On the Tracks of the Aggregation Mechanism of the PHF6 Peptide from Tau Protein: Molecular Dynamics, Energy, and Interaction Network Investigations

The formation of neurofibrillary tangles (NFTs), composed of tau protein aggregates, is a hallmark of some neurodegenerative diseases called tauopathies. NFTs are composed of paired helical filaments (PHFs) of tau protein with a dominant β-sheet secondary structuration. The NFT formation mechanism is not known yet. This study focuses on PHF6, a crucial hexapeptide responsible for tau aggregation. A 2 μs molecular dynamics simulation was launched to determine the keys of the PHF6 aggregation mechanism. Hydrogen bonding, van der Waals, and other non-covalent interactions as π-stacking were investigated. Parallel aggregation was slightly preferred due to its adaptability, but antiparallel aggregation remained widely present during the PHF6 aggregation. The analysis highlighted the leading role of hydrogen bonds identified at the atomic level for each aggregation process. The aggregation study emphasized the importance of Tyr310 during the β-sheets' complexation through π-stacking.