Simulated Faulty Folding: A Theoretical Model of Prion Propagation
Researchers have designed a protein that, in computer simulations, induces other proteins to misfold
Inside a live cell, strings of amino acids instantaneously fold into proteins with very specific shapes. Typically, no harm is done if a protein somehow folds into an unconventional configuration. But, very rarely, a misfolded protein will induce others to unfurl and misfold as well, with disastrous consequences: the nonconformists glom together, causing diseases such as bovine spongiform encephalopathy (BSE or mad cow), Creutzfeldt-Jakob, and Alzheimer’s.
Using computer simulations, a group of theoretical chemists at Warsaw University—Malolepsza, Boniecki, Kolinski and Piela—managed to get a glimpse of how such misfolded proteins—called prions— propagate. Recently, they designed a protein that, in computer simulations, induces other proteins to mis- fold. The work was published in Proceedings of the National Academy of Sciences in May.
Edyta Malolepsza, a graduate student involved in the work, says she hopes it will help advance our understanding of prion disease. “This is a small model with a protein designed by us, not by nature,” she says. “But because we used a very realistic force field, a real protein could behave similarly.”
Malolepsza’s work involved two primary steps: designing protein sequences that might have a propensity to misfold, and simulating what hap- pens when they interact. For the design process, she used trial and error to identify a set of 32-amino-acid chains that met specific criteria: they would naturally fold into a bundle of two alpha-helices, but, at only a slight- ly higher energy level, could also form a beta-sheet.
After selecting 14 appropriate sequences, Malolepsza began her simulations. Alone, each peptide folded to the native alpha-helical shape at a variety of temperature ranges. However, when allowed to interact with a frozen beta-sheet version of itself, one of the sequences (regardless of its starting conformation) unfolded and then refolded to a beta-sheet shape. It then formed a dimer with the pre-existing beta-sheet. In addition, allowing one frozen beta-sheet molecule to interact with two alpha-helices produced a beta-trimer—a larger aggregate similar to what develops in prion disease. Malolepsza cannot yet explain why one of the proteins could propagate misfolding while the related sequences could not. Figuring this out may yield clues about how to inhibit or reverse prion disease.
“Only one among the studied sequences exhibits the ability to induce prion disease,” says Malolepsza. And just a few amino acids—sometimes only one—made the difference between the protein that acted like a prion and the 13 others that didn’t. “Maybe a mutation occurs that allows propagation of the amyloid aggregations seen in prion disease,” says Malolepsza.
Malolepsza is hoping to simulate actual prion proteins soon. It’s a more complex task because prions are bigger—the fragment needed for simulations contains about 100 amino acids. “We need a faster simulating program,” she says. “I hope that we will eventually have another paper with a more complete answer as to how prions work.”