How the virus enters the cell: Carlos Simmerling models how the SARS-CoV-2 spike protein Receptor Binding Domain (RBD) binds to the host cell’s ACE-2 receptor, with the aim of drug discovery. Starting from cryo-EM structures inCell and Science, he reconstructs missing details and loops using BRIKARD (Coutsias), then performs MD and pathway computations to explore the protein’s motions and conformational changes.
The structures of the viral proteins: The structures of most COVID virus proteins are not yet known. The Dill group is computing those structures using MELD x MD, and testing in CASP 14. And the Kozakov group is computing structures of human-virus and virus-virus protein pairs.
Small molecule inhibitors of the viral protease: The Kozakov, Rizzo, and Dill groups seek inhibitors of the SARS-CoV-2 proteases that are necessary for viral reproduction. First, they perform rapid virtual screening of possible binders from a large database using DOCK and our template-based LigTBM, followed by atomistic physics Monte Carlo and MELD x MD.
A PROTAC linker to degrade viral proteins: The Kozakov and Dill groups are designing a PROTAC linker (PROteolysis-TArgeting Chimeras) that hooks a viral protein onto a host cell’s ubiquitin protein to send the viral protein to the cell’s `garbage disposal’ proteasome system. They use CLUSPRO protein docking software with atomistic refinement by MELD x MD. Peter Tonge’s group at SBU is making and testing the linkers.