Want to see what the SARS-CoV-2 virus actually looks like? An image search will not help. Most images are artist depictions. For those trying to understand how the virus burrows into human cells, the artists are not helping. The mechanism the virus employs cannot be ascertained from the brightly colored spheres with shapes that look like Shrek’s ears sticking out of them. And the color is creative license, same as they did when they colored all the dinosaurs green.
Excuse the artist depiction. A cutaway of the SARS-CoV-2 virus. See what the protein spike really looks like below. (Image courtesy of The Economist.)
But a more accurate and detailed picture of the SARS-CoV-2 virus emerged earlier this year, thanks to a University of Texas at Austin research team led by associate professor Jason McLellan. The team implemented a special electron microscope called a cryoEM, a Nobel-Prize-winning breakthrough in imaging of molecules and NVIDIA GPU processors. All that has led to the most accurate 3D model to date of the protein spike.
The tip of the spear. A 3D, atomic-scale map, or molecular structure, of the SARS-CoV-2 spike protein. The protein takes this shape, called the prefusion conformation, before it infects a host cell. Credit: Jason McLellan/Univ. of Texas at Austin.
The protein spike is the longest of the spikes that stick out from the body of the SARS-CoV-2 virus. Once the protein spike comes in contact with a cell, it tries to dock with a receptor on a human cell. If successful, the end of its spike binds to the receptor. The viral membrane fuses with the cell and the virus starts pumping its genome into the cell that will become the host. It will replicate itself thousands of times in the host cell, eventually exhausting it and bursting out of it to find other host cells. Antibodies that attack the invaders are overwhelmed. An inflammation and fever follow. The victim now has COVID-19.
Clearly, getting to the viral invaders early is key to stopping the disease. Front line researchers, like the University of Texas team, look for ways to create vaccines that trigger a small immunological reaction with a harmless version or part of the virus. The University of Texas researchers hope their atomic-scale model will help them—and other researchers—to create a vaccine using the protein spike as an ingredient in a vaccine.
How Was the Protein Spike Model Created?
The researchers used the genome map of the SARS-CoV-2 virus published earlier this year. They isolated the gene code of the protein spike and sent it to a lab that was able to create the gene. The researchers injected the gene into mammal cells to create the spike proteins. They used a fine detailing property of a cryogenic electron microscopy (cryEM) and biomolecule modeling software to get a 3D depiction of the spike proteins—right down to the location of each of its atoms.
In theory, the spike proteins could form the vaccine or be part of one, as the protein bits could be seen as an invader and be attacked, leaving the body’s immunological system ready and capable of attacking the same proteins on the actual, full SARS-CoV-2 virus.
Watching Movies
To create the model, the researcher had to watch a lot of movies, over 3200 of them. It took McLellan and his team 12 days to go from a raw sample to producing the atomic-scale model. In the animation, CryoSPARC 3D variability analysis give a side-view. The SARS-CoV-2 trimer is viewed from the side, along the viral membrane. (Movie provided by NVIDIA.)
The research paper explains the mechanism of the viral contact and infection:
To engage a host cell receptor, the receptor undergoes hinge-like movements that hide or expose the determinants of receptor binding. These two states are referred to as the “down” conformation and the “up” conformation, where down corresponds to the receptor-inaccessible state and up corresponds to the receptor accessible state.The 3D image processing features of the cryoSPARC software led to the 3D atomic model shown above. CryoSPARC was developed by Toronto-based startup Structura Biotechnology which had its start as a University of Toronto research project. cryoSPARC uses CUDA and CUDA libraries with NVIDIA V100 GPUs, and NVIDIA T4 GPUs on-premises and cloud service providers.
What is CryoEM?
An electron microscope can damage what it is inspecting with the bombardment of electrons. A cryoEM (cryogengic electron microscopy) inserts its samples in vitreous water the temperature of liquid ethane or a mix of liquid ethane of methane (about 100K, or -173 °C) to limit the damage. In 1981, Alasdair McDowall and Jacques Dubochet, scientists at the European Molecular Biology Laboratory, reported the first successful implementation of cryoEM. Dubochet, along with Joachim Frank and Richard Henderson were awarded the Nobel Prize in Chemistry in 2017 for developing a technique, using cryoEM, that led to images of biomolecules.