In a recent study submitted to the bioRxiv* Preprint server, the researchers examined the interactions of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) omicron and wild-type (wt) variants with the human angiotensin converting enzyme 2 (hACE2) receptor.
Meaning 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) other SARS-CoV-2 variants such as the Watchtower, Alpha and Delta. There is a massive spike in COVID-19 cases following the advent of the Omicron variant, which poses a major public health threat. Because of the changes in Omicron’s genomic sequence, it is more transmissible than the other SARS-CoV-2 variants, underscoring the importance of in-depth studies of its mutation pattern and pathogenesis in order to develop effective treatment strategies.
About the study
In the present study, the authors examined the interactions between the RBD of SARS-CoV-2 wt and Omicron variants with the hACE2 receptor using molecular dynamics (MD) studies and calculations of the binding free energy based on the generalized approach of the native surface determined (MM-GBSA).
The changes in the receptor binding motif (RBM) in all SARS-CoV-2 variants were determined by a comparative analysis. The data on 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 by the EBI-MUSCLE program.
Omicron’s RBD model structure for computational modeling was enhanced by the integration of 15 RBD substitutions (G496S, S371L, S373P, S375F, Y505H, N440K, G446S, S477N, T478K, E484A, 326 Q493R, G339D, Q17501R, N) and K4 received. into the originally resolved crystal structure with PyMOL software, which was then energy-minimized for the MD studies and the calculation of the binding free energy.
The protein-protein interaction of the SARS-CoV-2 Omicron and the wt variant RBD with the hACE2 receptor were examined and compared with the help of MD simulation studies. During MD simulations of the RBD-hACE2 complexes by the AMBER 18.0 package, the 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 with UCSF Chimera and VMD software. The free binding energies of Omicron and wt S RBD with the hACE2 receptor were then calculated using MM-GBSA calculations.
The results showed that the RBM sequence of the SARS-CoV-2 variants including Omicron has different amino acid substitutions at 22 different positions in the comparative sequence analysis.
A total of 10 mutations have been identified in Omicron RBM: E484A, G446S, G496S, T478K, N440K, Q493R, S477N, Q498R, Y505H and N501Y. Of the 10 mutations, six at positions G496S, G446S, Y505H, Q493R, Q498R and E484A were unique to Omicron and the remaining four mutations were also present in other SARS-CoV-2 variants.
During the MD simulations, the RBD: hACE2 complexes of the Omicron and wt variants showed some instability in the loop regions. However, the calculated root mean square fluctuation (RMSF) showed that the conformational flexibility of the RBD: hACE2 complex of the Omicron variant was not changed in comparison to the wt-RBD: hACE2 complex.
The free energy of binding of the Omicron-S protein to the hACE2 receptor was less than -8.6 kcal / mol compared to the wt-S protein affinity with the hACE2 receptor. Strong electrostatic interactions and hydrogen bonds with residues D30 / E35 and D38 of the hACE2 receptor RBD were observed between residues R493 and R498 of Omicron RBD.
Aside from that, several other mutated amino acids in Omicron RBD, including S496 and H505, had hydrogen bonds 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.
The study provided detailed information about the binding interaction pattern at the molecular level of the SARS-CoV-2 Omicron and the wt variant with the hACE2 receptor.
The differences between the free binding energy of the SARS-CoV-2 Omicron and the wt variant showed that the S protein of Omicron has a higher binding affinity for the hACE2 receptor, which leads to a higher infection rate.
Similarly, mutant 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 that stabilized the complex formation.
This detailed information about the RBD: hACE2 complex structure of the SARS-CoV-2-Omicron and wt variants, the residue-wise contributions to the binding of free energy and the binding mode, help to understand the transmissibility of Omicron and antiviral therapies against COVID-19 to develop and optimize.
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Rajender Kumar, Murugan Natarajan Arul, Vaibhav Srivastava. (2021). The improved binding affinity of the Omicron’s spike protein with the hACE2 receptor is the key factor for its increased virulence. bioRxiv. doi: https://doi.org/10.1101/2021.12.28.474338 https://www.biorxiv.org/content/10.1101/2021.12.28.474338v1