Computer Program Scan Amyloid Fibrils To Uncover Its Weaknesses

Computer Program Scan Amyloid Fibrils To Uncover Its Weaknesses
This is an amyloid fibril made up of 25 mis-folded amyloid
proteins.  (Right) A single color-coded amyloid protein. The
different colors represent key stability regions explored by
the algorithm developed at McGill. (Left)
Proteins sometimes run amuck, and the 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 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. They are responsible for diseases as seemingly different as diabetes and Alzheimer's, to name just a couple. 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.
Now, researchers have created a suite of computer programs that should speed up the process of drug discovery for diseases of this kind. The programs are designed to scan the fibrils looking for weak spots. The idea is to then design helpful genetic mutations to dissolve the bonds that hold the fibrils together. 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 the researchers have dubbed its suite of computer tools, the task is of a very different order. "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 - 50 possibilities that can now be explored further," the researchers said. "Typically biochemists can spend months or years in the lab trying to pinpoint these promising mutations."
Supercomputing to the rescue
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 research team were able to use Fibrilizer to pinpoint a limited number of possible genetic modifications to the compound that would act to reduce its toxicity.
The researchers believe that computers will play an increasingly important role in drug discovery in the future, and may prove to be the key to finding better medications for a whole range of systemic and neurodegenerative diseases, from arthritis to Parkinson's.
The three recent publications have described the research:
Complete characterization of the mutation landscape reveals the effect on amylin stability and amyloidogenicity. Proteins. (2015) Jun;83(6):1014-26. doi: 10.1002/prot.24795.

Computational re-engineering of Amylin sequence with reduced amyloidogenic potential. BMC Struct Biol. (2015) 15; 15: 7. doi: 10.1186/s12900-015-0034-4

Probing the binding affinity of amyloids to reduce toxicity of oligomers in diabetes. Bioinformatics. (2015) 31 (14):2294-2302.doi:10.1093/bioinformatics/btv143
Based on material originally posted by McGill University.