Pan Tong, Tan Yuan, Dong Xuewei, Tang Yiming, Yang Zhongyuan, Chen Yujie, Wei Guanghong
Department of Physics, State Key Laboratory of Surface Physics, Key Laboratory for Computational Physical Sciences (Ministry of Education), Fudan University, Shanghai 200438, China.
Center for Soft Condensed Matter Physics and Interdisciplinary Research & School of Physical Science and Technology, Soochow University, Suzhou , Jiangsu 215006, China.
J Phys Chem B. 2025 Jun 5;129(22):5449-5463. doi: 10.1021/acs.jpcb.5c01590. Epub 2025 May 22.
Abnormal aggregation of tau protein into β-sheet amyloid fibrils is closely associated with Alzheimer's disease and other tauopathies. Interactions between tau and cell membranes can lead to accelerated fibrillization and membrane deformation, serving as a toxicity pathway for tau aggregation. The tau fibril-nucleating core motif PHF6 (VQIVYK) has been reported to play a key role in tau-membrane interactions. However, the underlying molecular mechanisms remain largely unexplored, and the effect of terminal capping on PHF6-membrane interactions has often been overlooked. Herein, we performed extensive all-atom molecular dynamics simulations to investigate the interactions between four PHF6 terminal acetylation-amidation variant fibrils and a mixed POPC/POPG membrane. Our simulations highlight the pivotal role of N-terminal capping in modulating the membrane binding of PHF6 fibrils (bilayer β-sheets), as well as the resulting fibril stabilization and membrane disruption. We find that regardless of their C-terminal amidation states, the N-terminally acetylated PHF6 (Ac-PHF6 and Ac-PHF6-NH) fibrils are prone to bind to the membrane surface through electrostatic attraction between cationic side chains of K311 and anionic POPG lipids. This membrane binding reduces the dynamics of PHF6 fibril compared to that in solution, thus facilitating inter- and intrasheet interactions, and in turn stabilizes the overall fibril structure. In contrast, the N-terminally nonacetylated PHF6 (PHF6 and PHF6-NH) fibrils tend to insert into membranes via their cationic N-termini. This membrane insertion favors PHF6 intrasheet interactions but disfavors intersheet interactions due to the interference of lipid molecules during the insertion process and causes more severe membrane disruption than N-terminally acetylated PHF6 fibrils. Additionally, MD simulations on N-terminally nonacetylated PHF6 protofibrils (single-layer parallel β-sheets) show that membrane binding stabilizes the protofibrils, which are unstable in aqueous solution. These findings provide comprehensive atomistic insights into the role of terminal capping in membrane-associated tau peptide fibrillization and cytotoxicity.
tau蛋白异常聚集成β-折叠淀粉样原纤维与阿尔茨海默病和其他tau蛋白病密切相关。tau蛋白与细胞膜之间的相互作用可导致原纤维形成加速和膜变形，这是tau蛋白聚集的毒性途径。据报道，tau原纤维成核核心基序PHF6（VQIVYK）在tau-膜相互作用中起关键作用。然而，其潜在的分子机制在很大程度上仍未被探索，并且末端封端对PHF6-膜相互作用的影响常常被忽视。在此，我们进行了广泛的全原子分子动力学模拟，以研究四种PHF6末端乙酰化-酰胺化变体原纤维与混合的POPC/POPG膜之间的相互作用。我们的模拟突出了N端封端在调节PHF6原纤维（双层β-折叠）的膜结合以及由此产生的原纤维稳定和膜破坏中的关键作用。我们发现，无论其C端酰胺化状态如何，N端乙酰化的PHF6（Ac-PHF6和Ac-PHF6-NH）原纤维都倾向于通过K311阳离子侧链与阴离子POPG脂质之间的静电吸引结合到膜表面。与在溶液中相比，这种膜结合降低了PHF6原纤维的动力学，从而促进了片层间和片层内的相互作用，进而稳定了整体原纤维结构。相比之下，N端未乙酰化的PHF6（PHF6和PHF6-NH）原纤维倾向于通过其阳离子N端插入膜中。这种膜插入有利于PHF6片层内的相互作用，但由于插入过程中脂质分子的干扰不利于片层间的相互作用，并且比N端乙酰化的PHF6原纤维导致更严重的膜破坏。此外，对N端未乙酰化的PHF6原纤维（单层平行β-折叠）的分子动力学模拟表明，膜结合稳定了在水溶液中不稳定的原纤维。这些发现为末端封端在膜相关tau肽原纤维形成和细胞毒性中的作用提供了全面的原子水平见解。
