Defining the shapes of shapeshifting proteins

Photo of Sarah Rauscher
Tuesday, October 9, 2018 - 11:45am
Maeve Doyle

Computational biophysicist Sarah Rauscher joined the Department of Chemical and Physical Sciences in 2017. Rauscher studies a class of proteins called disordered proteins.

Rauscher says to think of proteins as tiny machines. These nanomachines come in different shapes or “structures” and have functions within the body.

Disordered proteins do not have recognizable structures. “They’re shapeshifters,” she says. “They change shape all the time.” She uses yarn as an analogy for protein.

“If you have a really long string of yarn and you knit it up to make a pair of mittens, because those mittens have a shape, they are able to have a function,” she says. “A protein starts out in a yarn-like state, then it folds into its structure and that structure allows it to function.”

However, disordered proteins remain in that yarn-like state. “Imagine if you threw a piece of yarn on the ground, it would have a certain shape. But if you picked it up and threw it again and again, each time you would see a different shape.”

Supercomputer

Rauscher applies principles from physics and chemistry to discovering the structures and dynamics of disordered proteins. Her calculations produce simulations of the proteins that she can observe and analyze to discover how the proteins work.

“Without access to a supercomputer, my research team and I wouldn’t be able to carry out our calculations. We need the supercomputer. It is essential,” she says. Their calculations use up to the equivalent of a thousand computers at one time.

Compute Canada, which provides supercomputing resources for academia and industry in Canada and their collaborators, awarded Rauscher with computer time valued at $165,000.

The supercomputer Niagara allows Rauscher and her lab to simulate larger proteins and larger systems over longer times.

“With our simulations, we can watch the proteins move,” says Rauscher. She says the simulations might allow her to identify regions of the proteins that are more mobile than others. If she observes that a part of a protein undergoes a larger fluctuation, she can potentially identify a new pocket that has opened and where a new drug can fit. “What we get from our simulations is knowledge about how proteins move and then that knowledge can provide relevant information that other researchers can use.”

Simulation of an unfolded protein submitted by Sarah RauscherU of T Mississauga's biophysics cluster

“Professor Rauscher’s molecular simulations provide unprecedented detail that cannot be revealed in the lab,” says Claudiu Gradinaru, professor and chair of the Department of Chemical and Physical Sciences.

Gradinaru calls Rauscher, and her colleague theoretical biophysicist Andreas Hilfinger who also joined the department last year, the perfect complement to their cluster of experimental biophysicists. That cluster includes Virgis Barzda, Claudiu Gradinaru, Voula Kanelis, Joshua Milstein and Scott Prosser.

Gradinaru says that Rauscher’s computational biophysics research has huge applications. “She can provide clues to our colleagues like Scott Prosser who studies cell signalling receptors, and Patrick Gunning who works on drug design.”

Gradinaru studies disordered proteins involved in autism and learning disabilities. He uses lasers and sensitive detectors to watch individual proteins. He collects experimental data about their function and malfunction, while Rauscher uses computational methods to simulate them.

“Together, the two methods of my single-molecule experiments and Professor Rauscher’s molecular dynamics simulations compose a more complete picture of how these proteins look and how they work,” says Gradinaru. “This allows us to make hypotheses about drug discovery, misfolded proteins and disease mechanisms.”

It’s complicated

Disordered proteins fascinate Rauscher. “I just find it very interesting that a protein in the body could have evolved to actually function in a way that is disordered. It doesn’t have a single structure and yet its carries out a function in a very complicated way.”

Rauscher was one of the ten researchers at the University of Toronto Mississauga who were awarded NSERC Discovery Grants this year. Rauscher has already committed the full $130,000 to training her research team of postdoctoral fellow, graduate students and an undergraduate research assistant.

Rauscher and her team of researchers are already at work improving the accuracy of the simulation methods that exist in order to answer questions that are currently unanswerable.

“Ideally, if we can understand how disordered proteins look in very accurate detail, the research community might one day be able to design drugs for these proteins,” says Rauscher. “That is what we are trying to work towards.”