In a recent study posted to the bioRxiv* preprint server, researchers evaluated the interactions of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron and wild-type (wt) variants with human angiotensin-converting enzyme 2 (hACE2) receptor.
Study: Improved binding affinity of the Omicron's spike protein with hACE2 receptor is the key factor behind its increased virulence. Image Credit: Fit Ztudio/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
Significance of the Omicron variant
A novel SARS-CoV-2 variant called Omicron identified in South Africa in November 2021 was later classified as a variant of concern (VOC) due to a large number of mutations in its spike (S) protein receptor-binding domain (RBD) compared to other SARS-CoV-2 variants like the wt, Alpha, and Delta. There is a massive surge in the COVID-19 cases after the emergence of the Omicron variant, which poses a major threat to public health. Due to the changes in Omicron’s genomic sequence, it is more transmissible than the other SARS-CoV-2 variants, which highlights the importance of more in-depth studies on its mutation pattern and pathogenesis to develop effective treatment strategies.
About the study
In the present study, the authors determined the interactions between the RBD of both SARS-CoV-2 wt and Omicron variants with the hACE2 receptor using molecular dynamics (MD) studies and binding free energy calculations based on molecular mechanics-generalized born surface area approach (MM-GBSA).
The receptor-binding motif (RBM) changes in all of the SARS-CoV-2 variants were determined by a comparative analysis. The data regarding the RBM sequences of the SARS-CoV-2 variants were collected from the NCBI database using the BlastP program. The redundant sequences were removed, and the remaining sequences were aligned through the EBI-MUSCLE program.
The RBD model structure of Omicron for the computational modeling was obtained by integrating 15 RBD substitutions (G496S, S371L, S373P, S375F, Y505H, N440K, G446S, S477N, T478K, E484A, 326 Q493R, G339D, Q498R, N501Y, and K417N) into the original resolved crystal structure using PyMOL software, which was then energy minimized for the MD studies and binding free energy calculations.
The protein-protein interaction of the SARS-CoV-2 Omicron and wt variants RBD with hACE2 receptor were explored and compared using MD simulation studies. During MD simulations of the RBD-hACE2 complexes by the AMBER 18.0 package, f14SB force field parameters were applied to the proteins. These complexes were solvated with water molecules and neutralized with counterions in an orthorhombic simulation box and low-temperature simulations were performed.
The non-covalent intermolecular interactions were analyzed using UCSF Chimera and VMD software. Subsequently, the binding free energies of Omicron and wt S RBD with the hACE2 receptor were computed using MM-GBSA calculations.
Results
The results indicated that the RBM sequence of the SARS-CoV-2 variants including Omicron has various amino acids substitutions in 22 different positions in the comparative sequence analysis.
A total of 10 mutations were identified in Omicron RBM: E484A, G446S, G496S, T478K, N440K, Q493R, S477N, Q498R, Y505H, and N501Y. Among the 10 mutations, six at positions G496S, G446S, Y505H, Q493R, Q498R, and E484A were unique for Omicron and the remaining four mutations were also present in other SARS-CoV-2 variants.
During the MD simulations, the RBD:hACE2 complexes of Omicron and wt variants showed some instability in the loop regions. However, the computed root mean square fluctuation (RMSF) indicated that the conformational flexibility of the Omicron variant RBD:hACE2 complex was not altered when compared to the wt RBD:hACE2 complex.
The binding free energy of Omicron S protein with the hACE2 receptor was less than -8.6 kcal/mol compared to wt S protein affinity with the hACE2 receptor. Between the R493 and R498 residues of Omicron RBD, strong electrostatic interactions and hydrogen bonding were observed with D30/E35 and D38 residues of the hACE2 receptor RBD, respectively.
Apart from that, various other mutated amino acids in Omicron RBD including S496 and H505 had hydrogen bonding with the hACE2 receptor.,. The pi-stacking interaction between the RBD and hACE2 tyrosine residues (RBD-Tyr501: hACE2-Tyr41) was identified in the Omicron RBD:hACE2 complex.
Conclusion
The study provided detailed information about the molecular level binding interaction pattern of the SARS-CoV-2 Omicron and wt variant with the hACE2 receptor.
The differences between the binding free energy of the SARS-CoV-2 Omicron and the wt variant indicated that the S protein of Omicron has a higher binding affinity for the hACE2 receptor resulting in a higher infection rate.
Similarly, mutated residues of Omicron RBD had strong interactions with the amino acid sequences of the hACE2 receptor. The pi-stacking interaction observed in the Omicron RBD:hACE2 complex was one of the key interactions stabilizing the complex formation.
This detailed information about the SARS-CoV-2 Omicron and wt variants’ RBD:hACE2 complex structure, residue wise contributions to binding free energy, and the binding mode help understand the transmissibility of Omicron and develop and optimize antiviral therapies against COVID-19.
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 9 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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