Molecular insight into the early stage of amyloid-β(1-42) Homodimers aggregation influenced by histidine tautomerism.

Abstract Aggregated amyloid β-peptide (Aβ) in small oligomeric forms inside the brain causes synaptic function disruption and the development of Alzheimer's disease (AD). Histidine is an important amino acid that may lead to structural changes. Aβ42 monomer chain includes 3 histidine residues that considering two e and δ tautomers 8 isomers, including (eee) and (eδδ) could be formed. Molecular dynamics simulation on homodimerization of (eee) (the most common type of tautomers) and (eδδ) tautomers with different initial configurations using monomer chains from our previous work were performed to uncover the tautomeric behavior of histidine on Aβ42 aggregation in a physiological pH which is still largely unknown and impossible to observe experimentally. We found a higher propensity of forming β-sheet in (eδδ) homodimers and specifically in a greater amount from Aβ42 than from Aβ40. A smaller amount of β-sheet formation was observed for (eee) homodimers compared with (eδδ). Additionally, interactions in (eδδ) homodimers may indicate the importance of the hydrophobic core and C-/N-terminals during oligomerization. Our findings indicate the important role of the tautomeric effect of histidine and (eδδ) homodimers at the early stage of Aβ aggregation.