Prion diseases are diseases of protein conformation where the folding of PrP displays non Anfinsenian behavior. We wish to understand the energy landscape that PrP must confront as it folds to form PrPC under normal physiological conditions and how it can refold to form aberrant pathologic conditions. In this project, we will use lattice models of proteins to explore the general features of sequences that allow prion-like behavior instead of more classical Anfinsenian folding. We will study the relevance of these ideas to the mechanisms for inherited disease. Finally, while we now he a better understanding of the three dimensional structure of PrPC from residues 125-231, we still do not know much about the structure of the holoprotein including the octarepeat region (23-90) complexed to copper. Our insight into the structure of PrPSc is even more limited. However, we believe that we can leverage our results on the PrPSc 106 mini prion to learn more about the structural constraints on PrPSc.
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