Research Group PLASMANT, Department of Chemistry, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium.
Sci Rep. 2019 Apr 2;9(1):5476. doi: 10.1038/s41598-019-41931-6.
The aggregation of insoluble amyloid beta (Aβ) peptides in the brain is known to trigger the onset of neurodegenerative diseases, such as Alzheimer's disease. In spite of the massive number of investigations, the underlying mechanisms to destabilize the Aβ aggregates are still poorly understood. Some studies indicate the importance of oxidation to destabilize the Aβ aggregates. In particular, oxidation induced by cold atmospheric plasma (CAP) has demonstrated promising results in eliminating these toxic aggregates. In this paper, we investigate the effect of oxidation on the stability of an Aβ pentamer. By means of molecular dynamics simulations and umbrella sampling, we elucidate the conformational changes of Aβ pentamer in the presence of oxidized residues, and we estimate the dissociation free energy of the terminal peptide out of the pentamer form. The calculated dissociation free energy of the terminal peptide is also found to decrease with increasing oxidation. This indicates that Aβ pentamer aggregation becomes less favorable upon oxidation. Our study contributes to a better insight in one of the potential mechanisms for inhibition of toxic Aβ peptide aggregation, which is considered to be the main culprit to Alzheimer's disease.
不溶性淀粉样蛋白 β（Aβ）肽的聚集被认为是引发神经退行性疾病（如阿尔茨海默病）的原因。尽管进行了大量研究，但导致 Aβ 聚集物不稳定的潜在机制仍知之甚少。一些研究表明氧化对破坏 Aβ 聚集物的重要性。特别是，冷等离体等离子体（CAP）诱导的氧化已证明在消除这些毒性聚集物方面具有广阔的前景。在本文中，我们研究了氧化对 Aβ 五聚体稳定性的影响。通过分子动力学模拟和伞状采样，我们阐明了在氧化残基存在下 Aβ 五聚体的构象变化，并估计了末端肽从五聚体形式中解离的自由能。末端肽的计算解离自由能也随氧化程度的增加而降低。这表明 Aβ 五聚体的聚集在氧化后变得不那么有利。我们的研究有助于更好地了解抑制有毒 Aβ 肽聚集的潜在机制之一，这被认为是阿尔茨海默病的主要罪魁祸首。
