The National Institute for Computational Sciences

Parkinson's Research

Study of Degenerative Disease Furthered by Kraken Supercomputer, Other XSEDE Resources

Muhammad Ali, Michael J. Fox, and Linda Ronstadt.

All legends in their respective fields; all diagnosed with Parkinson’s Disease, the dreaded degenerative disease that ranks as the 14th leading cause of death in the U.S. More than one million Americans currently battle Parkinson’s, joining an estimated four to six million people around the world who suffer from the disease.

One aspect of Parkinson’s is the presence of Lewy bodies, abnormal deposits of a protein called alpha-synuclein (aS) in the brain. These deposits are one of the most common causes of the dementia that often afflicts those with Parkinson’s, but little is known about aS and it’s role in the brain.

Enter Josh Vermaas and Emad Tajkhorshid, two researchers from the Beckman Institute for Advanced Science and Technology at the University of Illinois at Urbana-Champaign who have studied aS. Their paper “Conformational Heterogeneity of α-Synuclein in Membrane”—published in BBA-Biomembranes, 2014—has shed light on a point of contention about the protein.

Previous experiments performed by other scientists had found that a large part of aS’s physiology is membrane dependent, but an experimentally determined structural model for the protein in a biological membrane did not exist. Two distinct opinions emerged—some scientists thought that the protein held a linear helix shape, and others thought it maintained a horseshoe-like bent helix shape during those times.

“We were trying to address a point of contention in the aS literature,” Tajkhorshid said in an email interview. “Is aS a linear helix or a bent helix when it is bound to the membrane and fulfilling its normal physiological role?”

The duo used the Kraken supercomputer (now decommissioned) at the National Institute for Computational Sciences to perform simulations of aS binding to a highly mobile membrane mimetic (HMMM). Previous computational studies had placed the protein in a certain position in the membrance, but Vermaas and Tajkhorshid were able to observe spontaneous insertion of the peptide in the membrane.

Kraken was a resource of the National Science Foundation-funded Extreme Science and Engineering Discovery Environment (XSEDE). Computations were also performed on the XSEDE resources Ranger and Stampede at the Texas Advanced Computing Center (TACC).

Because each simulation involved a system of around 120,000 atoms, Vermaas said Kraken’s scale was key to their research. What would have taken more than five years on a normal desktop computer was accomplished in a month.

Their research found that aS actually transitions between the horseshoe-like conformation to a (more linear) semi-extended conformation. The point of contention was moot the whole time; alpha synuclein functions with a natural variability, shifting conformations to match the membrane to which it’s bound.

They also observed that, in the cases where the helix conformation was at its most extended, high concentrations of negatively charged phospholipids would break interactions between the two helices. The observation could be a clue to the membrane dependence of aS.

“This action, combined with the net positive charge of aS, is why negative phospholipids are essential to aS function,” Tajkhorshid said.

As scientists continue to research aS, they will do so with the knowledge that a range of conformations likely characterizes the protein’s native state. And because Parkinson’s disease is inherently a misfolding and aggregation of alpha synuclein into Lewey bodies, understanding aS’s native state is key to understanding Parkinson’s disease.

“Our research is primarily important in establishing the ‘normal’ behavior and function of alpha-synuclein,” Tajkhorshid said.


R. J. Vogt, science writer, NICS, JICS

Article posting date: 24 September 2014

About JICS and NICS: The Joint Institute for Computational Sciences (JICS) was established by the University of Tennessee and Oak Ridge National Laboratory (ORNL) to advance scientific discovery and state-of-the-art engineering, and to further knowledge of computational modeling and simulation. JICS realizes its vision by taking full advantage of petascale-and-beyond computers housed at ORNL and by educating a new generation of scientists and engineers well versed in the application of computational modeling and simulation for solving the most challenging scientific and engineering problems. JICS runs the National Institute for Computational Sciences (NICS), which had the distinction of deploying and managing the Kraken supercomputer. NICS is a leading academic supercomputing center and a major partner in the National Science Foundation's eXtreme Science and Engineering Discovery Environment, known as XSEDE. In November 2012, JICS sited the Beacon system, which set a record for power efficiency and captured the number one position on the Green500 list of the most energy-efficient computers.