural infection or vaccination with any vaccine currently available.

The mutations observed on the RBD of this new variant are exposed on the surface and are attacked by antibodies and nanobodies such as H11-H4, H11-D4 and Ty1, which are currently being developed as potential therapeutics against COVID-19. Of the 15 RBD mutations, 11 are at the ACE2-PD interface. Five of these mutations were previously shown by molecular dynamics simulations (MD) to interact with corresponding residues on the PD in the wild-type virus.

These interactions include salt bridges formed between K417-D30 and E484-K31, as well as hydrogen bonds between Q493-E35, Q498-Q42, Q498-K353, and Y505-E37. There is currently insufficient data to specify the effect of the Omicron mutations on the strength of the bond between Omicron RBD and ACE2. It is also currently unclear whether antibodies triggered by earlier variants of SARS-CoV-2 can neutralize the ACE2-RBD interactions and thus prevent the virus from entering.

To answer this question, the researchers performed Allatom simulations of the PD under suitable conditions.

Study results

The simulations were performed in the presence of a total of 200,000 explicit water and ions as well as the full length sugar molecules on both the RBD and ACE2 molecules. A total of 900 nanosecond (ns) simulation length was obtained using the same methods previously used to derive MD simulations of the wild type strain and both alpha and beta VOCs.

The researchers found that the interactions between the Omicron RBD and the ACE2 PD were much larger when compared to the wild-type RBD. This is due to a 250% increase in the total number of salt bridges, with seven new salt bridges being formed with the loss of two from the wild-type RBD-ACE2 interaction network.

In the meantime, the ten hydrophobic interactions formed by the wild-type variant were preserved while another was added between Y501-Y41 for a 10% increase. The hydrogen bond at the receptor-spike interface was decreased for an overall reduction of 10% compared to the wild type, which showed eight bonds, six of which occurred with the Omicron variant. Interestingly, all but one of these six bonds were newly formed hydrogen bonds that were not observed in the wild-type RBD-ACE2 interactions.

The conformation-based binding energies at the receptor binding interface for the two variants were estimated using the Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) method. In connection with the four simulation sets of the RBD-PD of the Omicron variant, this method showed an increase in the binding energy of 44% for the Omicron variant compared to the wild-type strain of SARS-CoV-2.

In the wild-type variant, the salt bridges occurred mainly at the interface of the contact regions (CR) CR1 and CR2, with most of the hydrogen bonds being present on CR3 and hydrophobic bonds on CR1. The mutations of the Omicron RBD have resulted in a more extensive and widespread network of bonds that extends to both sides of the interaction surface.

Localization of RBD mutations for the Omicron variant.
Localization of RBD mutations for the Omicron variant.


The results of the simulations and calculations presented in the current study show that the Omicron RBDs bind the ACE2 receptor more efficiently and thus infect the host cells more easily. More precisely, the network of lateral interactions around the interface of the RBD-PD for the Omicron variant is distributed over a larger area compared to the wild-type strain.

Second, the mutations in the Omicron variant seem to lead to a change in the distribution of the interaction network between the RBD virus and its binding receptor, the ACE2 molecule, on the PD.

The changes in the area of ​​interaction and the type and position of bonds could potentially change the way the virus binds to the receptor. It could also affect neutralization by therapeutic or vaccine-induced neutralizing antibodies and nanobodies.

For example, the E484K mutation could disrupt the formation of the salt bridge between E484-R52 and the hydrogen bond between E484-S57 by therapeutics such as H11-H4 or H11-D4. The same mutation can also eliminate the hydrogen bonds E484-N56 and E484-Y335 in Ty1.

This would prevent efficient binding and neutralization of the virus by these antibodies and nanobodies. In addition, the presence of the Q493R mutation could lead to the lack of hydrogen bonds Q493-Y104 and Q493-S104 in H11-H4 and H11-D4, respectively.

It is clear that the influence of these and other mutations on the susceptibility of the Omicron VOC to antibody-mediated neutralization needs to be clarified in future research.

*Important NOTE

bioRxiv publishes preliminary scientific reports that have not been peer-reviewed and should therefore not be considered conclusive, that guide clinical practice / health-related behavior or should be treated as established information.


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