Disruption\nof PHF6 Peptide Aggregation from Tau Protein:\nMechanisms of Palmatine Chloride in Preventing Early PHF6 Aggregation

The formation of\nneurofibrillary tangles (NFTs), composed\nof tau\nprotein aggregates, is a hallmark of neurodegenerative diseases known\nas tauopathies, including Alzheimer’s disease (AD). NFTs consist\nof paired helical filaments (PHFs) of tau protein with a dominant\nβ-sheet secondary structure. Within these PHFs, the PHF6 hexapeptide\n(Val<sub>306</sub>-Gln-Ile-Val-Tyr-Lys<sub>311</sub>) has been commonly\nhighlighted as a key site for tau protein nucleation. Palmatine chloride\n(PC) has been identified as an inhibitor of PHF6 aggregation, capable\nof reducing aggregation propensity at submicromolar concentrations.\nIn pursuit of novel anti-AD drugs targeting early tau aggregation\nstages, we conducted an <i>in silico</i> study to elucidate\nPC’s mechanism of action during PHF6 aggregation. Our observations\nsuggest that while PHF6 can still initiate self-aggregation in the\npresence of PC, PC molecules subtly influence PHF6 aggregation dynamics,\nfavoring smaller aggregates over larger complexes. The study underlined\nthe key roles of aromatic rings in PC binding to different PHF6 aggregates\nby interacting through π–π stacking with the PHF6\nTyr310 side chain. The presence of aromatic rings in compounds to\nbe able to inhibit the earlier complexation phase seems to be essential.\nThese <i>in silico</i> findings lay a foundation for the\ndesign of compounds that could intervene in resolving the neurotoxicity\nof protein aggregates in AD.