Structural Interconversion in Alzheimer's Amyloid-β(16-35) Peptide in an Aqueous Solution

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Chemistry

Background:

• Amyloid-beta (Aβ) peptides are implicated in Alzheimer's disease.
• Understanding Aβ peptide structure and folding is crucial for therapeutic development.
• The Aβ(16-35) fragment serves as a model for studying aggregation, excluding terminal effects.

Purpose of the Study:

• To investigate the structural properties and folding pathway of the Aβ(16-35) fragment.
• To elucidate the mechanism of Aβ peptide aggregation.
• To determine if the Aβ(16-35) fragment exhibits intrinsic disorder.

Main Methods:

• Replica-exchange molecular dynamics simulations were employed.
• All-atom and explicit aqueous solvation models were used to minimize structural bias.
• Principal component analysis was utilized to analyze conformational dynamics.

Main Results:

• The primary folding pathway involves direct conversion of coil to β-sheet structure.
• No long helical intermediates were observed in the folding process.
• The Aβ(16-35) fragment was found to be intrinsically disordered, similar to the full Aβ peptide.
• The folding mechanism lacks significant free-energy barriers and thermal capacity peaks.

Conclusions:

• The Aβ(16-35) fragment adopts a β-sheet structure through a direct coil-to-sheet transition.
• The folding pathway is barrierless and suggests intrinsic disorder.
• These findings provide insights into the early stages of amyloid-beta aggregation relevant to neurodegenerative diseases.