Disruption of PHF6 Peptide Aggregation from Tau Protein: Mechanisms of Palmatine Chloride in Preventing Early PHF6 Aggregation
Perturbation de l'agrégation du PHF6 de la protéine Tau : Mécanismes d'action du chlorure de palmatine dans la prévention de l'agrégation précoce du PHF6
Abstract
The formation of neurofibrillary tangles (NFTs),
composed of tau protein aggregates, is a hallmark of neuro-
degenerative diseases known as tauopathies, including Alzheimer’s
disease (AD). NFTs consist of paired helical filaments (PHFs) of
tau protein with a dominant β-sheet secondary structure. Within
these PHFs, the PHF6 hexapeptide (Val306-Gln-Ile-Val-Tyr-Lys311)
has been commonly highlighted as a key site for tau protein
nucleation. Palmatine chloride (PC) has been identified as an
inhibitor of PHF6 aggregation, capable of reducing aggregation
propensity at submicromolar concentrations. In pursuit of novel
anti-AD drugs targeting early tau aggregation stages, we conducted
an in silico study to elucidate PC’s mechanism of action during
PHF6 aggregation. Our observations suggest that while PHF6 can
still initiate self-aggregation in the presence of PC, PC molecules subtly influence PHF6 aggregation dynamics, favoring smaller
aggregates over larger complexes. The study underlined the key roles of aromatic rings in PC binding to different PHF6 aggregates
by interacting through π−π stacking with the PHF6 Tyr310 side chain. The presence of aromatic rings in compounds to be able to
inhibit the earlier complexation phase seems to be essential. These in silico findings lay a foundation for the design of compounds
that could intervene in resolving the neurotoxicity of protein aggregates in AD.