With the explosive growth of the omicron variant of the coronavirus 2 (SARS-CoV-2) severe acute respiratory syndrome, the threat of continuing the 2019 coronavirus disease (COVID-19) pandemic is great. Despite the continued success of vaccine deployments, emerging mutants threaten to extend the challenge of attenuating the virus. This is more distressing with the limited knowledge of the omicron variant.
Study: Mutations in the RBD of the Omicron variant of SARS-CoV-2 lead to stronger binding to the human ACE2 protein. Image Credit: Kateryna Kon / Shutterstock
In this context, researchers are studying the behavior of the omicron variant and understanding its pathogenesis around the world.
In a recent study, published on the Preprint Server, bioRxiv *, Using atomistic molecular dynamics simulations, Chinese researchers investigated the complex structure of the receptor binding domain (RBD) of the omicron variant with the human host receptor angiotensin-2 converting enzyme (ACE- 2).
Omicron variant of concern (VOC)
The new variant was designated VOC on November 26e, 2021, and the World Health Organization (WHO) named it (B.1.1.529) omicron. Many mutations, especially in spike proteins (which bind to the host receptor), are unprecedented. There are 15 mutations on RBD and over 30 mutations on the spike protein. About ten mutations are found at the RBD binding interface to the receptor protein, ACE2.
RBD on the spike protein is crucial for initiation of infection, leading to entry of the host cell. Since most drugs target the spike protein, it is crucial to study the impact of these mutations in the omicron variant.
In the present study, the researchers wondered whether the RBD of the omicron variant binds tightly to ACE2 and whether there is an alternative receptor that can facilitate infection of healthy cells.
For the current study, the researchers retrieved information on omicron mutations from the US CDC’s website. The researchers used computer modeling and dynamic simulations to study the interactions between SARS-CoV-2 RBD and ACE2 host proteins.
Previous studies were solved experimentally, with successful modeling and homology simulations for the RBD-ACE2 complex, and quantified the interactions – for SARS-CoV-2 infection in other animals.
Likewise, the researchers constructed and studied the structure of human ACE2 and the RBD of the omicron variant (noted ACE2-RBD??, where the exponent indicates omicron), using atomistic molecular dynamics simulations.
The researchers presented the phylogenetic tree of SARS-CoV-2, with the maximum number of spike protein mutations in the omicron variant so far. They also showed the mutation sites of receptor binding sites, especially near the ACE2 binding surface.
The researchers found that the RBD and ACE2-RBD complex structures were stable – even in the case of RBD?? where the mutations only slightly modify the structure compared to the wild type. Based on the mean square deviation (RMSD) of the structures, the researchers predicted that mutations in the omicron variant did not significantly reduce the stability of RBD; instead, the ACE2-RBD?? complex is even slightly more stable than the wild type complex.
Notably, the researchers reported that the RBD?? is more rigid than its wild type (1.5 versus 2.1, according to the average values of RMSF). While the 15 mutated residues caused fluctuations in the omicron variant compared to the wild type, the researchers observed that it is plausible that binding to ACE-2 stabilizes these residues – thus improving the stability of ACE. -2-RBD?? complex.
The researchers compared the hydrogen bond between the omicron RBD and ACE-2 with that of the wild-type bond and found that the interactions are enhanced in the omicron variant. In addition, to assess the binding affinity between ACE2 and RBD, the researchers also calculated and graphed the number of van der Waals contacts between ACE2 and RBD, as well as the buried area.
They discussed the electrostatic potential centered around the mutation sites and calculated the binding energies. The values obtained indicate a stronger bond between ACE-2 and RBD?? compared to wild type.
In conclusion, this study compared the wild-type ACE2-RBD complex system with RBD?? and found that omicron exhibits stronger binding to human ACE2 protein – performed a quantitative analysis on the stability of the binding. This suggests that the omicron variant infects cells by the same mechanism.
In addition, infectivity could be enhanced due to stronger binding interactions, although the mutation may not influence the effectiveness of the antibodies. Faced with the current variant of the omicron widespread across the world, this study provides an important understanding of the virus and its binding to the host receptor.
bioRxiv publishes preliminary scientific reports which are not peer reviewed and, therefore, should not be considered conclusive, guide clinical practice / health-related behavior, or treated as established information.