What it means: The model will be used to advance supercomputing simulations aimed at finding drug inhibitors to block the virus’s replication mechanism and help to end the COVID-19 pandemic. The team’s research results are available and were published on June 24 in the journal Nature Communications.
SARS-CoV-2 is the virus that causes the disease COVID-19. The virus reproduces by expressing long chains of proteins that must be cut into smaller lengths by the protease enzyme.
They said it: “The protease is indispensable for the virus life cycle,” said Oak Ridge National Laboratory’s Andrey Kovalevsky, corresponding author. “The protein is shaped like a valentine’s heart, but it really is the heart of the virus that allows it to replicate and spread. If you inhibit the protease and stop the heart, the virus cannot produce the proteins that are essential for its replication.”
Details: Building a complete model of the protein structure requires identifying each element within the structure and how they are arranged. X-rays are ideal for detecting heavy elements such as carbon, nitrogen, and oxygen atoms. Because of the intensity of the X-ray beams at most large-scale synchrotron facilities, biological samples typically must be cryogenically frozen to around 100 K, or approximately -280°F , to withstand the radiation long enough for data to be collected.
To extend the lifetime of the crystallized protein samples and measure them at room temperature, ORNL researchers grew crystals larger than required for synchrotron cryo-studies and used an in-house X-ray machine that features a less intense beam.
What’s next: The researchers’ next step in completing the 3D model of the SARS-CoV-2 main protease is to use neutron scattering at ORNL’s High Flux Isotope Reactor and the Spallation Neutron Source. Neutrons are essential in locating the hydrogen atoms, which play a critical role in many of the catalytic functions and drug design efforts.
The protease plasmid DNA used to make the enzyme was provided by the Structural Biology Center at Argonne National Laboratory’s Advanced Photon Source. Crystallization of the proteins used in the X-ray scattering experiments was performed at ORNL’s Center for Structural and Molecular Biology.
