Molecular insights into Aβ₄₂ protofibril destabilization with a fluorinated compound D744: A molecular dynamics...

Area of Science:

• Neuroscience
• Biochemistry
• Computational Chemistry

Background:

• Alzheimer's disease (AD) progression is linked to amyloid beta-peptide (Aβ42) aggregation into toxic structures.
• Halogen-substituted compounds show potential in disassembling Aβ protofibrils, but their inhibitory mechanisms are unclear.
• Understanding Aβ42 protofibril destabilization is crucial for developing effective AD therapeutics.

Purpose of the Study:

• To elucidate the inhibitory mechanism of the fluorinated compound D744 on Aβ42 protofibril destabilization.
• To investigate how D744 affects the structural integrity and binding interactions within Aβ42 protofibrils.

Main Methods:

• Combined molecular docking and molecular dynamics (MD) simulations were employed.
• Analysis included structural changes, hydrogen bonding, salt bridge interactions, and binding free energy calculations (MM-PBSA).

Main Results:

• D744 binds to Aβ42 protofibril chain A via hydrophobic and multipolar interactions.
• MD simulations showed D744 decreases β-sheet content, increases coil/bend structures, and weakens interchain binding.
• Key residues in chain A contribute significantly to the binding free energy (ΔGbinding = -44.87 kcal/mol).

Conclusions:

• D744 effectively destabilizes Aβ42 protofibrils through specific molecular interactions and structural alterations.
• These findings provide critical insights into the mechanism of small molecule inhibition of Aβ42 aggregation.
• The study supports the development of D744 and similar compounds as potential therapeutic agents for Alzheimer's disease.