电场破坏二聚体β-淀粉样体。

IF 3.7 Q2 CHEMISTRY, PHYSICAL
Pablo Andrés Vargas-Rosales, Alessio D’Addio, Yang Zhang and Amedeo Caflisch*, 
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引用次数: 1

摘要

淀粉样蛋白Aβ肽的早期低聚物与阿尔茨海默病有关,但其短暂性使其结构和毒性的表征复杂化。在这里,我们研究了最小毒性物质,即β-淀粉样蛋白二聚体,在振荡电场存在下的稳定性。我们首先使用深度学习(AlphaFold多聚体)生成Aβ42二聚体的初始模型。然后通过多次分子动力学(MD)分析了模型的柔性和二级结构含量。结构稳定的模型类似于微秒长MD采样的系综代表。最后,我们使用经验证的模型作为在存在外部振荡电场的情况下MD模拟的起始结构,并观察到在高场强下β-片含量的快速衰减。使用42个残基亮氨酸拉链肽的螺旋二聚体的对照模拟显示出比Aβ42二聚体更高的结构稳定性。模拟结果提供了证据,证明外部电场(以1GHz振荡)可以破坏淀粉样蛋白低聚物,这应该通过体外和最终体内的脑类器官实验进行进一步研究。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Disrupting Dimeric β-Amyloid by Electric Fields

Disrupting Dimeric β-Amyloid by Electric Fields

The early oligomers of the amyloid Aβ peptide are implicated in Alzheimer’s disease, but their transient nature complicates the characterization of their structure and toxicity. Here, we investigate the stability of the minimal toxic species, i.e., β-amyloid dimers, in the presence of an oscillating electric field. We first use deep learning (AlphaFold-multimer) for generating initial models of Aβ42 dimers. The flexibility and secondary structure content of the models are then analyzed by multiple runs of molecular dynamics (MD). Structurally stable models are similar to ensemble representatives from microsecond-long MD sampling. Finally, we employ the validated model as the starting structure of MD simulations in the presence of an external oscillating electric field and observe a fast decay of β-sheet content at high field strengths. Control simulations using the helical dimer of the 42-residue leucine zipper peptide show higher structural stability than the Aβ42 dimer. The simulation results provide evidence that an external electric field (oscillating at 1 GHz) can disrupt amyloid oligomers which should be further investigated by experiments with brain organoids in vitro and eventually in vivo.

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来源期刊
CiteScore
3.70
自引率
0.00%
发文量
0
期刊介绍: ACS Physical Chemistry Au is an open access journal which publishes original fundamental and applied research on all aspects of physical chemistry. The journal publishes new and original experimental computational and theoretical research of interest to physical chemists biophysical chemists chemical physicists physicists material scientists and engineers. An essential criterion for acceptance is that the manuscript provides new physical insight or develops new tools and methods of general interest. Some major topical areas include:Molecules Clusters and Aerosols; Biophysics Biomaterials Liquids and Soft Matter; Energy Materials and Catalysis
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