Polyproline chains destabilize the Alzheimer's amyloid-β protofibrils: A molecular dynamics simulation study

Area of Science:

• Neurodegenerative Diseases
• Biochemistry
• Computational Biology

Background:

• Alzheimer's disease is a fatal neurodegenerative disorder characterized by amyloid-β plaques.
• Currently, no cure exists for Alzheimer's disease.

Purpose of the Study:

• To investigate the interaction of proline with amyloid-β-sheet structures.
• To assess proline's potential as a therapeutic agent for Alzheimer's disease.

Main Methods:

• Docking simulations
• All-atom molecular dynamics simulations

Main Results:

• Proline effectively breaks amyloid protofibrils and disrupts β-sheet structures.
• Proline can induce the formation of 3₁₀ helices, potentially aiding in β-sheet unfolding.
• Proline disrupts inter-chain hydrogen bonds and salt bridges, loosening fibril packing.
• Proline exhibits strong electrostatic interactions with amyloid fibrils, with less significant hydrophobic interactions.

Conclusions:

• Proline demonstrates the ability to dismantle amyloid fibrils.
• Proline holds promise for the development of novel peptide-based therapeutics targeting Alzheimer's disease and other protein misfolding conditions.