As seen in the Pitt Research September 2021 Newsletter
In the early days of the COVID pandemic, Pitt biophysicist Lillian Chong received an email from graduate student Terra Sztain at the University of California San Diego. The student’s question: would it be possible to simulate the opening of the spike protein on the SARS-CoV-2 virus molecule that penetrated and infected human cells?
Professor Chong creates innovative molecular dynamics simulations of atomic-level protein systems in action. Together with Daniel Zuckerman (Oregon Health and Science University) and her former graduate student, Matthew Zwier (Drake University), she developed the WESTPA software package, which has become a recognized standard for enhancing the efficiency of creating and analyzing simulations. The algorithms of the tool kit create unprecedented views of systems of thousands of atoms acting over longer timescales than previously possible with even the most powerful supercomputers, in some cases taking only weeks compared to the years required by conventional simulations.
The email from Terra Sztain helped propel Chong and her graduate student Anthony Bogetti into a research collaboration between 28 computational and experimental scientists from multiple disciplines and 10 institutions. In November 2020, this team won a distinction known as the Nobel Prize of Supercomputing – the Gordon Bell Prize – for multiple teams working together using advanced computation in studying COVID-19, Chong’s WESTPA team among them.
Chong led her team in a study published in August in Nature Chemistry that far advances understanding of the opening of the spike protein – the spiky structures protruding from the round surface of the cell of the virus in the now-familiar image. Researchers know through cryogenic electron microscope images that the spike protein opens to infect the host cell. But still images can’t reveal how it opens. Dynamic simulations of many possible pathways within a system of a half million atoms showed that one glycan – sugar molecules covering the spike protein – acts as a lever, pushing the spike receptor from a “down” to an “up” position. Collaborators from two experimental labs validated the results of the simulation. More details and video of the simulations are available in the collaborative press release.
The implications of this study are profound – if it is possible to alter the glycan’s function in opening the spike protein, it would be possible to interrupt the process of infecting cells.
“This was the most fun I’ve ever had in science,” says Chong. “The molecular dynamics simulation field can be competitive, and there is often a gap between researchers who do computer simulations and researchers who do lab experiments. But this was an amazing collaboration with five labs working together on a shoot-for-moon project about a critical problem.”
One of Chong’s primary collaborators was Rommie Amaro, a computational biophysical chemist at the University of California San Diego, known for developing detailed visualizations of the spike protein that became well-known early in the pandemic. Amaro and Chong are co-senior authors on the paper, which includes members of their labs and the labs of Jason McClellan (UT Austin), Joachim Frank (Columbia University) and J. Andrew McCammon (UC San Diego). Terra Sztain, the UC San Diego graduate student who first contacted Chong, is co-first author with Surl-Hee Ahn, a postdoc at UC San Diego.