Impact of Amidation on Aβ_25–35 Aggregation

Toxic oligomeric species are suspected in the etiology of Alzheimer's disease. The full-length Aβ₄₂ can be studied by the fragment Aβ_25-35 as it retains neurotoxicity. According to experimental studies, amidation of the Aβ_25-35 carboxyl terminal decreases fibrillation activity while retaining its neurotoxic properties. Our molecular dynamics simulation studied the aggregation of the Aβ_25-35 trimer from two initial structures (fibril and randomized helical structures) in their amidated and nonamidated forms. Comparing the amidated and nonamidated systems, the results suggest that antiparallel chains are dominant in nonamidated systems, while the amide group leads to parallel chains. In terms of secondary structures, a higher helix content with a corresponding decrease in β-sheet content is observed as a consequence of amidation. Despite the variation in secondary structures, the chain-chain contacts are still mediated by the Gly motif (GxxxG) and Ile residues in both amidated and nonamidated systems. As neurotoxicity does not change upon amidation, our results imply that clumping of peptides sustained by the Gly motif is a greater contributing factor to toxicity than secondary and quaternary structures.