Computational and Experimental Studies of the Amyloid Fibril Formation by PAPf39

PAPf39 淀粉样原纤维形成的计算和实验研究

基本信息

批准号：
8279567
负责人：
GEORGE I MAKHATADZE
金额：
$ 23.22万
依托单位：
RENSSELAER POLYTECHNIC INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-01 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8279567
关键词：
Algorithms Alzheimer&apos s Disease Amino Acid Substitution Amyloid Amyloid Fibrils Amyloid fibers Amyloidosis Area Atomic Force Microscopy Binding Biochemical Biological Biological Models Biomedical Research Cells Circular Dichroism Spectroscopy Collaborations Computational Biology Computational Science Computer Analysis Computer Simulation Computing Methodologies Data Data Storage and Retrieval Development Disease Drug Delivery Systems Electronics Exhibits Fluorescence Heterogeneity Human Hydrogen Imagery Kinetics Lead Mass Spectrum Analysis Methods Molecular NIH Program Announcements Non-Insulin-Dependent Diabetes Mellitus Outcome Parkinson Disease Peptides Pharmaceutical Preparations Phosphoric Monoester Hydrolases Prion Diseases Process Prostatic Proteins Research Research Project Grants Role Sampling Seminal fluid Solutions Structure System Technology Testing Therapeutic Validation Viral Water amyloid fibril formation amyloid formation analytical tool base biomedical informatics computer studies computerized tools data integration database design design graphical user interface human disease innovation insight models and simulation molecular dynamics monomer novel particle polypeptide prevent programs protein aggregation research and development research study response simulation therapeutic target three dimensional structure tool

项目摘要

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.

描述（由申请人提供）：该研究项目的主题是开发和实验验证一种新型的计算方法，以分析在很大程度上是单体且非结构溶液中但具有形成淀粉样纤维的能力的蛋白质和肽中的结构合奏。目前，用于此类系统的全原子计算机模拟的工具欠发达，这对我们对淀粉样变性的分子决定因素产生了重大影响。为了将计算工具的开发放在生物学环境中，我们将将其应用于人类酸性前列腺磷酸酶的39个残留肽，该肽已知形成原纤维结构。这些原纤维结构已被证明对于增强人类细胞病毒感染性很重要。计算研究将通过一系列实验方法来验证，包括NMR，原子力显微镜，荧光和圆形二分法光谱以及氢交换质谱。公共卫生相关性：淀粉样蛋白原纤维与一系列令人衰弱的人类疾病有关。了解结构 - 序列关系在淀粉样蛋白和肽中的作用将提供详细的机械洞察力，以了解淀粉样变性的过程，并有助于设计治疗疗法。