Unveiling How Hydroxytyrosol Destabilizes α-Syn Oligomers Using Molecular Simulations

Area of Science:

• Neuroscience
• Biochemistry
• Pharmacology

Background:

• Parkinson's disease (PD) pathogenesis involves alpha-synuclein (α-Syn) fibrillogenesis.
• Hydroxytyrosol (HT), a polyphenol from olive oil, exhibits neuroprotective effects.
• HT's mechanism in destabilizing α-Syn oligomers and reducing PD cytotoxicity is unclear.

Purpose of the Study:

• To investigate the molecular mechanism of HT in destabilizing α-Syn oligomers.
• To examine the impact of HT on α-Syn oligomer structure and binding.
• To explore HT's potential as a therapeutic agent for PD.

Main Methods:

• Molecular dynamics (MD) simulations were employed to analyze HT-α-Syn interactions.
• Secondary structure analysis assessed changes in α-Syn conformation.
• Binding free energy calculations quantified HT's affinity for α-Syn trimers.

Main Results:

• HT significantly reduced β-sheet content and increased coil content in α-Syn trimers.
• HT formed hydrogen bonds with α-Syn, weakening interchain interactions and disrupting oligomers.
• Favorable binding free energy (ΔGbinding = -23.25 ± 7.86 kcal/mol) confirmed HT's destabilizing effect on α-Syn trimers.

Conclusions:

• HT destabilizes α-Syn oligomers by altering secondary structure and weakening interchain interactions.
• These findings provide mechanistic insights into HT's neuroprotective effects against PD.
• HT demonstrates potential as a therapeutic strategy for disrupting α-Syn aggregation in Parkinson's disease.