Computational and Experimental Studies of the Amyloid Fibril Formation by PAPf39

描述(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多肽中的结构系综，这些蛋白质和多肽在溶液中主要是单体和非结构化的，但有能力形成淀粉样纤维。目前，用于这类系统的全原子计算机模拟的工具还不够发达，这对我们理解淀粉样变性的分子决定因素有着重要的影响。为了将计算工具的开发放在生物学的背景下，我们将把它们应用到人类酸性前列腺磷酸酶的39个残基上，已知这种多肽形成纤维状结构。这些纤维状结构已被证明对增强人类细胞的病毒感染性很重要。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、荧光和圆二色谱以及氢交换质谱学。

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.