ICDS News

The image shows the native folded structure of the protein phosphoglycerate kinase (PGK) on the left and one of the misfolded PGK structures predicted in this study on the right, with the entangled regions highlighted in red and blue. Credit: Provided by Yang Jiang via Penn State News

ICDS co-hire leads research on protein misfolding

EDITOR’S NOTE: A version of this story was originally published on Penn State News.

UNIVERSITY PARK, Pa. — A team of researchers at Penn State, including Ed O’Brien, Penn State Institute for Computational and Data Sciences co-hire and professor of chemistry in the Eberly College of Science, have found that proteins which naturally fold into complex structures to function correctly, can misfold and potentially lead to disease.

The new study, which was published on March 14 in the journal Science Advances, described a potential mechanism that could explain why some proteins misfold. According to the researchers, correcting this mishap requires high-energy or unfolding, which slows the folding process and leading to the first observed unexpected pattern in the 1990s.

“Misfolded proteins can malfunction and lead to disease. So, understanding the mechanisms involved in the folding processes can potentially help researchers prevent or develop treatments for diseases caused by misfolding,” O’Brien said in an article with Penn State News.

The team has identified this misfolding as a non-covalent lasso entanglement, which shows that a loop of the protein traps another segment of the protein, intertwining itself incorrectly, O’Brien said.

Researchers used a combination of computer simulations and refolding experiments to describe the folding kinetics of a protein called phosphoglycerate kinase (PGK). The folding pattern of PGK was observed for the first time experimentally over 25 years ago. PGK’s molecules followed a different pattern — or “stretched-exponential refolding kinetics — to the typical “two-state model” to reach a fully folded state. The structural mechanism to explain the difference in patterns was a mystery until the team’s study, which hypothesizes that this new class of misfolding could potentially be responsible for PGK’s pattern of folding.

The team built a computer model to simulate the folding process of the PGK protein and explored the intermediate stages of the folding processes to better understand the structure and see if there were changes that could explain the stretched refolding. The researchers found that the misfolded states predicted in the simulations were consistent with the structural signals observed in the refolded protein. Additionally, they suggested that these misfolded states were a crucial component of the observed stretched-exponential folding kinetics.

The research team includes: Yiang Jiang, assistant research professor of chemistry in the Eberly College of Science and first author on the paper; Ian Sitarik, Penn State graduate student; Hyebin Song, assistant professor of statistics at Penn State; Stephen Fried and his lab out of Johns Hopkins University; Yingzi Xia and Piyoosh Sharma, co-first authors at Johns Hopkins University.

Researchers used ICDS’ Roar supercomputer for their computer simulations and data analysis.

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