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Finding order in intrinsically disordered proteins

Intrinsically disordered proteins, proteins that do not have a well-defined structure, have been implicated in a number of diseases, including early-onset Parkinson’s, Alzheimer’s and other neurodegenerative diseases when such proteins aggregate in the human body.

Jeetain Mittal, the P.C. Rossin Assistant Professor of Chemical Engineering, and his group have developed a highly accurate method of simulating how these intrinsically disordered proteins, or IDPs, fold. The simulation method is a major advance and could lead to a much better understanding of not only how proteins fold, but also how they sometimes misfold, leading to pathogenesis of various diseases.

Recent advances in protein structure prediction using bioinformatics have accuracy limitations, especially when it comes to IDPs, says Mittal.

“We know disordered proteins function, but their lack of structure is only well-established outside the cellular environment,” he says. “Are these proteins really disordered inside the cell? The only way to really know for certain is to use physics-based, not statistics-based, modeling. It removes any guesswork.”

Mittal and his group don’t insert information based on previously identified protein structures in their model. Rather, they define only the interactions of atoms in their models and let these interactions dictate the resulting protein structure.

The group has already been able to show that a well-known IDP, N-terminal TAD domain of p53, a tumor-suppressor protein, can actually fold transiently, something that is difficult to detect with even the most sophisticated biophysical experimental techniques. Identifying such subtle IDP features might someday be useful in pinpointing the aspects of protein structure that are involved in the development of diseases.

Cayla Miller ’15 is working with Mittal to compare properties of human and rat Amylin peptides, which are known to be disordered in solution and which, in humans, are often linked with β-cell death in type 2 diabetes. The comparison might help explain what causes the aggregation of the human Amylin, but not the rat Amylin peptides.

Apratim Bhattacharya, a Ph.D. candidate, is studying IDP properties including their folding when binding to another protein, a process known as coupled folding and binding. This is an important step to understand if IDPs are really disordered in the context of the cellular environment.

Mittal’s team uses computing resources provided by NSF to develop and run their models. Their goal is to identify remaining inaccuracies in their model and improve it further.