Computational Study on Structure and Aggregation Pathway of Aβ₄₂ Amyloid Protofibril

Area of Science:

• Neuroscience
• Biochemistry
• Computational Biology

Background:

• Amyloid deposits of amyloid-beta (Aβ) protein in neurons are a hallmark of Alzheimer's disease.
• Aβ42 is a particularly toxic Aβ isoform, with its toxicity attributed to its structural characteristics.

Purpose of the Study:

• To elucidate the conformational stability and aggregation mechanisms of the S-shaped triple-β structure of Aβ42.
• To correlate the unique structural features of Aβ42 with its high toxicity.

Main Methods:

• Extensive straight molecular dynamics simulation.
• Steered molecular dynamics simulation.
• Replica-exchange molecular dynamics (REMD) simulation.

Main Results:

• The S-shaped triple-β motif of Aβ42 exhibits significant stability due to intricate residual interactions forming hydrophobic cores.
• Analysis revealed differential stability between the two hydrophobic cores, suggesting a 'lock phase' mechanism.
• REMD simulations demonstrated distinct roles for each of the three β-sheet sequences in the docking of monomeric Aβ42 to the fibril.

Conclusions:

• The remarkable stability of the triple-β structure contributes to the high toxicity of Aβ42.
• Understanding these structural and aggregation mechanisms provides insights into Alzheimer's disease pathogenesis.