Probling the Principles of Amyloid Formation

描述(申请人提供)：已知蛋白质的结合 序列被认为是阿尔茨海默氏症和其他疾病的主要原因 神经退行性疾病。聚集后，某些蛋白质形成纤维状。 被认为是必要的致病因素的结构。这个 多肽链聚集形成的机制 纤维状结构在很大程度上是未知的。到目前为止，实验已经提供了 仅某些斑块聚集态的低分辨率结构 形成多肽。此外，构象波动的性质 导致多肽链聚集的机制尚未完全阐明。这个 这项研究的长期目标是阐明 负责多肽缔合和纤维形成的原理。 为了实现这一目标，国际刑警组织提出了一种多方面的方法，包括 开发和使用新的计算方法。他们将雇用所有 用原子分子动力学模拟探讨金属离子的凝聚机制 β-多肽(在水中结构为单体多肽)和人胰淀素 (在单体状态下为无结构)。这将使他们能够监控 详细说明引发(成核)纤维的结构的性质 队形。多肽结合途径的完整表征 将通过直接模拟蛋白质-蛋白质结合来实现， 结合反应路径算法的应用进行探索 蛋白质二聚化和纤维伸长。去发现一般原理 关于淀粉样蛋白的形成，施特劳布博士将补充详细的分子 涉及粗粒度模型的研究的动力学模拟 多肽。这是必要的，因为需要的时间长得令人望而却步 用于所有原子模拟，以检查大量的多肽序列。vbl.使用 非晶格和晶格模型(带有侧链)，施特劳布博士建议 考察多肽缔合的相行为、能量学和动力学。一个 进一步的目标是探索折叠中间体在促进 聚合。简化的模型将被用来研究 多肽序列和初始条件影响原纤维的形成。初步 结果表明，原子化模型和粗粒度模型都是有效的 用于探索蛋白质动力学和平衡的细节的工具 在聚合过程中。建议的计算组合 方法将导致对聚合的概念性理解， 分子水平，在多肽链中，这是理解 淀粉样变性疾病。

DESCRIPTION (provided by applicant): The association of proteins of known sequence is believed to be the principal cause of Alzheimer's and other neurodegenerative diseases. Upon aggregation, certain proteins form fibrillar structures that have been implicated as necessary pathogenic factors. The mechanisms of aggregation of polypeptide chains that lead to the formation of fibrillar structures is largely unknown. To date, experiments have provided only low resolution structures of the aggregated states of certain plaque forming peptides. In addition, the nature of conformational fluctuations leading to aggregation of polypeptide chains has not been fully elucidated. The long-term goal of this research is the elucidation of the fundamental principles responsible for polypeptide association and fibrillar formation. To achieve this goal, the PI's propose a multifaceted approach that includes the development and use of novel computational methods. They will employ all atom molecular dynamics simulations to probe the aggregation mechanism in Abeta-peptide (structured as monomeric peptide in water) and human amylin (structureless in the monomeric state). This will enable them to monitor in detail the nature of initiating (nucleating) structures responsible for fibril formation. The complete characterization of the peptide association pathways will be achieved through the direct simulation of protein-protein association, in conjunction with the application of reaction pathway algorithms to explore protein dimerization and fibril elongation. To discover the general principles governing amyloid formation, Dr. Straub will supplement the detailed molecular dynamics simulations with studies involving coarse grained models of polypeptides. This is necessary due to the prohibitively long times required for all atom simulations to examine a large number of peptide sequences. Using off-lattice and lattice models (with side chains), Dr. Straub proposes to examine the phase behavior, energetics and kinetics of peptide association. A further objective is to probe the role of folding intermediates in facilitating aggregation. Simplified models will be used to examine how the details of peptide sequence and initial conditions influence fibril formation. Preliminary results suggest that both atomistic and coarse-grained models can be effective tools for exploring the details of protein dynamics and equilibriums that arise in the aggregation process. The proposed combination of computational approaches will lead to a conceptual understanding of aggregation, at the molecular level, in polypeptide chains that is central to the understanding of amyloid diseases.