Supercomputer works to ‘untangle’ amyloid fibrils

"Amyloid research has accelerated in the last 10 years. But computers may prove to be the key to finding better medications for a whole range of systemic and neurodegenerative diseases, from arthritis to Parkinson's," says Jérôme Waldisühl. (Credit: martinak15/Flickr)

A new suite of computer programs could speed up the process of drug discovery for diseases, such as diabetes and Alzheimer’s, that involve amyloid fibrils.

Proteins sometimes run amuck and all the good stuff—the useful genetic and biological material—they contain can get distorted.

Mutations in specific amino acids can cause long strands of proteins to curl in on themselves, like a ball of wool a cat has played with, and refuse to break apart.

These strands, known as amyloid fibrils, can be extremely toxic and are usually harmful. They attach to organs like the brain and pancreas, preventing them from functioning as they should.

Developing effective medications to treat these diseases and cause the fibrils to dissolve typically involves biochemists in a lengthy and expensive process of trial and error.

Meet the ‘Fibrilizer’

Researchers led by Professor Jérôme Waldisühl of McGill University’s School of Computer Sciences have designed the new programs to scan the fibrils (or misfolded proteins) looking for weak spots. The idea is to then design helpful genetic mutations to dissolve the bonds that hold the fibrils together—a bit like finding the right strand of wool to tug on to unravel a whole knotted ball.

It’s potentially a gargantuan task, because looking for the mutations that will prove useful in drug development involves exploring millions of possible structural combinations of genetic material.

But for the Fibrilizer, as McGill has dubbed the suite of computer tools, the task is of a very different order.

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“Within the space of a week, by using our programs and a supercomputer, we were able to look at billions of possible ways to weaken the bonds within these toxic protein strands. We narrowed it down to just 30 to 50 possibilities that can now be explored further,” says Mohamed Smaoui, a postdoctoral fellow and the first author of three recent papers on the research.

“Typically biochemists can spend months or years in the lab trying to pinpoint these promising mutations.”

Diabetes drug possibilities

The researchers tested their program on a medical compound that scientists have been trying to improve for the last couple decades. The compound is administered as part of a drug that is used by diabetes patients to boost the performance of insulin and is sold under the name Symlin.

The synthetic compound is based on a version of the protein amylin, yet is known to be toxic to the pancreas over the long-term, creating amyloid fibrils. The team was able to use Fibrilizer to pinpoint a limited number of possible genetic modifications to the compound that would act to reduce its toxicity.

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Waldispühl believes that computational research of this kind will play an increasingly important role in drug discovery in the future. “Computers are transforming the way that drugs are being developed,” says Waldispühl. “Amyloid research has accelerated in the last 10 years. But computers may prove to be the key to finding better medications for a whole range of systemic and neurodegenerative diseases, from arthritis to Parkinson’s.

“Without supercomputers and programs of this kind, it would take much longer and be much more expensive to do this kind of research and come up with these possible solutions to the problem.”

The research has appeared in the journals Proteins, BMC Structural Biology, and Bioinformatics.

The Canadian Institutes of Health Research (CIHR) System Biology Training program at McGill University, the Fonds de recherche Nature et technologies Quebec, and the Natural Science and Engineering Research Council of Canada (NSERC) supported the work.

Source: McGill University