Credit: Pixabay/CC0 public domain
According to a study published in eLife today, scientists have simulated the SARS-CoV-2 spike proteins structure's transition from when it recognizes a host cell to when its entry is granted.
Research has shown that the structure of spike protein sugar molecules could be crucial for cell entry. It could also be that disruption of this structure could be an option to stop virus transmission.
SARS-CoV-2's ability to attach to host cells to transfer its genetic material is an essential part of its lifecycle. This is achieved by the spike protein. It is composed of three components: a transmembrane package that anchors spike to virus and two S subunits (S1 & S2) on the outside of virus. The S1 subunit binds with ACE2 on the surface cells of human cells to infect them. The S2 subunit then detaches and fuses their cell membranes. This process is well-understood, but the order it takes place is not yet known. Understanding the movements at microsecond and atomic levels of these protein structures may reveal targets for COVID-19 treatment.
"Most current SARS-CoV-2 vaccines and treatments have focused on the ACE2 recognition stage of virus invasion. However, an alternative strategy is for the virus to fuse with human host cells." Jos N. Onuchic is co-author of the study and the Harry C & Olga K Wiess professor of Physics at Rice University in Houston, Texas, USA. He also serves as Co-Director for the Center for Theoretical Biological Physics. It is difficult to probe these transient intermediate structures experimentally. Therefore, we created a computer simulation that allows us to examine this complex system, but retains enough physical details to capture its dynamics as it changes between pre-fusion or post-fusion forms.
The role of sugar molecules in spike proteins, also known as glycans, was particularly important to the team. They performed thousands of simulations with an all-atom-structure-based model to determine if glycans played a role during the membrane fusion stage. These models can predict the trajectory of atoms over the course of time by taking into account steric factors, which is how the movements of neighboring atoms.
Simulations showed that glycans create a "cage", trapping the "head" (S2 subunit) and causing it to pause between when it separates from the S1 and when the cell and viral membranes fuse. The S2 subunit was much more comfortable in this form if the glycans weren't present.
Simulations show that the S2 subunit can recruit host cells by holding its head in a certain position. This allows for the expansion of short proteins known as fusion peptides. Glycosylation of S2 increased the probability that a fusion protein would reach the host cell membrane. This was in contrast to when glycans were absent.
"Our simulations show that glycans may cause a pause in the spike protein transition. This gives the fusion peptides a crucial opportunity to capture the host cell," says Paul C. Whitford (Associate Professor at the Center for Theoretical Biological Physics, Northeastern University in Boston, USA). The viral particle would not be able to enter the host if it were not for glycans. This study shows how sugars can control infection and provides the foundation for experimentally studying factors that affect the dynamics of this deadly and pervasive pathogen.
Learn more Glycans are active in infection in the SARS/CoV-2 spike protein.
More information: Esteban Rojas et. al., Sterically restricted rearrangements of SARS–CoV-2 Spike Protein control Cell Invasion, eLife (2021). Information from eLife Esteban DoderoRojas and colleagues, Sterically confined rearrangements SARS-CoV-2 Spike proteins control cell invasion, (2021). DOI: 10.7554/eLife.70362