Nathi Magubane, Penn Today
Prions, mysterious shape-shifting proteins, can lead to brain disorders such as Creutzfeldt-Jakob disease in humans and bovine spongiform encephalopathy, “mad cow disease” in cattle, yet they can also play essential roles in yeast survival and long-term memory formation in mice.
Given their wide-ranging and complicated effects, investigating their structure and function could help better understand disease and explore potential applications. However, few computational models that allow for experimental design, hypothesis testing, and control exist, hindering a richer understanding of prionic behavior.
Now, an interdisciplinary team of researchers at the University of Pennsylvania has developed a simple, biologically inspired mechanical model of how prions pass on their shape to neighboring proteins.
In a study published in Cell Newton, the researchers show that a barebones five-bar linkage can catch a “bad” shape from its neighbor and pass it along—dominoes-style—just like its biomolecular counterpart. Their findings could offer key insights into neurological disorders such as Parkinson’s disease and pave the way for novel drug delivery systems.
“There’s just so much that can be done with these sorts of interactions, from a fundamentals perspective,” adds first author Mathieu Ouellet, who recently completed his Ph.D. in Lee C. Bassett’s Quantum Engineering Lab[1] at the School of Engineering and Applied Science. “Because there is this sort of amplification process, I think it could be useful in nonliving systems like in quantum processing.”
“It’s a profound shift,” says Kieran Murphy, a co-author on the study and a postdoctoral researcher in Dani Bassett’s Complex Systems Lab at Penn. “This kind of simplicity is powerful. We’re not relying on the messy intricacies of biochemistry; we’re distilling it down to geometry and physics. That opens the door to entirely new ways of studying prions and designing systems inspired by them.”
Leaning into modeling prionic mechanics
Recalling the initial spark for investigating prions as a physical system, Ouellet credits author Kurt Vonnegut. “I was reading “Cat’s Cradle” way too late in life,” Ouellet laughs. “Vonnegut’s ice-nine is this fictional crystal that forces all water it touches to freeze into ice—even at room temperature—and it got me thinking, ‘Could we build something just complex enough to mimic that kind of self-propagating transformation?’”
Looking to computational tools, the researchers began a multiyear effort to determine the mechanics of how prions act to convert healthy proteins into prions themselves. They simulated thousands of spring-and-hinge polygons, jostling each one in virtual environments to best mimic molecular interactions and match the biological systems.
In the end, a five-bar pentagon with a lock-and-key notch emerged as their top candidate, with the prion-like pentagon “P” transitioning the healthy “H” to the P conformation faster than the reverse transition. This asymmetric propagation is a key feature of prion spreading behavior, the researchers note.
With the virtual model working as intended, the team moved to the workshop. Ouellet fabricated physical prototypes using 3D-printed resin, designing the springs to mirror the simulated flexibility and embedding small magnets at precise points to mimic the binding forces seen in proteins.
When gently shaken inside a simple tabletop setup, these models remained inert until a prion-state unit was introduced. Then, just as predicted, the system began to change; the healthy units snapped into the prion shape one by one, setting off a visible and audible cascade.
“We built it out of what happened to be lying around: a printer, some plastic, some magnets,” Ouellet says. “The fact that it just works tells us the mechanism is incredibly robust.”