Physics Colloquium: “MD Simulations, Free-Energy Calculations, and Machine Learning Applied to SARS-CoV-2 Proteins”

James (JC) Gumbart

Georgia Institute of Technology, School of Physics

Abstract: The SARS-CoV-2 virus is a strain of coronaviruses, named for the characteristic trimeric spike (S) glycoproteins that protrude from the viral membrane surface. The S proteins are type I fusion proteins, which upon recognition of ACE2, their host cell receptor, undergo substantial conformational change leading to membrane fusion and viral entry. Using molecular dynamics simulations, we have investigated several aspects for both the conformational landscape of the pre-fusion S protein as well as the receptor-binding process. Before binding, the receptor-binding domain on the S protein must first open to make the binding site accessible. We have carried out free-energy calculations to determine the minimum-free-energy pathway for this opening on the nation’s largest supercomputer, Summit at Oak Ridge National Laboratory. Our simulations reveal, in particular, the role of S-protein glycans in modulating the opening process as well as the roles of key mutations. Next, machine learning applied to multiple microsecond-scale trajectories has allowed us to identify key residues that differentiate between SARS-CoV and SARS-CoV-2 S-protein binding to the receptor. Free-energy perturbation of selected residues further reveals the energetic contributions of individual mutations. Finally, we have also determined the contributions of ACE2 receptor glycans to binding, illustrating in part why SARS-CoV-2 may bind more easily than SARS-CoV.

Bio: Dr. James C. (JC) Gumbart is an Associate Professor of Physics at the Georgia Institute of Technology in Atlanta, GA.  He obtained his BS from Western Illinois University in 2003 and his PhD in Physics from the University of Illinois, Urbana-Champaign in 2009 under the mentorship of Klaus Schulten, focusing on the area of computational biophysics.  After two years as a postdoctoral fellow at Argonne National Lab working with Benoit Roux, he started his lab at Georgia Tech in early 2013.  His lab carries out molecular dynamics simulations aimed primarily at understanding the composition, construction, and function of the Gram-negative bacterial cell envelope and the proteins embedded within.

All lectures are via Zoom: https://mines.zoom.us/j/98686472990?pwd=REFBbFBJZk9MbXhldGRzemNaczlTZz09