Mutations within the spike protein in Sars variants of concern
This demonstration depicts the structure of the δ variant spike protein, shown here is one protomer in the "up" conformation. Mutations differentiating δ from the Wuhan strain are schown in yellow: .
The δ variant is characterized by a shorter incubation period caused by a faster fusion of the virus with the cell membrane. At the time of the first positive PCR after infection the viral load is 10³ larger compared to other sars variants. This gain in speed may be attributed also to mutations in other parts of the virus.
Some immune evasion was detected in δ. The reasen for this are mutations in the aminoterminal domain (NTD) of the spike protein:
(tested in vitro with monoclonal antibodies isolated from COVID-19 convalescent individuals).
Here the whole spike complex
with the sugar decoration shown in brown.
The previously detected variants of concern have different mutations, projected here on the δ variant (exchanged amino acids yellow):
(exchanges orange)
(exchanges green)
(exchanges red)
In view of these mutations the omicron variant came as a surprise (mind that structural changes cannot yet be shown): . In nonstructural proteins there are another 19 mutations. In all, that is quite a number for a single new variant!
Clinical data are scarce until today, the type of mutations may indeed provoke severe immune evasions. The introduction of two prolines may have consequences for the stability of the structure.
General aspects of the spike structure:
The secondary structure is domiated by helices and pleated sheets which provokes a rather rigid structure of the protein. The "unordered" regions are flexible in theory, because the Cα-Cβ bond of an amino acid is free to be turned. A flexible structure may be fixed if neighboring cystein residues use their sulfur side chains to form disulphide bridges. The spike protein contains 15 of these . They seem essential for corona viruses: in no variant from α to µ one of the cys is exchanged. To have a closer view, use the mouse: click and zoom with the wheel and turn the molecule.
Prolin is another amino acid important for stucture and antigenicity. Because of its ring structure the Cα-Cβ bond cannot be twisted, at all pro residues the protein structure is stiffened. A large number of prolines is distributed all over the "unordered" parts of the spike (use the mouse!). All prolines seem to be essential - only in the γ-variant one P26S (deirectly beneath P25) exchange is found. In the picture the positions of the additional omicron pro are marked red. On the other side of the molecule the positions of the additional P986/7 of the vaccine spikes are in cyan.
The importance of a "framing" of antigenic epitopes by prolin was stated (http://www.mamanatur.de/diss/Poliovirus - ein Antigen.pdf). The antigenicity enhancing effect of prolines in near distance is countercted by the glycolisation of the protein - in all 40% of the surface is protected against antibodies by the sugar decoration. Sugar molecules are bound to asparagin; this amino acid is conserved as well, only asn501 is exchanged against tyr in α, β, γ, µ and ο (this position is in the receptor binding domain); in δ no bound sugar was found. In omicron also asn547 and 856 are replaced by lys . In the picture pro are marked bright brown and sugar molecules dark brown, the additional omicron pro are red. Actual descriptions of omicron antigenicity await further laboratory evaluations.
this demonstration.
Literature:
structural data: 7sbl.pdb from J Zhang et al, Science 10.1126/science.abl9463 (2021)
omicron data: https://github.com/cov-lineages/pango-designation/issues/343