Insights into Stabilizing Forces in Amyloid Fibrils of Differing Sizes from Polarizable Molecular Dynamics Simulations
Insights into Stabilizing Forces in Amyloid Fibrils of Differing Sizes from Polarizable Molecular Dynamics Simulations
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DOI：
10.1016/j.jmb.2018.05.020
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发表时间：
2018-10-12
影响因子：
5.6
通讯作者：
Lemkul, Justin A.
中科院分区：
文献类型：
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作者：
Davidson, Darcy S.;Brown, Anne M.;Lemkul, Justin A.
淀粉样蛋白形成蛋白的病理性聚集是许多人类疾病的标志，包括阿尔茨海默氏症、2型糖尿病、帕金森氏症等。尽管具有非常不同的一级氨基酸序列，这些淀粉样蛋白形成相似的超分子，原纤维结构，对物理和化学变性具有高度弹性。为了更好地了解疾病相关的淀粉样蛋白的结构稳定性，并获得更好的理解的因素，稳定功能性淀粉样蛋白组件，深入了解三级和四级相互作用是必要的。我们对人类tau蛋白、淀粉样蛋白-β和胰岛淀粉样蛋白多肽原纤维进行了分子动力学模拟，以确定导致其独特特征和原纤维结构的关键理化性质。这些模拟是第一次采用极化力场来探索局部电场对偶极特性和其他有助于淀粉样蛋白稳定性的静电力的特性。在这些不同的淀粉样原纤维中，我们重点关注潜在的力如何稳定原纤维，以阐明蛋白质聚集背后的驱动力。极化模型允许侧链的偶极矩，结构化的水分子在原纤维核心的性能，以及盐桥周围的局部环境如何有助于形成的界面，对原纤维的稳定性至关重要的调查。通过系统地研究三种淀粉样蛋白的各种原纤维大小的关键结构特性和稳定力，我们揭示了淀粉样蛋白结构的性质相关的疾病和功能状态在原子水平。(C)2018爱思唯尔有限公司版权所有。
Pathological aggregation of amyloid-forming proteins is a hallmark of a number of human diseases, including Alzheimer's, type 2 diabetes, Parkinson's, and more. Despite having very different primary amino acid sequences, these amyloid proteins form similar supramolecular, fibril structures that are highly resilient to physical and chemical denaturation. To better understand the structural stability of disease-related amyloids and to gain a greater understanding of factors that stabilize functional amyloid assemblies, insights into tertiary and quaternary interactions are needed. We performed molecular dynamics simulations on human tau, amyloid-beta, and islet amyloid polypeptide fibrils to determine key physicochemical properties that give rise to their unique characteristics and fibril structures. These simulations are the first of their kind in employing a polarizable force field to explore properties of local electric fields on dipole properties and other electrostatic forces that contribute to amyloid stability. Across these different amyloid fibrils, we focused on how the underlying forces stabilize fibrils to elucidate the driving forces behind the protein aggregation. The polarizable model allows for an investigation of how side-chain dipole moments, properties of structured water molecules in the fibril core, and the local environment around salt bridges contribute to the formation of interfaces essential for fibril stability. By systematically studying three amyloidogenic proteins of various fibril sizes for key structural properties and stabilizing forces, we shed light on properties of amyloid structures related to both diseased and functional states at the atomistic level. (C) 2018 Elsevier Ltd. All rights reserved.