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Omicron-VOC structure: binding and antigenicity

Receptor binding domain interaction with human ACE2
The first step in the infection pathway of covid-19 is the docking of the spike to the receptor (Angiotensin converting enzyme). Mutations in the binding motif determine the efficiency . The original glutamine (in the Wuhan and δ strains) at position 493 is replaced by arginine; so a hydrogen bond is replaced by a salt bridge . At position 498 there is also a glu-arg change; here the arg keeps a hydrogen bond and adds a salt bridge . An additional hydrogen bond is introduced by mutation G496S. Serine instead of glycine interacts with a lysine in ACE2 . The additional bonds compensate for a loss of a salt bridge between δLys 417 and ACE2; in omicron there is an asparagine which is too distant from ACE2 D30 to form any bond. The net result is a similar bonding strength of omicron to delta.

Antigenicity - omicron vs. Wuhan
Antibodies against the Wuhan-covid-strain were recovered from convalescents and cloned to monoclonal antibodies. Many of these are neutralizing antibodies apt to treat infections (some of which are commercially available). By competition experiments scientist were able to group the antibodies acting on specific regions on the surface of the coronavirus spike protein. They found five clusters (or other numbers according to the aim of the investigation) and could describe the corresponding surface areas by identifying the binding amino acids on the spike surface . This classification may seem rather academic, but it helps to sort out combinations of neutralizing antibodies for therapeutic purposes.

At the omicron-turn of the pandemic it is of interest how antibodies raised by a Wuhan-vaccination (or convalescence from a previous VOC infection) may still work on omicron. Structural and epitope data are listed for a lot of known antibodies in the IEDB database (listed in Verma & Subbarao). Of urgent interest are antibodies targeting the receptor binding domain of the spike - they will prevent binding to the host ACE2. Binding strength of prototypical antibodies in each cluster are known. Scientists calculated the binding strength of these antibodies by sophisticated algorithms in regard of the mutated spike surface of omicron. An example is shown here . Antibody CB6 binds to atoms marked yellow in the ACE2-binding region; changed amino acids in omicron vs. Wuhan are marked red (shown for one "up" RBD only). Verma & Subarrao list the energy changes of the individual components (van der Waals, electrostatic, solvation) for the exchange of the four amino acids; the net amount is a binding energy change from -92.25 kcal/mol to -51.94 kcal/mol for the mutant complex. So this antibody is useless in a fight against omicron.
Calculations for other clusters had similar results with various losses of binding energy:
  Ab REGN10933 - binding loss 23 kcal/mol
  Ab S309 - binding loss 24 kcal/mol
  Ab S2X259 - binding loss 23 kcal/mol. This antibody neutralizes the α, β, γ and ε VOCs.

Cluster 5 maps away from the receptor binding domain to the aminoterminal domain of the spike protein. Three database-antibodies (4A8, DH1050.1 and DH1052) are affected by mutations of the omicron strain . Deletion mutations in omicron are marked white for the neighboring residues. The topology of this region is severely changed by the deletions, diminishing the binding abilities of neutralizing antibodies. A detailed analysis is found in Gobeil et al.

this demonstration.

D. Ni et al, Structural analysis of the Spike of the Omicron SARS-COV-2 variant by cryo-EM and implications for immune evasion,
D. Mannar et al, SARS-CoV-2 Omicron Variant: ACE2 Binding, Cryo-EM Structure of Spike Protein-ACE2 Complex and Antibody Evasion,
J. Zhang et al, Structural and functional impact by SARS-CoV-2 Omicron spike mutations,
J. Verma & N. Subbarao, Structural insight into antibody evasion of SARS-CoV-2 omicron variant,
S. M-C. Gobeil et al, Structural diversity of the SARS-CoV-2 Omicron spike,
Spike structure: 7t9k.pdb (Mannar et al)

30-01-2022 © Rolf Bergmann