GROWTH MECHANISMS OF AMYLOID FIBRILS

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 肽或蛋白质聚集是当前非常感兴趣的领域，因为其与神经退行性疾病（如阿尔茨海默病、帕金森病）密切相关。 虽然许多研究者都在对这一问题的不同方面进行研究，但是由于其复杂性，仍有许多问题有待解决。 在这项提案中，我们将研究β-淀粉样肽（Abeta）自我聚集问题的一个方面，它被认为是阿尔茨海默病的罪魁祸首。 在Abeta的自聚集过程的许多复杂程度中，淀粉样蛋白形成的一些特征最近出现在实验和模拟研究中。特别有趣的是建议的原纤维生长的码头锁机制，首先建议的实验，然后验证模拟与短肽段的Abeta。 这也表明，这种行为可能是纤维形成的普遍现象。目前，对淀粉样蛋白原纤维形成过程的计算机模拟研究，旨在直接或间接地阐明原纤维形成的详细途径，是一个热门的课题。然而，大多数模拟仅限于Abeta肽的短片段或基于粗粒度模型。 在这篇报告中，我们打算在全原子显水条件下研究Abeta（1-42）的纤维形成过程。实际原纤维形成过程的时间尺度是从几小时到几天。为了避免这种时间尺度上的困难，我们将从已经形成的聚集原纤维开始模拟，然后加热它，直到一个单体即将离开原始原纤维。在这一点上，我们开始模拟在室温下（300 K）观察到的自发沉积过程中的单体到一个预先形成的原纤维。本研究的目的是验证原纤维生长过程的对接锁定机制，以找到这种原纤维生长的主要驱动力，以确定聚集过程的核的大小，并发现脱水在生长过程的对接阶段的作用。计算机模拟Abeta原纤维生长过程的一个长期目标是找到破坏或减缓这种神经退化过程的方法。

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. Peptide or protein aggregation is a field of great current interest, because of its close relationship to neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease. Although many researchers are working in the different aspects of the problems, however, due to their complexity, many questions remain to be answered. In this proposal, we will study one aspect of the self-aggregation problem of beta-amyloid peptides (Abeta), believed to be the main culprit of Alzheimer's disease. Among many levels of complications of the self-aggregation processes of Abeta, some characteristic features of amyloid formation emerge recently in both the experimental and simulational investigations. Particularly interesting is the suggested dock-lock mechanism for fibril growth, first suggested by experiments and then verified by simulations with short-peptide segments of Abeta. It is also suggested that such behavior might be general phenomena in fibril formation. Currently, computational studies on amyloid fibril formation process, aiming at elucidating directly and indirectly the detailed fibril formation pathways, are a hot subject. However, most of the simulations are restricted to short-segments of the Abeta peptides or based on coarse-grained models. In this report, we propose to study the fibril formation process of Abeta(1-42) under the all-atom explicit water condition. The time scale of the actual fibril formation process is from several hours to several days. To circumvent this time scale difficulty, we will start the simulation from an aggregated fibril already formed and then heat it up, until one monomer is about to leave the original fibril. At this point, we begin the simulation at room temperature (300 K) to observe the spontaneous deposition process of a monomer onto a preformed fibril. The objectives of this study are to verify the dock-lock mechanism of the fibril growth process, to find the main driving force of this fibril growth, to determine the size of the nuclei of the aggregation process, and to discover the roles of dehydration in the docking phase of the growth process. A long-range goal for the computer simulations of the fibril growth process of Abeta is to find ways to disrupt or slow down this neurodegerative process.