Computational Study on Structure and Aggregation Pathway of Aβ42 Amyloid Protofibril

Amyloid deposits of A beta protein in neuronal cells are known to be a major symptom of Alzheimer's disease. In particular, A beta(42) shows relatively high toxicity among the different A beta isoforms, and its toxicity is thought to be because of its structural features. Recent ssNMR and cryo-EM experiments identified that A beta(42), shows an S-shaped triple-beta structure, in contrast to the previously suggested U-shaped beta-arch structure. In order to associate the high toxicity of A beta(42) with its structural features, it is essential to explain the conformational stability and aggregation mechanisms of this triple-beta 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-beta motif showed remarkable structural stability because of its complex residual interactions that form stable hydrophobic cores. The triple-beta structure of A beta(42) is primarily made up of three beta-sheet regions and two hydrophobic cores formed between beta-sheet regions. Our analysis of beta-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 A beta(42) to the fibril motif using REMD simulations showed that each of the three beta-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-beta structure A beta(42).