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-beta (A beta), which is a hallmark of Alzheimer's disease (AD). A2V A beta 40 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 A beta 40 monomers and consider the tautomerism of histidine. The collective effects of the mutation and tautomerism leads A2V A beta 40 to much higher beta-sheet and lower alpha-helix contents than WT A beta 40, which may explain the enhanced aggregation kinetics of A2V A beta 40 with respect to WT A beta 40. The current research provides new insights on understanding the pathology of AD.