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

Aggregated amyloid beta-peptide (A beta) 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. A beta 42 monomer chain includes 3 histidine residues that considering two epsilon and delta tautomers 8 isomers, including (epsilon epsilon epsilon) and (epsilon delta delta) could be formed. Molecular dynamics simulation on homodimerization of (epsilon epsilon epsilon) (the most common type of tautomers) and (epsilon delta delta) tautomers with different initial configurations using monomer chains from our previous work were performed to uncover the tautomeric behavior of histidine on A beta 42 aggregation in a physiological pH which is still largely unknown and impossible to observe experimentally. We found a higher propensity of forming beta-sheet in (epsilon delta delta) homodimers and specifically in a greater amount from A beta 42 than from A beta 40. A smaller amount of beta-sheet formation was observed for (epsilon epsilon epsilon) homodimers compared with (epsilon delta delta). Additionally, interactions in (epsilon delta delta) 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 (epsilon delta delta) homodimers at the early stage of A beta aggregation.