Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland 20742, United States.
Fischell Department of Bioengineering, University of Maryland, College Park, Maryland 20742, United States.
J Phys Chem B. 2024 Nov 7;128(44):10831-10840. doi: 10.1021/acs.jpcb.4c05636. Epub 2024 Oct 25.
Neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Huntington's, affect millions worldwide and share a common feature: the aggregation of intrinsically disordered proteins into toxic oligomers that interact with cell membranes. In Alzheimer's disease (AD), amyloid-beta (Aβ) peptides accumulate and bind to plasma membranes, potentially disrupting cellular function. The complex interplay between amyloidogenic peptides and lipid membranes, particularly the role of anionic lipids, is crucial in disease pathogenesis but challenging to characterize experimentally. The literature presents conflicting results on the influence of anionic lipids on peptide aggregation kinetics, highlighting a knowledge gap. To address this, we used coarse-grained molecular dynamics (CG-MD) simulations to study interactions between a model amyloidogenic peptide, amyloid-β's KLVFFAE fragment (Aβ), and mixed lipid bilayers. We used phosphatidylserine (PS) and phosphatidylcholine (PC) as representative anionic and zwitterionic lipids, respectively, examining the mixed bilayer compositions of 0% PS-100% PC, 10% PS-90% PC, and 30% PS-70% PC. Our simulations revealed that membranes enriched in anionic lipids enhance peptide adsorption and interaction kinetics. The aggregation dynamics was modulated by two competing factors: increased local peptide concentration near negatively charged membranes, which promoted aggregation, and peptide-lipid interactions, which slowed it down. Higher percentages of anionic lipids led to smaller and more ordered aggregates and enhanced lipid demixing, leading to the formation of PS clusters. These findings contribute to understanding membrane-mediated peptide aggregation in neurodegenerative disorders, potentially guiding new therapeutic strategies targeting the early stages of protein aggregation in various neurodegenerative diseases.
神经退行性疾病，如阿尔茨海默病、帕金森病和亨廷顿病，影响着全球数百万人，它们具有一个共同的特征：原本无规则的蛋白质聚集形成毒性寡聚物，与细胞膜相互作用。在阿尔茨海默病（AD）中，淀粉样β（Aβ）肽积累并与质膜结合，可能破坏细胞功能。淀粉样肽与脂膜之间的复杂相互作用，特别是阴离子脂质的作用，在疾病发病机制中至关重要，但在实验上难以进行表征。文献中关于阴离子脂质对肽聚集动力学的影响存在相互矛盾的结果，突出了这方面的知识空白。为了解决这个问题，我们使用粗粒化分子动力学（CG-MD）模拟研究了一种模型淀粉样肽，即淀粉样-β的 KLVFFAE 片段（Aβ）与混合脂质双层之间的相互作用。我们使用磷脂酰丝氨酸（PS）和磷脂酰胆碱（PC）分别作为代表性的阴离子和两性离子脂质，研究了 0% PS-100% PC、10% PS-90% PC 和 30% PS-70% PC 的混合双层组成。我们的模拟结果表明，富含阴离子脂质的膜增强了肽的吸附和相互作用动力学。聚集动力学受到两个竞争因素的调节：带负电荷的膜附近局部肽浓度的增加促进了聚集，而肽-脂质相互作用则减缓了聚集。较高比例的阴离子脂质导致较小且更有序的聚集体，并增强了脂质去混合，导致 PS 簇的形成。这些发现有助于理解神经退行性疾病中膜介导的肽聚集，可能为靶向各种神经退行性疾病中蛋白质聚集早期阶段的新治疗策略提供指导。
