Ermilova Inna, Lyubartsev Alexander P
Department of Materials and Environmental Chemistry, Stockholm University Stockholm Sweden
RSC Adv. 2020 Jan 23;10(7):3902-3915. doi: 10.1039/c9ra06424a. eCollection 2020 Jan 22.
Aggregation of amyloid beta (Aβ) peptides in neuronal membranes is a known promoter of Alzheimer's disease. To gain insight into the molecular details of Aβ peptide aggregation and its effect on model neuronal membranes, we carried out molecular dynamics simulations of the Aβ(25-35) fragment of the amyloid precursor protein in phospholipid bilayers composed of either fully saturated or highly unsaturated lipids, in the presence or absence of cholesterol. It was found that the peptide does not penetrate through any of the considered membranes, but can reside in the headgroup region and upper part of the lipid tails showing a clear preference to a polyunsaturated cholesterol-free membrane. Due to the ordering and condensing effect upon addition of cholesterol, membranes become more rigid facilitating peptide aggregation on the surface. Except for the case of the cholesterol-free saturated lipid bilayer, the peptides have a small effect on the membrane structure and ordering. It was also found that the most "active" amino-acid for peptide-lipid and peptide-cholesterol interaction is methionine-35, followed by asparagine-27 and serine-26, which form hydrogen bonds between peptides and polar atoms of lipid headgroups. These amino acids are also primarily responsible for peptide aggregation. This work will be relevant for designing strategies to develop drugs to combat Alzheimer's disease.
淀粉样β（Aβ）肽在神经元膜中的聚集是已知的阿尔茨海默病的促进因素。为了深入了解Aβ肽聚集的分子细节及其对模型神经元膜的影响，我们对淀粉样前体蛋白的Aβ（25 - 35）片段在由完全饱和或高度不饱和脂质组成的磷脂双层中进行了分子动力学模拟，模拟过程中存在或不存在胆固醇。结果发现，该肽不会穿透任何一种所考虑的膜，但可以存在于脂质头部区域和脂质尾部的上部，并且明显更倾向于不含胆固醇的多不饱和膜。由于添加胆固醇后产生的有序化和凝聚作用，膜变得更加刚性，有利于肽在表面聚集。除了不含胆固醇的饱和脂质双层的情况外，肽对膜结构和有序性的影响较小。还发现，肽与脂质和肽与胆固醇相互作用中最“活跃”的氨基酸是甲硫氨酸 - 35，其次是天冬酰胺 - 27和丝氨酸 - 26，它们在肽与脂质头部基团的极性原子之间形成氢键。这些氨基酸也是肽聚集的主要原因。这项工作将有助于设计开发抗阿尔茨海默病药物的策略。
