Computational Study on Structure and Aggregation Pathway of Aβ42 Amyloid Protofibril.

Abstract

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.