Intrinsic Origin of Amyloid Aggregation: Collective Effects of the Mutation and Tautomerism of Histidine.

Mutation is considered an important factor in the accumulation of amyloid-β (Aβ), which is a hallmark of Alzheimer's disease (AD). A2V Aβ40 shows a higher aggregation tendency; however, the existing knowledge is not sufficient to explain the mechanism. We performed replica-exchange molecular dynamics simulations (REMD) to investigate the structural properties of A2V Aβ40 monomers and consider the tautomerism of histidine. The collective effects of the mutation and tautomerism leads A2V Aβ40 to much higher β-sheet and lower α-helix contents than WT Aβ40, which may explain the enhanced aggregation kinetics of A2V Aβ40 with respect to WT Aβ40. The current research provides new insights on understanding the pathology of AD.