Deciphering the Inhibitory Mechanism of Naphthoquinone-Dopamine on the Aggregation of Tau Core Fragments PHF6*and PHF6

The formation of neurofibrillary tangles by abnormalaggregationof tau protein is considered to be an important pathological characteristicof tauopathies, including Alzheimer's disease and chronic traumaticencephalopathy. Two hexapeptides (275)VQIINK(280) and (306)VQIVYK(311) in the microtubule bindingregion, named PHF6* and PHF6, are known to be aggregation-prone andresponsible for tau fibrillization. Previous experiments reportedthat naphthoquinone-dopamine (NQDA) could effectively inhibitthe aggregation of PHF6* and PHF6 and disrupt the fibrillar aggregatesinto nontoxic species, displaying a dual effect on the amyloid aggregation.However, the underlying molecular mechanism remains mostly elusive.Herein, we performed all-atom molecular dynamics (MD) simulationsfor 114 & mu;s in total to systematically investigate the impactsof NQDA on the oligomerization of PHF6* and PHF6. The conformationalensembles of PHF6* and PHF6 peptides generated by replica exchangeMD simulations show that NQDA could effectively prevent the hydrogenbond formation, reduce the ability of peptides to self-assemble intolong & beta;-strand and large & beta;-sheets, and induce peptidesto form a loosely packed and coil-rich oligomer. The interaction analysisshows that the binding of NQDA to PHF6* is mainly through hydrophobicinteractions with residue I277 and hydrogen bonding interactions withQ276; for the PHF6 peptides, NQDA displays a strong & pi;-& pi;stacking interaction with residue Y310, thus impeding the Y310-Y310 & pi;-& pi; stacking and I308-Y310 CH-& pi; interactions.The DA group of NQDA displays a stronger cation-& pi; interactionthan the NQ group, while the NQ group exhibits a stronger & pi;-& pi;stacking interaction. MD simulations demonstrate that NQDA preventsthe conformational conversion to & beta;-sheet-rich aggregates anddisplays an inhibitory effect on the oligomerization dynamics of PHF6*and PHF6. Our results provide a complete picture of inhibitory mechanismsof NQDA on PHF6* and PHF6 oligomerization, which may pave the wayfor designing drug candidates for the treatment of tauopathies.

Automated summary

Naphthoquinone-dopamine (NQDA) effectively inhibits the aggregation of PHF6* and PHF6 and disrupts fibrillar aggregates. Molecular dynamics simulations show that NQDA prevents hydrogen bond formation, reduces self-assembly of peptides into β-strands and β-sheets, and induces the formation of loosely packed, coil-rich oligomers. The binding interactions between NQDA and PHF6* involve hydrophobic interactions and hydrogen bonding, while for PHF6 peptides, NQDA displays strong π-π stacking interactions.