Structural properties and aggregation tendency can be significantly influenced by histidine behaviors (histidine on Nδ-H state is defined as δ, likewise, Nε-H: ε and both Nδ-H and Nε-H: p). In current study, we investigated structural properties of Aβ(1–40) peptide during protonation evolution stage of one, two, and three by total 19 independent replica exchange molecular dynamics simulations using implicit solvent. Our results show that any kind of protonated state will promote β-sheet structure formation in comparison with deprotonated (εεε). With increase in number of protonation, the lowest β-sheet content increased. The highest averaged β-sheet structure content was detected in (δpδ) (46.0 %), (εpp) (36.8 %), and (ppp) (16.0 %) in each protonation stage. With three β-strand structures, (δpδ) shows more stable features and high hydrophobic properties. Further analysis confirmed that H13 and H14 are more important than H6. Specifically, H13 and H14 have a synergistic effect for structural formations by controlling H-bond networks in H13(p) with V39/V40 and H14(p/δ) with G37/G38. Finally, the Pearson correlation coefficient results confirmed that experimental result (ref. 44) is corresponding to our (εpp) system. Our current study will be conducive to understanding the effects of the histidine behaviors, it provides new insights for exploration protein folding and misfolding processes.

Protein folding and misfolding

Aggregation mechanism

Histidine behaviors

AD pathogenesis

Deprotonated and protonated states

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