Computational Study on Structure and Aggregation Pathway of Aβ₄₂ Amyloid Protofibril

Amyloid deposits of Aβ protein in neuronal cells are known to be a major symptom of Alzheimer's disease. In particular, Aβ₄₂ shows relatively high toxicity among the different Aβ isoforms, and its toxicity is thought to be because of its structural features. Recent ssNMR and cryo-EM experiments identified that Aβ₄₂ shows an S-shaped triple-β structure, in contrast to the previously suggested U-shaped β-arch structure. In order to associate the high toxicity of Aβ₄₂ with its structural features, it is essential to explain the conformational stability and aggregation mechanisms of this triple-β motif. We utilized several different simulation methods, including extensive straight molecular dynamics simulation, steered molecular dynamics simulation, and replica-exchange molecular dynamics simulation. The S-shaped triple-β motif showed remarkable structural stability because of its complex residual interactions that form stable hydrophobic cores. The triple-β structure of Aβ₄₂ is primarily made up of three β-sheet regions and two hydrophobic cores formed between β-sheet regions. Our analysis of β-sheet rupture patterns between adjacent chains showed that its two hydrophobic cores have different degrees of stability, indicating a lock phase mechanism. Our analysis of the docking pathway of monomeric Aβ₄₂ to the fibril motif using REMD simulations showed that each of the three β-sheet sequences plays a distinct role in the docking process by changing their conformational features. Our results provide an understanding for the stability and consequent high toxicity of the triple-β structure Aβ₄₂.