The structural analysis of the Omicron peak reveals an immune leak similar to that of Houdini

Omicron is the latest escape variant. Not only does it escape natural and vaccine-acquired immunity, it also escapes most, but not all, neutralization of monoclonal antibodies. A recent article by Wang et al. It not only describes a novel broadly neutralizing antibody, but also provides a deep understanding of the structural properties of the Omicron Spike protein used to facilitate immune evasion while remaining sensitive to neutralization by some monoclonal antibody treatments. Here we describe some of Wang’s et al.the most surprising observations.

As has been well established, the Omicron BA.1 Spike and all subsequent variants of the Omicron family have the most mutated Spike protein of any natural variant up to this point in the pandemic. In the binding domain of the Omicron BA.1 receptor alone, there are 15 mutated sites.

Monoclonal antibodies are described by where they bind, divided into four groups: classes 1, 2, 3 and 4. Mutations in the binding domain of the Omicron receptor are located in such a way that they interfere with the binding of all four classes of antibodies. In their investigation of the 35B5 antibody, Wang et al. note that “most of the 15 mutation sites, including N501Y, G496S, K417N, Q493R and G446S … severely modify the epitope residues of class 1 and 2 mAbs. Mutations G339D and N440K are found in epitopes for mAbs class 3 … while S371L, S373P and S375F are at the RBD interface with the class 4 “mAbs.

In addition to the amino acids that modify the structural binding dynamics of the Spike, the mutations also induce electrostatic changes on the surface of the Spike. Altering the charge or polarity of a binding site further inhibits an antibody’s ability to bind, acting as a sort of shield. In particular, Wang et al. note an increase in the positive charges for the regions affecting class 1 and 2 antibodies, as well as an increase in the hydrophobic characteristics at the class 4 interface.

The Spike Micron also exhibits eight mutations in the N-terminal domain, which plays a role in the stability of the Spike. Mutations such as T95I and A67V increase hydrophobic interactions in the N-terminal domain, while other deletions such as del69-70 and insertions such as ins214EPE create disorder and antigenic shifts.

The Omicron S2 sub-region contains six other mutations. Mutations of N764K and N856K create additional hydrogen bonds and strengthen the interaction between the different domains of the Spike. Other mutations, such as D796Y and L981F, increase hydrophobic interactions in S2 structures, producing tighter packing and interaction than Spike’s trimer, which we will explore in a later article.

However, hidden workarounds exist for monoclonal antibodies that do not involve mutated Omicron residues. These are conserved amino acids that are crucial for basic SARS-CoV-2 functions.

The 35B5 antibody that Wang et al. specifically studied avoids mutated residues in the binding domain of the receptor and attacks conserved regions. This makes 35B5 and antibodies targeting conserved residues like it a major threat to Omicron replication and furthermore, any variant of SARS-CoV-2 with these conserved sequences.

The SARS-CoV-2 Spike protein is made up of a series of sheets and rings, which are structures made of linked amino acids. The stability of one of these sheets, beta 5/6, is directly related to the ACE2 binding efficiency. In their investigation of 35B5, Wang et al. found that residues R346, S349 and Y351 are found in the L2 ring, which interacts directly with amino acids in beta 5/6 and stabilizes the conformation of that sheet. An additional residue in the L2 loop, V350, inserts a hydrophobic pocket below the beta 5, providing additional support for the sheet. The researchers conclude that the amino acids conserved in L2 are crucial for beta 5/6 binding and ACE2 in general.

We note that there are mutations in the Omicron Spike protein that are known to decrease ACE2 binding affinity. McCallum et al. analyzed in detail the mutations in the binding domain of the receptor, noting that some mutations, such as lysine in asparagine at position 417 (K417N) and glutamine in arginine at position 493 (Q493R), individually reduce ACE2 binding affinity, while others such as tyrosine asparagine at position 501 (N501Y) and asparagine serine at position 477 (S477N) increase affinity.

Although, despite competing mutations in ACE2 binding efficiency, the Omicron BA.1 variant still binds 2.4 times more tightly than the wild type. In addition to mutations that increase binding affinity, it is possible that L2 residues from positions 344 to 354 are conserved to compensate for the reduced affinity mutations. The necessary storage of these residues is therefore a glaring target for 35B5 antibody or similar antibodies targeting the same region.

This is one of the many structural complexities of Omicron and SARS-CoV-2 in general. This analysis will be followed by further discussion of how Omicron differs from all previous variants of concern and interest, informing monoclonal antibody treatment moving forward.

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