Researchers at the Francis Crick Institute have compared the original SARS-CoV-2 spike protein with a mutated version which arose last spring. They have found structural differences which could help to explain why the mutated version remains the dominant form circulating in all recent variants of concern, such as the UK and South African strains.
Different conformations observed of D614G SARS-CoV-2 variant spike protein.
As SARS-CoV-2 has spread and evolved, mutations impacting the structure of the viral spike protein have affected how it binds to and infects cells, which is part of what controls a virus’ infectivity. These changes have had huge implications for the spread of disease as new variants dominate in part due to changes in the fitness of the virus.
In their study, published in PNAS, the researchers used electron cryomicroscopy to gain detailed images of a variant form of SARS-CoV-2 spike protein. They then compared this to a previous study examining the original ‘Wuhan’ form of the virus. The variant spike called G614, is a mutated version which first arose around spring 2020 and is now the dominant version of the spike in circulation, including in the recently identified variants of concern.
By analysing their structures, the researchers found that the mutated G614 spike would more easily bind to human cells due to its open and flexible structure. While the original spike adopted a generally more closed form, they observed that the mutant spike could adopt a greater number of open and erect conformations, which would prime the protein for binding to the human cell receptor ACE2.
Co-lead author and postdoctoral training fellow in the Structural Biology of Disease Processes Laboratory at the Crick, Donald Benton explains: “As this mutant version likely binds more easily to cells, it has an advantage over the original spike. This could be one reason why this variant now predominates over the initial spike, and it is more wide-spread in circulation.”
However, the researchers suggest that this advantage could eventually become problematic for the virus. This is because its more open and flexible structure could mean that it is more exposed to circulating antibodies.
Antoni Wrobel, co-lead author and postdoctoral training fellow in the Structural Biology of Disease Processes Laboratory at the Crick, says: “During the first wave of infection, most people didn’t have antibodies to SARS-CoV-2, so this open-structured mutant spike could have been beneficial to the virus. However, as time goes on, more people will have antibodies as a result of previous infection or vaccination. And as this mutant spike presents more surface area, it is more exposed to these antibodies, which could be a disadvantage.”
Steve Gamblin, author and group leader of the Structural Biology of Disease Processes Laboratory at the Crick, says: “Studying structural changes in the virus as it continues to mutate helps us to better understand the mechanics of the virus, why one mutant or variant may behave differently to another. This is vital for us to identify strengthens and weaknesses in the virus as it evolves.”
The team continues to analyse emerging mutations and how they affect the spike structure.
