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Abstract Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), the virus causing COVID‐19, has continued to mutate and spread worldwide despite global vaccination efforts. In particular, the Omicron variant, first identified in South Africa in late November 2021, has become the dominant strain worldwide. Compared to the original strain identified in Wuhan, Omicron features 50 genetic mutations, with 15 mutations in the receptor‐binding domain (RBD) of the spike protein, which binds to the human angiotensin‐converting enzyme 2 (ACE2) receptor for viral entry. However, it is not completely understood how these mutations alter the interaction and binding strength between the Omicron RBD and ACE2. In this study, we used a combined steered molecular dynamics (SMD) simulation and experimental microscale thermophoresis (MST) approach to quantify the interaction between Omicron RBD and ACE2. We report that the Omicron brings an enhanced RBD‐ACE2 interface through N501Y, Q498R, and T478K mutations; the changes further lead to unique interaction patterns, reminiscing the features of previously dominated variants, Alpha (N501Y) and Delta (L452R and T478K). Among the Q493K and Q493R, we report that Q493R shows stronger binding to ACE2 than Q493K due to increased interactions. Our MST data confirmed that the Omicron mutations in RBD are associated with a five‐fold higher binding affinity to ACE2 compared to the RBD of the original strain. In conclusion, our results could help explain the Omicron variant's prevalence in human populations, as higher interaction forces or affinity for ACE2 likely promote greater viral binding and internalization, leading to increased infectivity.
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Structure, dynamics and free energy studies on the effect of point mutations on SARS-CoV-2 spike protein binding with ACE2 receptor
The ongoing COVID-19 pandemic continues to infect people worldwide, and the virus continues to evolve in significant ways which can pose challenges to the efficiency of available vaccines and therapeutic drugs and cause future pandemic. Therefore, it is important to investigate the binding and interaction of ACE2 with different RBD variants. A comparative study using all-atom MD simulations was conducted on ACE2 binding with 8 different RBD variants, including N501Y, E484K, P479S, T478I, S477N, N439K, K417N and N501YE484K- K417N on RBD. Based on the RMSD, RMSF, and DSSP results, overall the binding of RBD variants with ACE2 is stable, and the secondary structure of RBD and ACE2 are consistent after the point mutation. Besides that, a similar buried surface area, a consistent binding interface and a similar amount of hydrogen bonds formed between RBD and ACE2 although the exact residue pairs on the binding interface were modified. The change of binding free energy from point mutation was predicted using the free energy perturbation (FEP) method. It is found that N501Y, N439K, and K417N can strengthen the binding of RBD with ACE2, while E484K and P479S weaken the binding, and S477N and T478I have negligible effect on the binding. Point mutations modified the dynamic correlation of residues in RBD based on the dihedral angle covariance matrix calculation. Doing dynamic network analysis, a common intrinsic network community extending from the tail of RBD to central, then to the binding interface region was found, which could communicate the dynamics in the binding interface region to the tail thus to the other sections of S protein. The result can supply unique methodology and molecular insight on studying the molecular structure and dynamics of possible future pandemics and design novel drugs.
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- Award ID(s):
- 2200138
- PAR ID:
- 10474543
- Publisher / Repository:
- Plos One
- Date Published:
- Journal Name:
- PloS one
- Edition / Version:
- 1
- Volume:
- 18
- Issue:
- 10
- ISSN:
- 1932-6203
- Page Range / eLocation ID:
- e0289432
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Journal Article:
- https://doi.org/10.1371/journal.pone.0289432
