Centro de Investigación en Ingeniería Molecular - CIIM, Vicerrectorado de Investigación, Universidad Católica de Santa María, Samuel Velarde 320, Arequipa, Peru.
Facultad de Ciencias Farmacéuticas, Bioquímicas y Biotecnológicas, Departamento de Farmacia, Bioquímica y Biotecnología, Universidad Católica de Santa María, Samuel Velarde 320, Arequipa, Peru.
J Mol Model. 2019 Dec 13;26(1):1. doi: 10.1007/s00894-019-4247-5.
The aggregation of proteins in the brain is one of the main features of neurodegenerative diseases. In Alzheimer's disease, the abnormal aggregation of Aβ-42 is due to intrinsic and extrinsic factors. The latter is due to variations in the environment, such as temperature, salt concentration, and pH. We evaluated the effect of protonation/deprotonation of residues that are part of trimeric and pentameric oligomers at pH 5, pH 6, and pH 7. Molecular dynamics simulation at 200 ns in the canonical ensemble was implemented. The results have revealed that histidine, glutamic acid, and aspartic acid residues showed a protonation/deprotonation effect in oligomers. The root mean square deviation analysis was used to analyze the structural stability at different pHs. We found an increase in hydrophobicity in the side chains of the trimer, while in the pentamer, the structural instability of a compact structure at pH 5 caused the hydrophobic core to open, revealing the hydrophobic region to the environment. At this point, we believe that conformational changes mediated by pH are essential in the aggregation of Aβ-42 oligomers.
蛋白质在大脑中的聚集是神经退行性疾病的主要特征之一。在阿尔茨海默病中，Aβ-42 的异常聚集是由于内在和外在因素造成的。后者是由于环境的变化，如温度、盐浓度和 pH 值。我们评估了处于 pH 5、pH 6 和 pH 7 时位于三聚体和五聚体寡聚物部分的残基质子化/去质子化的效果。在正则系综中进行了 200ns 的分子动力学模拟。结果表明，组氨酸、谷氨酸和天冬氨酸残基在寡聚体中表现出质子化/去质子化效应。均方根偏差分析用于分析不同 pH 值下的结构稳定性。我们发现三聚体中侧链的疏水性增加，而在五聚体中，pH 5 时紧凑结构的结构不稳定性导致疏水性核心打开，暴露出疏水区与环境接触。在这一点上，我们认为 pH 介导的构象变化对于 Aβ-42 寡聚物的聚集是必不可少的。
