Computational and Experimental Studies of the Amyloid Fibril Formation by PAPf39

描述（由申请人提供）：本研究项目的主题是开发和实验验证一种新的计算方法来分析蛋白质和肽中的结构集合，这些蛋白质和肽在溶液中主要是单体和非结构化的，但具有形成淀粉样蛋白纤维的能力。全原子计算机模拟的工具，这样的系统是目前欠发达的，这对我们的理解淀粉样变性的分子决定因素有显着的后果。为了将计算工具的发展放在生物学的背景下，我们将把它们应用到一个39个残基的肽从人类酸性前列腺磷酸酶，已知形成纤维状结构。这些纤维状结构已被证明对于增强人类细胞的病毒感染性是重要的。计算研究将通过一系列实验方法进行验证，包括NMR，原子力显微镜，荧光和圆二色谱，氢交换质谱。 公共卫生相关性：淀粉样蛋白原纤维与一系列使人衰弱的疾病有致病性相关。了解淀粉样蛋白和肽的结构-序列关系的作用，将提供详细的机制了解淀粉样变性的过程，并将有助于治疗设计。

DESCRIPTION (provided by applicant): The subject of this research project is to develop and experimentally validate a novel computational approach to analyze structural ensembles in proteins and peptides that are largely monomeric and unstructured in solution but have the ability to form amyloid fibers. The tools for all-atom computer simulations for such systems are currently underdeveloped which has significant consequences for our understanding of the molecular determinants of amyloidosis. In order to put the development of computational tools in a biological context, we will apply them to a 39-residue peptide from human acidic prostatic phosphatase that is known to form fibrillar structures. These fibrillar structures have been shown to be important for enhancement in viral infectivity of human cells. The computational study will be validated by a battery of experimental methods including NMR, atomic force microscopy, fluorescence and circular dichroism spectroscopies, and hydrogen exchange mass spectroscopy. PUBLIC HEALTH RELEVANCE: Amyloid fibrils are pathogenically associated with a range of debilitating human diseases. Understanding the role of the structure-sequence relationship in amyloidogenic proteins and peptides will provide detailed mechanistic insight into the process of amyloidosis and will aid design of therapeutics.