Deciphering the Role of ATP on PHF6 Aggregation

Area of Science:

• Neuroscience
• Biochemistry
• Computational Biology

Background:

• Tau protein aggregation is a hallmark of Alzheimer's disease and related tauopathies.
• The hexapeptide sequence PHF6 (paired helical filament 6) from Tau's repeat 3 is crucial for aggregation.
• Inhibiting Tau aggregation is a primary therapeutic strategy for tauopathies.

Purpose of the Study:

• To investigate the effect of adenosine triphosphate (ATP) on the aggregation of the PHF6 peptide.
• To understand the molecular mechanisms by which ATP influences PHF6 self-assembly.

Main Methods:

• Classical molecular dynamics simulations were employed.
• Analysis focused on peptide conformation, interpeptide interactions, and peptide-ATP interactions.

Main Results:

• PHF6 aggregates exhibit a stable β-sheet conformation due to their hydrophobic core.
• ATP effectively inhibits PHF6 aggregation, promoting random coil conformations.
• ATP-PHF6 interactions, primarily through hydrogen bonding and hydrophobic contacts, replace interpeptide interactions.
• The adenosine moiety of ATP plays a more significant role in these interactions than the triphosphate chain.

Conclusions:

• ATP demonstrates significant inhibitory activity against Tau PHF6 aggregation.
• ATP's ability to dissolve protein aggregates suggests potential therapeutic applications.
• Further exploration of ATP's therapeutic effects for Alzheimer's disease treatment is warranted.