Amyloid-β (Aβ42) Peptide Aggregation Rate and Mechanism on Surfaces with Widely Varied Properties: Insights from Brownian Dynamics Simulations.
Amyloid-β (Aβ42) Peptide Aggregation Rate and Mechanism on Surfaces with Widely Varied Properties: Insights from Brownian Dynamics Simulations.
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DOI：
10.1021/acs.jpcb.0c02926
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发表时间：
2020-07-09
期刊：
影响因子：
--
通讯作者：
Chang CA
中科院分区：
文献类型：
--
作者：
Cholko T;Barnum J;Chang CA
淀粉样蛋白β(Aβ)斑块是由无害的Aβ肽单体聚集成更大的纤维形成的，是阿尔茨海默病等神经退行性疾病的特征。治疗阿尔茨海默病的努力集中在阻止或逆转导致纤维形成的聚集过程。然而，由于该过程的某些未知方面，有效的治疗是难以捉摸的。许多假说指出，吸附的Aβ单体或低聚物破坏了细胞膜，但Aβ如何在性质差异很大的表面(如细胞中存在的那些表面)上表现和聚集尚不清楚。阐明不同表面对Aβ动力学的影响，以及从本体溶液到表面吸附多聚体的聚集过程的动力学有助于确定是什么驱动了聚集，从而导致了通过抑制药物或其他手段进行干预的新方法。在这项工作中，我们使用全原子布朗动力学模拟来研究两个不同的Aβ42单体构象与表面吸附或自由漂浮的Aβ42二聚体的结合。我们计算了缔合时间、表面相互作用能、表面扩散系数、表面停留时间，以及在四种不同表面和两种不同本体溶液情景下的缔合机理。在有表面存在的情况下，大多数单体经历了一种主要依赖于Aβ42与自组装单分子膜表面的静电相互作用的二维表面介导的缔合。此外，对Aβ42具有高亲和力和电荷分布不均的表面对聚集有很大的抑制作用。我们的结果可以用来确定扰乱或逆转Aβ42聚合过程的新机会。
Amyloid-β (Aβ) plaques, which form by aggregation of harmless Aβ peptide monomers into larger fibrils, are characteristic of neurodegenerative disorders such as Alzheimer’s disease. Efforts to treat Alzheimer’s disease focus on stopping or reversing the aggregation process that leads to fibril formation. However, effective treatments are elusive due to certain unknown aspects of the process. Many hypotheses point to disruption of cell membranes by adsorbed Aβ monomers or oligomers, but how Aβ behaves and aggregates on surfaces of widely varying properties, such as those present in a cell, is unclear. Elucidating the effects of various surfaces on the dynamics of Aβ and the kinetics of the aggregation process from bulk solution to a surface-adsorbed multimer can help identify what drives aggregation, leading to new methods of intervention by inhibitory drugs or other means. In this work, we used all-atom Brownian dynamics simulations to study the association of two distinct Aβ42 monomer conformations with a surface-adsorbed or free-floating Aβ42 dimer. We calculated the association time, surface interaction energy, surface diffusion coefficient, surface residence time, and the mechanism of association on four different surfaces and two different bulk solution scenarios. In the presence of a surface, the majority of monomers underwent a two-dimensional surface-mediated association that depended primarily on an Aβ42 electrostatic interaction with the self-assembled monolayer (SAM) surfaces. Moreover, aggregation could be inhibited greatly by surfaces with high affinity for Aβ42 and heterogeneous charge distribution. Our results can be used to identify new opportunities for disrupting or reversing the Aβ42 aggregation process.
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影响因子：
15.1
作者：
Kayed R;Head E;Sarsoza F;Saing T;Cotman CW;Necula M;Margol L;Wu J;Breydo L;Thompson JL;Rasool S;Gurlo T;Butler P;Glabe CG
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