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并实验验证一种新的计算方法来分析蛋白质和肽的结构集成，这些蛋白质和肽在溶液中大部分是单体和非结构化的，但具有形成淀粉样纤维的能力。这类系统的全原子计算机模拟工具目前尚不发达，这对我们理解淀粉样变性的分子决定因素具有重要意义。为了将计算工具的发展置于生物学背景下，我们将把它们应用于人类酸性前列腺磷酸酶的39个残基肽，该肽已知可形成纤维状结构。这些纤维结构已被证明对增强病毒对人类细胞的感染性很重要。计算研究将通过一系列实验方法进行验证，包括核磁共振、原子力显微镜、荧光和圆二色光谱以及氢交换质谱。

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.