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The iNatureSARS-CoV-2 Omicron variant (Omicron, B.
1.
1.
529) has received great attention from the world due to its multiple mutations that may have effects on transmissibility and immune evasion
.

Compared to wild type (WT), Omicron carries up to 30 single point mutations, 3 deletion mutations and 1 insertion mutation on its spike protein
.

For comparison, the current major variant, Delta (B.
1.
617.
2), has only 2 mutations (L452R and T478K) in its RBM, and sometimes additional K417N and E484K mutations
.

Therefore, Omicron variants may significantly affect binding affinity for ACE2 and the effectiveness of currently available mAbs
.

Therefore, Omicron mutants have attracted a lot of attention, and many countries have imposed entry restrictions to prevent their rapid spread
.

However, the infectivity and immune evasion risks of Omicron have not been properly assessed
.

On January 5, 2022, Xu Zhijian, Zhu Weiliang and Gong Likun of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences jointly published an online article entitled "SARS-CoV-2 Omicron RBD shows weaker binding affinity than the currently dominant Delta variant to human ACE2", which showed that the Omicron variant has comparable binding affinity to human ACE2 compared to the wild-type SARS-CoV-2 by both molecular dynamics simulations and ELISA bioassay results , but much weaker than the Delta variant
.

 Therefore, if the transmissibility depends mainly on binding affinity, the Omicron variant may have similar infectivity to the WT virus, but milder than the Delta
.

 Furthermore, molecular dynamics simulations showed that the new variant Omicron has a high risk of immune evasion
.

Therefore, Omicron's high risk of immune evasion may make it susceptible to transmission, and Omicron should be closely watched
.

In addition, on December 28, 2021, a team including Xu Huaqiang and Yin Wanchao from Shanghai Institute of Materia Medica, Chinese Academy of Sciences jointly published a non-peer-reviewed article entitled "Structures of the Omicron Spike trimer with ACE2 and an anti-Omicron" on the preprint platform bioRxiv.
Antibody" research paper, which reports the structure of the Omicron spike trimer by itself or in complex with ACE2 and an anti-Omicron antibody
.

These structures show that most Omicron mutations are located on the surface of the spike protein, which confer stronger ACE2 binding but resistance to many therapeutic antibodies
.

Importantly, the closed conformation of the RBD and Omicron spike trimers is thermodynamically unstable, making the spike trimer prone to random open conformations
.

Unusual RBD-RBD interactions in the ACE2-spike complex unique to Omicron were observed to support the open conformation and ACE2 binding, providing the basis for Omicron's higher infectivity
.

A broad-spectrum therapeutic antibody that has completed Phase 1 clinical trials was found to interact with the same two RBDs to inhibit ACE2 binding in a pattern different from all previous antibodies, providing potent inhibition of Omicron by this antibody Structural basis
.

Together with biochemical data, the structure provides important insights into Omicron's higher infectivity, antibody evasion and inhibition (click to read)
.

The SARS-CoV-2 Omicron variant (B.
1.
1.
529) has received great attention from the world due to its multiple mutations that may have implications for transmissibility and immune evasion
.

Compared to wild type (WT), Omicron carries up to 30 single point mutations, 3 deletion mutations and 1 insertion mutation on its spike protein
.

Strikingly, 15 mutations were observed in the Omicron receptor-binding domain (RBD), 10 of which were located in receptors that directly interact with human angiotensin-converting enzyme 2 (ACE2) and most monoclonal antibodies (mAbs).
body binding motif (RBM)
.

For comparison, the current major variant, Delta (B.
1.
617.
2), has only 2 mutations (L452R and T478K) in its RBM, and sometimes additional K417N and E484K mutations
.

Therefore, Omicron variants may significantly affect binding affinity for ACE2 and the effectiveness of currently available mAbs
.

Therefore, Omicron mutants have attracted a lot of attention, and many countries have imposed entry restrictions to prevent their rapid spread
.

However, the infectivity and immune evasion risks of Omicron have not been properly assessed
.

The spike protein of WT SARS-CoV-2 has 1273 amino acids, its RBD consists of residues 319-541, and its RBM consists of residues 437-507, and the currently dominant Delta variant has only 4 mutations
.

The RBD (RBDDelta) mutation is much smaller than the Omicron RBD (RBDOmicron)
.

It can be seen that the 15 mutations of RBDOmicron are not evenly distributed in the RBD, but concentrated in its RBM, with 10 residues, namely N440K, G446S, S477N, T478K, E484A, Q493K, G496S, Q498R, Y505H
.

By examining the effect of single mutations on ACE2 binding affinity reported by Bloom et al.
, it was found that nine RBDOmicron mutations (S371L, S373P, S375F, K417N, G446S, E484A, G496S, Q498R, Y505H) should reduce ACE2 binding affinity, while the other six Mutations (G339D, N440K, S477N, T478K, Q493K, N501Y) should increase binding affinity, leading to challenges in predicting their transmissibility and potential immune evasion risk
.

Therefore, molecular dynamics (MD) simulations and ELISA bioassays were employed to investigate the binding affinity between WT/Delta/Omicron RBD and ACE2/mAb
.

Binding affinity of ACE2 to RBD of WT, Delta and Omicron variants (Figure from Signal Transduction and Targeted Therapy) Experimentally, this study measured the affinity of human ACE2 for RBDWT, RBDDelta and RBDOmicron, respectively, by using a non-competitive ELISA method Constant (Kaff)
.

The determined Kaff values ​​for ACE2-RBDWT, ACE2-RBDDelta and ACE2-RBDOmicron were 6.
01 ± 3.
02 × 107, 26.
91 ± 0.
46 × 107 and 0.
37 ± 4.
66 × 107 , respectively
.

Statistically, the Delta variant was significantly stronger than WT and Omicron, while there was no significant difference between WT and Omicron
.

To assess the potential immune evasion risk of the Omicron variants, the binding affinities between the five mAbs and the WT/Delta/Omicron RBD were calculated by the MD simulation-based MM/GBSA method
.

Notably, RBDOmicron had much weaker binding affinity for the two introduced monoclonal antibodies, indicating a high risk of immune evasion by Omicron for both mAbs
.

To explore the details of the interaction mechanism between RBD and ACE2 at the molecular and atomic levels, the binding free energies were decomposed to each mutated residue according to the MD trajectory, and the energies of residues 498, 493, 505 and 496 in RBDOmicron were found The contribution is weaker than that of WT, while the energy contribution of Y501 in Omicron is much stronger than that of N501 in WT
.

The opposite effects complicate changes in the interaction between RBDOmicron and ACE2, but ultimately result in similar binding affinity of RBDOmicron-ACE2 to RBDWT-ACE2
.

Taken together, both MD simulation and ELISA bioassay results indicate that the Omicron variant has comparable binding affinity to human ACE2 compared to wild-type SARS-CoV-2, but much weaker than the Delta variant
.

Therefore, if the transmissibility depends mainly on binding affinity, the Omicron variant may have similar infectivity to the WT virus, but milder than the Delta
.

Furthermore, MD simulations showed that the new variant Omicron has a high risk of immune evasion
.

Therefore, Omicron's high risk of immune evasion may make it susceptible to transmission, and Omicron should be closely watched
.

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