PROTEIN AGGREGATION AND AMYLOIDAL FIBRIL FORMATION IN NANOPOLYMERIC

纳米聚合物中的蛋白质聚集和淀粉样纤维形成

• 批准号: 8360155
• 负责人: GUSTAVO E LOPEZ-QUINONES
• 金额: $ 10.2万
• 依托单位: UNIVERSITY OF PUERTO RICO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360155
• 关键词: Address; Amino Acid Sequence; Biomedical Research; Cereals; Charge; Computer Simulation; Coupled; Degenerative Disorder; Deposition; Development; Environment; Funding; Grant; Hydrophobicity; Insulin; Ionic Strengths; Membrane; Molecular; Molecular Conformation; Myoglobin; National Center for Research Resources; Nature; Peptides; Play; Principal Investigator; Proteins; Puerto Rico; Research; Research Infrastructure; Resources; Role; Sampling; Series; Solvents; Source; Structure; System; Techniques; Thermodynamics; Tissues; United States National Institutes of Health; cost; design; molecular dynamics; protein aggregate; protein aggregation; protein structure; research study; trend

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Recent experimental studies have shown that various degenerative diseases are associated with deposition in the body tissues of insoluble protein aggregates that have a particular (3-sheet conformation. These aggregates have been termed amyloidal fibrils. It has been proposed that the formation of amyloidal fibrils is determined by the nature of the intermediate unfolding species. Moreover, recent experimental studies have shown that amyloidal fibril formation might be favor when proteins are confined in membranes. However, not enough theoretical or experimental considerations have been focused on elucidate the extend of the effect and/or role that membranes plays in the amyloidal fibril formation. This becomes an important issue to address since polymeric protein delivery systems provide a suitable environment for protein fibrillization to occur. We propose to develop state-of-the-art computer simulations and experimental techniques to study the formation of the amyloidal fibrils under a series of well-defined and biologically relevant conditions. Specifically, coarse-grained and all-atom potentials will be used and/or develop to properly describe the interparticle forces. Monte Carlo and Molecular Dynamic simulations will be coupled to appropriate sampling techniques to determine the structure and stability of the aggregates. Experimental techniques will be designed and implemented to characterize the extend to which a given peptide will eventually form fibrils or amorphous aggregates. The results are expected to uncover basic trends (such as amino acid sequence, charge, ad hydrophobicity) on the molecular description of amyloidal fibril formations. These basic trends will permit the development of prediction capabilities for the possible fibril formation given the system (protein structure) and the experimental set-up (solvent, ionic strength, thermodynamic state, and presence of a membrane). By recognizing membrane compliance as an important additional consideration, we expect to deepen our understanding of the role of membrane composition and interface as a possible controller of fibrilar formation. Examples of these systems are insulin, lysozime, myoglobin, and STVIIE. Polymeric membranes of various composition, that provide a range of polarities, will be used.

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 最近的实验研究表明，各种退行性疾病与体内组织中沉积的具有特殊(3-折叠)构象的不溶性蛋白质聚集体有关。这些聚集体被称为淀粉样纤维。有人提出，淀粉样纤维的形成是 由中间展开物种的性质决定。此外，最近的实验研究表明，当蛋白质被限制在膜中时，淀粉样原纤维的形成可能是有利的。然而，还没有足够的理论或实验考虑来阐明这种影响的程度。 和/或膜在淀粉样纤维形成中所起的作用。这成为一个需要解决的重要问题，因为聚合物蛋白递送系统为蛋白质纤化的发生提供了合适的环境。我们建议开发最先进的计算机模拟和实验技术来研究淀粉样纤维在一系列明确的和生物相关的条件下的形成。具体地说，将使用和/或开发粗粒和全原子势来适当地描述粒间力。蒙特卡罗和分子动力学模拟将与适当的采样技术相结合，以确定聚集体的结构和稳定性。将设计和实施实验技术来表征给定肽最终形成纤维或无定形聚集体的程度。这些结果有望揭示淀粉样原纤维形成的分子描述的基本趋势(如氨基酸序列、电荷和疏水性)。这些基本趋势将允许在给定系统(蛋白质结构)和实验设置(溶剂、离子强度、热力学状态和膜的存在)的情况下，开发对可能的原纤维形成的预测能力。通过承认膜顺应性是一个重要的额外考虑因素，我们希望加深我们对膜成分和界面作为纤维形成可能控制器的作用的理解。这些系统的例子有胰岛素、溶菌素、肌红蛋白和STVIIE。将使用提供一系列极性的各种组成的聚合膜。