COMPUTATIONAL STUDIES OF PRION PROTEIN STRUCTURE

朊病毒疾病是蛋白质构象的疾病，其中PrP的折叠表现出非安氏行为。我们希望了解PrP在正常生理条件下折叠形成PrPC时必须面对的能量景观，以及它如何折叠形成异常病理条件。在这个项目中，我们将使用蛋白质的晶格模型来探索允许朊病毒样行为的序列的一般特征，而不是更经典的Anfinsenian折叠。我们将研究这些观点与遗传性疾病机制的相关性。最后，虽然我们现在从残基125-231对PrPC的三维结构有了更好的了解，但我们对包括与铜络合的八重区（23-90）在内的全蛋白的结构仍然知之甚少。我们对PrPSc结构的了解更加有限。然而，我们相信我们可以利用我们在PrPSc 106迷你朊病毒上的结果来了解更多关于PrPSc的结构限制。

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.