Brookhaven National Laboratory

Blocking the COVID-19 Virus's Exit Strategy

Students conduct computational studies, explore inhibitor drugs to disrupt viral proteins that help infectious particles escape from cells

Newswise — Detailed knowledge of how SARS-CoV-2, the virus that causes COVID-19, replicates and how the body responds can point to different strategies for stopping it. Many researchers have been working to block the interaction of the coronavirus “spike” protein with the human-cell receptors to which it binds—the first step of infection. In contrast, three High School Research Program students participating in research with scientists in the Computational Science Initiative at the U.S. Department of Energy’s Brookhaven National Laboratory this summer took aim at one of the final steps—the virus’s exit strategy.

“After the virus is replicated and assembled, it needs to leave the cell,” explained Peggy Yin, a rising senior at Port Jefferson High School. “Our body has an immune response in the form of a protein called ‘tetherin’ that tethers the newly replicated virus particles to the cell membrane so they can't get free to infect other cells. This is a really useful tactic that our body has built in to try to protect us.”

Unfortunately, SARS-CoV-2 has a way around this defense. The virus makes a protein that interferes with the tethering protein. “So maybe, if we inhibit the virus protein, we can let ‘tetherin’ do its thing,” Yin said.

The first step was to learn more about how the virus protein works.

Modeling molecular interactions

Yin and fellow HSRP students Jacob Zietek and Christopher Jannotta—who’d just graduated from Farmingdale and Eastport South Manor high schools, respectively—ran protein-protein docking studies to model how the viral protein and the tethering protein interact.

“Using this program, we can see where these proteins are talking to each other, where they're binding to each other, and how the virus actually inhibits tetherin,” said Jannotta.

The modeling studies confirmed a suggestion the students had read about in the literature—that the virus protein binds to parts of the tether that get glycosylated (have sugar groups added), a necessary step for tetherin to work.

“We know that glycosylation happens in the endoplasmic reticulum, an internal organelle of the host cell,” Jannotta said. “That means if we were to develop some type of inhibitor of the virus protein, we might have to get it into this internal organelle. But at least now we knew where on the viral protein to look to dock possible inhibitors.”

Searching for inhibitors

The students conducted more docking studies—this time looking at the interactions of the virus protein with many possible small drug-like molecules, or “ligands,” to see which might work to stop the virus from blocking glycosylation.

“What these protein-ligand docking studies do is they try to fit the little ligands into the pocket that blocks glycosylation to find which one and which conformation, or ‘pose’ of the ligand, binds to the pocket best,” Yin said. From starting with 60 candidate ligands, the students narrowed the search to six or seven.

Then the team took the research even further by conducting molecular dynamics simulations of those candidate ligands. As Zietek explained, instead of just predicting whether a particular ligand will fit into a pocket on the protein—like a key fitting into a lock—molecular dynamics simulations predict how the shapes of the protein and ligand will conform to one another and change over time.

“These are much more complicated to compute,” Zietek said, because it gets down to what’s happening with individual atoms. “The program will calculate all the forces of atoms interacting with other atoms, and change the positions of the atoms relative to each other over time to match what would happen in real life as close as possible.”

Supercomputing power

“Because the project these students were working on is contributing to a broader collaboration—the National Virtual Biotechnology Laboratory (NVBL)—they had access to Brookhaven’s supercomputing clusters to run the molecular dynamics simulations,” said Hubertus Van Dam, their mentor.

That’s important because tracking the molecular interactions between each ligand and the viral protein for just 10 nanoseconds—10 billionths of a second—takes 8-12 hours to run even on such powerful machines. “On regular computers, it would take way too long!” Zietek noted.

Ten nanoseconds may not seem like a lot of time, but the simulations capture what happens every two femtoseconds—millionths of a billionth of a second, Jannotta noted. “The computer slows it down so we can see it in real time,” he said.

“It’s like a slow-motion camera,” Yin added.

As the team discovered by at first running even shorter simulations, 10 nanoseconds is long enough “to find out if a ligand will stick inside of a protein or if it'll rip off,” Zietek said.

The students have quantified the results from the molecular dynamics simulations and are honing in on the best potential inhibitors, and identifying which pieces of the small drug-like molecules bind best to the virus protein. They are also looking at candidates to inhibit the viral protein in other ways. These initial computational studies pave the way for future experiments—and could even lead to other scientists, most likely at pharmaceutical companies, developing these ideas into actual drugs to inhibit SARS-CoV-2.

“I definitely think what we did is going to help all the scientists working on these therapeutic agents,” said Jannotta, who will begin biomedical engineering and premed studies at Stony Brook University this fall. “It’s going to help them get a more narrow view of what inhibitors might actually be worth pursuing in the pharmacology area. Other researchers maybe in pharmaceutical companies may take it up and carry it on. So I’m very excited for that.”

Virtual is reality

As Van Dam noted, “This is real-world research, with real potential impact. The fact that these internships ran ‘virtually’ really didn’t make a difference. Throughout the pandemic, even our professional computational scientists have been conducting similar computational studies working from our homes.”

