A wrong molecular turn leads down the path to type 2 diabetes

Computing resources at the U.S. Department of Energy’s (DOE) Argonne National Laboratory have helped researchers better grasp how proteins misfold to create the tissue-damaging structures that lead to type 2 diabetes. The structures, called amyloid fibrils, are also implicated in neurodegenerative conditions such as Alzheimer’s and Parkinson’s, and in prion diseases like Creutzfeldt-Jacob and mad cow disease.

The results pinpoint a critical intermediate step in the chemical pathway that leads to amyloid fibril formation. With the new culprit in view, future work could target a possible treatment, such as designing an inhibitor to interfere with the harmful pathway. The results also helped reconcile earlier data from other labs that until now appeared contradictory.

An amyloid fibril is a large structure consisting of misfolded proteins. Such fibrils form plaques, or areas of tissue damage, that researchers can observe with microscopes. Fibrils are believed to arise when proteins deviate from their normal 3D structures and instead adopt misfolded states that tend to clump together.

Like puzzle pieces, proteins are only useful when they have the correct shape. And since the fibrils they form when misfolded are strong, scientists believe that hope primarily lies not in dismantling them, but in heading off the folding errors.

The researchers used two main approaches to identify the intermediate step and understand the pathway. University of Wisconsin-Madison professor Martin Zanni used a sophisticated technique that relies on 2-D infrared spectroscopy to follow the sequence of events in the chemical reactions leading to fibril formation. His technique can measure extremely fast processes using very small samples.

Then Juan de Pablo and Chi-Cheng Chiu from the University of Chicago’s Institute for Molecular Engineering interpreted Zanni’s measurements with data from molecular simulations to arrive at a complete picture of the early events leading to amyloid formation.

De Pablo and Chiu used Intrepid, an IBM Blue Gene/P computer system at the Argonne Leadership Computing Facility (ALCF), and resources at the University of Chicago Research Computing Center. De Pablo and Chiu composed, ran and interpreted large-scale computer simulations of the pathway in action, and the results supplied an essential model of the molecular steps involved in the reaction.

“Using only one of the two methods would have been like running a race with only one leg,” de Pablo said. “By combining both computation and experiment, we can get to our answers faster and more dependably.”

Together, researchers located an entire step that had been missing, and whose absence had been fueling confusion.

An earlier study indicated that the intermediate step was likely a floppy loop area formed by proteins, which didn’t seem compatible with the tough, damaging fibril as an end result. Researchers believed that the fibrils should come from a rigid structure called a β-sheet.