Lycopene destabilizes preformed Aβ fibrils: Mechanistic insights from all-atom molecular dynamics simulation

Area of Science:

• Biochemistry
• Neuroscience
• Computational Chemistry

Background:

• Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) fibrils.
• Natural compounds show potential in destabilizing Aβ fibrils for AD therapy.
• Lycopene, a carotenoid, has high antioxidant potential and crosses the blood-brain barrier, making it a promising drug lead.

Purpose of the Study:

• To investigate the potential of lycopene in destabilizing different polymorphic forms of Aβ fibrils.
• To elucidate the underlying mechanism of lycopene-mediated Aβ fibril destabilization using molecular dynamics simulations.

Main Methods:

• Molecular Dynamics (MD) simulations were employed to study lycopene's interaction with Aβ fibril polymorphs (2NAO and 2BEG).
• Analysis focused on binding sites, residue interactions (van der Waals, π-π), and changes in fibril structure (H-bonds, hydrophobic interactions, β-sheet content).

Main Results:

• Lycopene binds to the outer surface of Aβ fibril (2NAO) via van der Waals and π-π interactions with specific residues.
• Binding destabilizes the fibril by disrupting H-bonds and hydrophobic interactions, reducing β-sheet content and inhibiting aggregation.
• Lycopene also destabilizes another Aβ fibril polymorph (2BEG) by accessing its cavity and lowering β-sheet content.
• The extent of destabilization did not show a linear correlation with lycopene concentration.

Conclusions:

• Lycopene effectively destabilizes major Aβ fibril polymorphs, indicating its therapeutic potential for Alzheimer's disease.
• The study elucidates the molecular mechanisms behind lycopene's anti-amyloidogenic activity.
• Lycopene represents a viable candidate for developing novel therapeutic strategies against AD.