ABSTRACT

Several neurodegenerative disorders arise from the abnormal protein aggregation in the nervous tissue leading tointracellular inclusions or extracellular aggregates in specific brain areas. In case of Alzheimer Disease, the accumulation of the Amyloid Beta peptide in the brain is proposed to be an early important event in the pathogenesis. Despite significant research efforts in this field, the molecular mechanisms of protein misfolding and aggregation remain somewhat unrevealed.Within this framework, computer simulations represent a powerful tool able to connect macroscopic experimental findings to nanoscale molecular events.However, from the computational point of view, insufficient sampling often limits the ability of computer simulations to fully address this point. One of the main challenges of MD simulations is the ability to sample experimentally relevant millisecond to second timescales.The present review describes the applications of molecular dynamics techniques to elucidate the conformational states and the aggregation pathway of the Amyloid Beta peptide responsible for AD. Moreover, the computational studies focused on the impact of Amyloid Beta assemblies on cell membranes will be also described. Finally, the interaction mechanisms between promising small molecules and Amyloid Beta assemblies will be discussed within the field of designing new efficient drugs against neurodegenerative disorders.

Abbreviations

AD: Alzheimer disease; AB: amyloid beta; ABOs: amyloid beta oligomers; MD: molecular dynamics

中文翻译：

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淀粉样β组装的分子模拟

摘要

几种神经退行性疾病是由神经组织中异常的蛋白质聚集引起的，从而导致特定大脑区域的细胞内包裹物或细胞外聚集物。在阿尔茨海默氏病的情况下，大脑中淀粉样β肽的积累被认为是发病机理中的早期重要事件。尽管在该领域进行了大量研究，但蛋白质错折叠和聚集的分子机制仍未得到揭示。在此框架内，计算机模拟代表了一种强大的工具，能够将宏观实验结果与纳米级分子事件联系起来。采样不足通常会限制计算机仿真完全解决这一点的能力。MD模拟的主要挑战之一是能否从实验相关的毫秒到第二个时标进行采样。本综述描述了分子动力学技术在阐明负责AD的β淀粉样肽的构象状态和聚集途径方面的应用。此外，还将描述侧重于淀粉样蛋白β组装体对细胞膜影响的计算研究。最后，在设计针对神经退行性疾病的新型有效药物领域内，将讨论有希望的小分子与β淀粉样蛋白组装体之间的相互作用机制。本综述描述了分子动力学技术阐明负责AD的淀粉样β肽的构象状态和聚集途径的应用。此外，还将介绍针对淀粉样蛋白β组装体对细胞膜影响的计算研究。最后，将在设计针对神经退行性疾病的新型有效药物领域内讨论有前途的小分子与β淀粉样蛋白组装体之间的相互作用机制。本综述描述了分子动力学技术阐明负责AD的淀粉样β肽的构象状态和聚集途径的应用。此外，还将描述侧重于淀粉样蛋白β组装体对细胞膜影响的计算研究。最后，在设计针对神经退行性疾病的新型有效药物领域内，将讨论有希望的小分子与β淀粉样蛋白组装体之间的相互作用机制。

缩略语

AD：阿尔茨海默氏病；AB：β淀粉样蛋白；ABOs：淀粉样β寡聚物；MD：分子动力学