As the world grappled with the initial waves of coronavirus infections, mutated versions of the virus soon emerged. A variant initially dubbed the "British variant" quickly replaced the original Covid strain as the most prevalent one. Named after the countries where they were first identified, these "variants-of-concern" sparked questions about what made certain strains spread more than others.
Stronger bondsThe secret weapon employed by the British variant appears to be that it sticks to our cells in our nose and throat more strongly. A research team led by Utrecht University biophysicist Prof. Jan Lipfert looked into how strong the virus sticks to our cells. Presenting their conclusions in Nature Nanotechnology , the team demonstrates that the British variant, also called the Alpha variant, is able to create a much stronger binding than the original virus. This feat may have helped the virus stay in place and prevent being dislodged by coughing and sneezing reflexes of its host.
By breaking the bonds between coronavirus proteins and human cell proteins, researchers demonstrated the stronger attachment of the Alpha variant
Breaking the bondLipfert and his team delved into the mechanical stability of the binding between the virus and human cells, by using a highly sensitive technique called "magnetic tweezers". This technique enables researcher to study the bond between a single virus particle and a host cell. They measured the force required to break the bond between the virus’s spike protein and the part of the cell surface it binds to, which is called the ACE2 receptor.
They found that the Alpha or British variant has a higher force stability (i.e. a larger force is required to break the bond to the cell) than the original strain, while other variants, including Beta, Gamma, Delta and Omicron have similar force stabilities than the original version.
Simulating molecular dynamicsTo understand the molecular-level details of these interactions, the group teamed up with Prof. Rafael Bernardi’s group at the University of Auburn. Prof. Bernadi’s team simulated the measured processes in a supercomputer using so-called molecular dynamics simulations. With the help of the computer simulations, the researchers were able to understand exactly which sections of the virus proteins contribute to the force stability in the different variants.
Pinpointing genetic mutationsThe team found that a genetic mutation called N501Y increases the force stability of the interactions by binding more strongly to the surface of the receptor.
Remarkably, the exact same mutation is also present in the Beta and Gamma variants. Still these two variants have weaker bonds, just like the original coronavirus strain. Lipfert explains this apparent contradiction by the fact that the Beta and Gamma also have other mutations that more or less neutralize the stabilizing benefits that N501Y brings. These additional mutations change the electrostatic charge on the surface of the spike protein, and destabilize the binding to the cell.
Evade the immune systemEventually these mutations did provide an overall advantage for Beta and Gamma, as they helped the viruses evade the immune system. The kind of changes present in Beta and Gamma, which modify charges on the surface of the protein, can keep antibodies from binding that our immune system makes in response to a vaccination or a previous infection. Therefore, the more recent strains (Delta, Omicron), which became dominant after wide spread immunity was established in particular by vaccinations, seem to not benefit from higher force stability, but from evading the immune system more efficiently, amongst other factors.
Developing new corona vaccinesWhile the British variant may not be the dominant coronavirus strain anymore, Lipfert’s study may provide valuable insights for the future. The research team hopes that their methods can not only enhance our understanding of mutation effects but also aid in predicting and preparing for future variants, ultimately contributing to the development of updated vaccines. Lipfert expects this could prove to be very relevant when developing a vaccination programme against coronavirus infections, similar to flu vaccination programmes.
PublicationSingle-molecule force stability of the SARS-CoV-2-ACE2 interface in variants-of-concern
Magnus S. Bauer, Sophia Gruber, Adina Hausch, Marcelo C.R. Melo, Priscila S.F.C. Gomes, Thomas Nicolaus, Lukas F. Milles, Hermann E. Gaub, Rafael C. Bernardi, and Jan Lipfert