Elucidating How Terminal Capping of Tau Hexapeptide PHF6 Modulates the Interactions between PHF6 Fibrils and Membranes

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 (³⁰⁶VQIVYK³¹¹) 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-NH₂) 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-NH₂) 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.