Zietek, who will be attending Purdue University in the fall, said, “I never would have imagined that I'd be working on such a relevant and pressing topic as COVID-19 when I first applied for the Brookhaven program. I knew I wanted to work on a computational science project to learn more about how computers can be applied in a research setting. But this was just about the most emotional topic you could get for a project. I was very excited to get the opportunity to contribute.”

Yin was all in on the COVID angle from the start.

“In January, when I applied, I mentioned wanting to perform computational biology research in my essay. And as the pandemic situation worsened, I emailed about the possibility of me performing COVID-19 research, because I really wanted to help,” she said. “I’m hoping that since we know so little about coronaviruses in general, if somehow our research could shed light onto the mechanisms of how these viruses work, maybe this could help with other areas of coronavirus research and prevent other pandemics in the future.”

The CSI virus protein/drug-development modeling work is supported by the DOE Office of Science (BER) through the National Virtual Biotechnology Laboratory (NVBL), a consortium of DOE national laboratories focused on response to COVID-19, with funding provided by the Coronavirus CARES Act.  Student participation in this project was supported through the HSRP, a program run by Brookhaven Lab’s Office of Educational Programs with funding from Brookhaven Science Associates—a partnership between Battelle and The Research Foundation for the State University of New York on behalf of Stony Brook University—which manages Brookhaven Lab..

Brookhaven National Laboratory is supported by the U.S. Department of Energy’s Office of Science. The Office of Science is the single largest supporter of basic research in the physical sciences in the United States and is working to address some of the most pressing challenges of our time. For more information, visit

Follow @BrookhavenLab on Twitter or find us on Facebook


Filters close

Showing results

110 of 3782
Newswise: COVID-19: Dexamethasone discovery carries treatment implications
Released: 27-Oct-2020 9:00 AM EDT
COVID-19: Dexamethasone discovery carries treatment implications
University of Virginia Health System

A new discovery about how the body transports dexamethasone, a drug that can increase the survival chances of patients with severe COVID-19, suggests diabetes and other factors may reduce its potentially lifesaving effect.

Released: 27-Oct-2020 9:00 AM EDT
Investigator on the AstraZenea vaccine trial will take questions at Live Event on Oct. 29, 3PM

Dr. Edward Jones-Lopez, joins a Newswise Live Expert Panel on Thursday Oct. 29, from 3-4 PM EDT to discuss the AstraZenea COVID-19 vaccine trial.

Newswise: Johns Hopkins Medicine Hosts Briefing on Women’s Health
Released: 26-Oct-2020 4:00 PM EDT
Johns Hopkins Medicine Hosts Briefing on Women’s Health
Johns Hopkins Medicine

Since its inception in 1995, the mission for A Woman’s Journey has remained the same: to empower women to make the right health care decisions for their families and themselves.

Newswise: COVID-19's effect on Halloween is more trick than treat
Released: 26-Oct-2020 3:35 PM EDT
COVID-19's effect on Halloween is more trick than treat
University of Delaware

Let’s not sugarcoat it: the coronavirus (COVID-19) is hurting our holidays, even if it is, possibly, helping our teeth. A new University of Delaware study shows 42% of American households plan to consume less candy this year, and trick-or-treating could be down 41%.

Newswise: Data scientists in Chicago fill in gaps on race, ethnicity in COVID-19 testing
Released: 26-Oct-2020 3:15 PM EDT
Data scientists in Chicago fill in gaps on race, ethnicity in COVID-19 testing
DePaul University

Thousands of people are being tested for COVID-19 each day, but collecting complete demographic information, including race and ethnicity, has proven difficult. Data science researchers at DePaul University have stepped up in Chicago to help public health officials fill in this missing information.

Released: 26-Oct-2020 3:10 PM EDT
Scientists to improve food plant worker safety, product supply
Cornell University

A Cornell University-led project will use computer modeling and outreach to find optimal strategies to minimize COVID-19 cases and transmission among workers in food processing facilities, while maintaining the best possible production.

Newswise: Safety and prevention are priority for Penn State Health as COVID-19 pandemic continues
Released: 26-Oct-2020 2:10 PM EDT
Safety and prevention are priority for Penn State Health as COVID-19 pandemic continues
Penn State Health

The number of new daily cases of COVID-19 is rising sharply statewide – and the trend is reflected in central Pennsylvania and in Penn State Health’s hospitals and outpatient clinics. As the increase is not unexpected, care teams across Penn State Health remain prepared to provide care for all patients who need it – whether for COVID or any other health issue.

Newswise: Ultrasounds Show Impact of COVID-19 on the Heart
22-Oct-2020 9:35 AM EDT
Ultrasounds Show Impact of COVID-19 on the Heart
Mount Sinai Health System

International study may guide therapeutic strategies in patients with and without underlying heart conditions

Newswise: DFW COVID-19 Prevalence Study Expands
Released: 26-Oct-2020 12:20 PM EDT
DFW COVID-19 Prevalence Study Expands
UT Southwestern Medical Center

Key Points: - As North Texas braces for a second COVID wave and flu season, a major COVID-19 study by UT Southwestern and Texas Health Resources is expanding. - The study is expanding from its original invitation-only format to offer more members of Dallas and Tarrant County communities a chance to participate. - Testing in the study is still free and includes testing for active and past infections.

Showing results

110 of 3782