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Supercomputer aids Parkinsons disease discovery

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Using the Jaguar supercomputer at Oak Ridge National Laboratory (ORNL), researchers at North Carolina State University in the USA have figured out how copper induces misfolding in the protein associated with Parkinson’s disease, leading to creation of the fibrillar plaques which characterise the disease. This finding has implications for the study of Parkinson’s progression, as well as for future treatments.

The protein in question, alpha-synuclein, is the major component of fibrillar plaques found in Parkinson’s patients. Researchers had already discovered that certain metals, including copper, could increase the rate of misfolding by binding with the protein, but were unsure of the mechanism by which this binding took place.

‘We knew that the copper was interacting with a certain section of the protein, but we didn’t have a model for what was happening on the atomic level,’ said Frisco Rose, lead author of the paper describing the research. ‘Think of a huge swing set, with kids all swinging and holding hands—that’s the protein. Copper is a kid who wants a swing. There are a number of ways that copper could grab a swing, or bind to the protein, and each of those ways would affect all of the other kids on the swing set differently. We wanted to find the specific binding process that leads to misfolding.’

Rose and North Carolina State colleagues Miroslav Hodak, research assistant professor of physics, and Jerzy Bernholc, Drexel professor of Physics and director of the Center for High Performance Simulation, developed a series of computer simulations designed to ferret out the most likely binding scenario. According to Hodak, the team simulated the interactions of hundreds of thousands of atoms, which required multiple hundred thousand CPU-hour runs to study the onset of misfolding and the dynamics of the partially misfolded structures.

The number of calculations was so large that Hodak and Bernholc had to devise a new method to make it possible for a computer to process them. Only supercomputers like Jaguar, the most powerful supercomputer at ORNL—and within the United States—were suitable and the simulations finally revealed the binding configuration most likely to result in misfolding.

Their results appear in the 14 June edition of Nature Scientific Reports.