08.03.2023
An international research team led by Gerhard Hummer, Director of the Department of Theoretical Biophysics at the Max Planck Institute for Biophysics, has investigated the connection of different variants of the coronavirus to living cells. The researchers found that the delta and omicron variants are stronger and last longer than the original Wuhan strain of the virus.
With this discovery, they explain the increased infectivity and resistance to the host’s immune system that occurs in the newer corona variants.
Coronavirus spike proteins bind to ACE2 receptors on the cell surface
When cells are infected with the SARS-CoV-2 virus, the spike-shaped proteins on its surface play a crucial role. These spike proteins can be thought of as three-armed pincers that dock onto so-called ACE2 receptors, which occur naturally on host cells and allow the virus to inject its genetic material.
In 2020, a research team from the Max Planck Institute (MPI) for Biophysics in collaboration with the Paul Ehrlich Institute and the European Molecular Biology Laboratory (EMBL) showed that these gripping forceps are not completely rigid, but rather have a flexible handle on the virus are attached. This allows multiple spike proteins to simultaneously “scan” the cell in search of and bind to ACE2 receptors (Turonová et al., Science 2020).
This stalk is also almost entirely stocked with long carbohydrate chains that make it difficult for the host’s immune system to recognize the virus as a pathogen. The few uncovered regions become the target of antibodies upon vaccination or infection, leading to rapid evolution of the virus and the emergence of new variants that evade immune response by altering these regions. .
Now researchers from the Department of Theoretical Biophysics, led by Gerhard Hummer at the MPI for Biophysics, together with an international team of experts in experimental biophysics, have addressed the question of how exactly the three-armed spikes bind to the ACE2 receptors. How strong is the binding and what is the impact of changes in the spike protein in newer viral mutants such as delta and omicron? They recently published their answers to these questions in the journal “Nature Communications”.
Researchers investigated the binding of spike proteins to living cells experimentally and with computer simulations
Hummer’s team looked at the binding of the spike protein to cellular ACE2 receptors using molecular dynamics simulations. “We calculate how individual spike proteins and the cellular receptors move and how they interact with each other,” explains Mateusz Sikora, a postdoc in Hummer’s department and one of the first authors of the study.
In collaboration with research teams from Austria, Sweden and Canada, the scientists at the MPI for Biophysics combined their computer simulations with atomic force microscopy on living cells (Zhu, Canena, Sikora et al., Nature Communications 2022). This technique uses hooks as small as a few ten-thousandths of a millimeter to pull bonds apart to measure forces between molecules, or to quickly scan surfaces and observe molecular motion in real time.
By combining theoretical and experimental methods, the researchers showed that the handle and, above all, the three arms of the spiked gripping tongs are much more flexible than previously thought. As a result, up to three arms can bind to up to three different ACE2 receptors in a very short time. The scientists observed multiple bindings primarily in the original Wuhan strain and in the Delta variants.
A single arm of the delta spike protein sticks regarding 10 times more strongly to an ACE2 receptor than an arm of the Wuhan spikes. In the case of the omicron variants, the research team even found that the binding was around 100 times stronger. However, they observed less frequently that two or even three grippers bind simultaneously.
Improved binding properties of the spike proteins of the delta and omicron variants increase infectivity
“All in all, the virus binds more firmly and longer to the cell surface in both Delta and Omicron,” summarizes Sikora. “The viruses are therefore less easily shed by increased blood or mucus flow or reflexes such as coughing or sneezing.” This explains why the delta and omicron variants of the SARS-CoV-2 virus are much more infectious and transmissible compared to the original Wuhan strain.
International interdisciplinary cooperation led to success
In containing the corona pandemic, cohesion and cooperation in the international community were of central importance, including in science. When investigating the binding properties of the spike protein, Gerhard Hummer’s team used its expertise in molecular dynamics simulation of biophysical systems and phenomena in collaboration with several renowned international research groups.
Peter Hinterdorfer and his team from the Johannes Kepler University Linz in Austria carried out the experiments with their in-depth experience in atomic force microscopy. Josef M. Penninger from the University of British Columbia in Canada had contributed to elucidating the role of the ACE2 receptors in coronavirus infections in 2020 and the team benefited from his knowledge and many years of experience in medical research.
As experts in viral diseases, researchers led by Ali Mirazimi from the Karolinksa Institute in Sweden completed the team. Mateusz Sikora sums it up: “For a project like this you need a lot of people with experience in different areas, who complement each other with their strengths and contribute different perspectives. Good science thrives on teamwork.”
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