Researchers use technology to uncover the relationship between membranes and proteins in viruses

Since 2020, professor of biochemistry Michael Overduin and a team of two undergraduate students have been working to identify how proteins in viruses interact with cell membranes. Their findings could give scientists the upper hand in tackling SARS-CoV-2 — the virus that causes COVID-19 — and other potentially deadly viruses.

In a paper recently published in iScience, Overduin — together with students Troy Kervin and Anh Tran — proposes that cell membranes play a much larger role than previously understood in allowing spike proteins on viruses such as the SARS-CoV-2 to infect cells. 

Using software developed by Overduin and other academic researchers along with Molsoft, a California-based technology company, the team identified interactions between proteins and membranes within cells. Called Membrane Optimal Docking Area (MODA), it’s “the only software available in the world that does this to this level of accuracy,” explains Overduin. 

When the pandemic shut down labs at the University of Alberta, Kervin was unable to work on the research project he was supposed to do with Overduin. MODA made it possible for them to shift their sights to a project Kervin could do outside of a lab.

Kervin’s revised research focused on assembling all of the proteins in one family of membrane-binding domains, and using MODA to predict which regions on these domains bind to membranes. That work yielded some interesting results, namely that cell membranes — the barrier around cells made of fat molecules called lipids — play a more significant role in viruses binding to cells than previously thought.

“This was a very simple project, but it was highly productive,” says Kervin. “We were using the MODA program for its intended purpose on a large scale, and we found something that is highly significant.” 

Those findings became the foundation for additional research about cell-binding activity, when Tran contacted Overduin about the possibility of getting research experience. “I spoke to Anh about what his interests were, and tried to design a project around the things that really excited him. And at that time, of course, COVID was beginning to become a serious problem,” recalls Overduin.

Overduin had already been thinking about expanding on the work he and Kervin had done, and talked to Tran about their theory that the spike proteins on coronaviruses — the red barbs that can be seen on images of the COVID-19 virus — appeared to be membrane binders. He knew that their software worked to identify how proteins bind to membranes, but no one had looked at whether spike proteins bind to membranes yet. “I thought, ‘This sounds like a crazy project, but it might just work’,” says Overduin.

The consensus in the scientific community had been that the job of spike proteins in SARS-CoV-2 is to bind to angiotensin converting enzyme-2 (ACE-2) receptors that are on the outside of cells, not to the cell membrane. With Anh on board, they began the process of using MODA to compare a large number of structures of spike proteins in both the original — or ‘wild type’ — virus and the variants.

“We found out how the spike protein engages the lipids of our lung cells and gets in. Then we found that the Omicron variant was super active. We thought that's really, really exciting. Maybe that's contributing to how it gets in easier and spreads more quickly.” says  Overduin.

The team thinks that other viruses aside from SARS-CoV-2 use similar mechanisms to enter cells, but until recently the process has been difficult to observe. The development of software like MODA makes it easier to make predictions like this and describe how proteins really behave in a cell. “We're at the beginning of this digital age where we can really see so much more than we could see even two years ago, where we can look at every protein in the human genome and measure how every one could interact with membranes,” says Overduin.

Computational biology research, like the work this team is doing with MODA, means students can be involved in research even if they don’t have access to a lab. “I personally felt that our students were disadvantaged during COVID, so I've taken seven students on the last two summers, and they've been really, really talented,” explains Overduin. “They each have their own protein family, and they're analyzing other questions. Some are looking at the proteins that cause other illnesses like Alzheimer's disease or cancer.” 

“That's the thing about Michael is he's really open to undergraduate students, which I really appreciate. Michael's goal really is to involve us in every way possible, and really immerses us in the science of the entire project,” says Tran.

The opportunities Overduin gives to undergraduate students are paying off. This summer, Tran is researching NMT1, a protein that is a breast cancer target, with funding received from the Cancer Research Institute of Northern Alberta. Kervin’s work on this project resulted in him being invited to study for the summer at The Rockefeller University in New York City, where he is learning to do the experimental work needed to validate their hypothesis. The team also has more publications coming out of their work, including one invited by iScience explaining the protocol used in their research.

“We would like to understand how all of our proteins bind membranes, as well as how all viral proteins and all bacterial proteins. Bacteria and viruses really make use of these membrane binding sites to get into our cells and cause damage. I think there is hope that research is delivering; we are understanding much better how these viruses operate and we're coming up with new ways to tackle the virus and stop it in its tracks before it creates trouble.” says Overduin.