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 leadi
|Contact: Brian Grabowski|
DOE/Argonne National Laboratory