Computer Simulations of Protein Aggregation

描述(申请人提供)：正常溶解的蛋白质异常地聚集成有序的聚集体，称为淀粉样纤维，是许多不同人类疾病的原因或相关症状，包括阿尔茨海默氏症、帕金森氏症和亨廷顿病、普恩病毒疾病和成人糖尿病。这些疾病统称为淀粉样变性，其特征是特定蛋白质缓慢沉积到淀粉样纤维中，然后积累成斑块，破坏受影响组织的功能，通常会导致退行性疾病，最终导致致命后果。了解导致蛋白质聚集成淀粉样蛋白的分子水平机制对于发现潜在的治疗策略和诊断至关重要。作为我们由NIH赞助的揭示支配蛋白质聚集的一般物理原理的努力的一部分，我们开发了一个中等分辨率的蛋白质模型，该模型允许在快速工作站上几天内使用不连续分子动力学(DMD)对多蛋白质系统进行模拟。最近的一项突破使我们能够模拟48个16个残基的丙氨酸肽从随机卷曲状态开始组装成纤维状结构。这表明，中等分辨率模型可以作为一种计算工具来探索短肽中纤维的形成。该项目有三个具体目标：(1)通过使用DMD模拟包含使用我们的中分辨率模型建模的聚丙氨酸链的多蛋白质系统，学习控制蛋白质原纤维形成的基本物理原理；(2)通过将中分辨率模型扩展到治疗多谷氨酰胺侧链，然后执行DMD模拟，阐明导致聚谷氨酰胺聚集的分子水平的机制，该蛋白质的纤化与亨廷顿病有关；以及(3)研究包含特定淀粉样肽的多蛋白质系统的聚集和可能的纤化。特别是阿尔茨海默氏肽Abeta(1-40)和Abeta(1-42)，通过将中分辨率模型扩展到所有20个残基的粗粒度表示，执行DMD模拟，并将我们的结果与实验进行比较。这项工作应该最终形成一幅详细的分子水平的纤化过程图，从而提供洞察力，以指导直接参与开发治疗策略或抑制剂的医学研究人员绕过纤化过程中对细胞损伤负有最大责任的步骤。

DESCRIPTION (provided by applicant): The aberrant assembly of normally soluble proteins into ordered aggregates, called amyloid fibrils, is a cause or associated symptom of many different human disorders including Alzheimer's, Parkinson's and Huntington's diseases, the prion diseases and adult-onset diabetes. Known collectively as the amyloidoses, these diseases are characterized by the slow deposition of a specific protein into amyloid fibrils, which then accumulate into plaques, destroying the function of the affected tissue, usually with degenerative and ultimately fatal consequences. An understanding of the molecular-level mechanisms that result in the aggregation of proteins into amyloid is essential for the discovery of potential therapeutic strategies and diagnostics. As-part of our NIH-sponsored effort to uncover the general physical principles that govern protein aggregation, we developed an intermediate-resolution protein model that allowed the simulation using discontinuous molecular dynamics (DMD) of multi-protein systems within days on a fast workstation. A recent breakthrough enabled us to simulate assembly of 48 16-residue alanine peptides into a fibrillar structure starting from the random coil state. This suggests that the intermediate-resolution model could be used as a computational tool to explore fibril formation in short peptides. The project has three specific aims: (1) to learn the basic physical principles governing protein fibril formation by using DMD to simulate multi-protein systems containing polyalanine chains modeled using our intermediate-resolution model, (2) to shed light on the molecular-level mechanisms responsible for the aggregation of polyglutamine, the protein whose fibrillization is linked to Huntington's disease, by extending the intermediate-resolution model to the treatment of polyglutamine side chains and then performing DMD simulations, and (3) to investigate the aggregation and possible fibrillization of multi-protein systems containing specific amyloidogenic peptides, particularly the Alzheimer's peptides Abeta(1-40) and Abeta(1-42), by extending the intermediate-resolution model to a coarse-grained representation of all 20 residues, performing DMD simulations, and comparing our results with experiment. This work should culminate in a detailed molecular-level picture of the fibrillization process, thereby providing insights to guide medical research workers directly involved in developing therapeutic strategies or inhibitors to circumvent those steps in the fibrillization process that are most responsible for cell damage.