New Insights into the Structural and Binding Properties on Aβ Mature Fibrils Due to Histidine Protonation Behaviors

Histidine tautomeric behaviors have been considered origin factors for controlling the structure and aggregation properties of misfolding peptides. Except for tautomeric behaviors, histidine protonation behaviors definitely have the same capacities due to the net charge changes and the various N/N–H orientations on imidazole rings. However, such phenomena are still unknown. In the current study, Aβ mature fibrils substituted with various protonation states were performed by molecular dynamics simulations to investigate the structure and binding properties. Our results show that all kinds of protonation states can increase the ΔG1 stability and decrease ΔG2 and ΔG3 stabilities. A significantly higher averaged β-sheet content was detected in (εεp), (εpp), and (ppp) fibrils in one, two, and three protonation stages, respectively. Impressively, we found that the substituted fibril with specific protonated states can control the N-terminus structural properties. Further analysis confirmed that H6 and H13 are more important than H14 since the H-bond donor and receptor cooperate among C1/C3/C8_H6, C1/C3/C8_H13, and C1/C3/C8_E11. Furthermore, the mechanism of protonation behaviors was discussed. The current study is helpful for understanding the histidine protonation behaviors on one, two, and three protonation stages, which provides new horizons for exploring the origin of protein folding and misfolding.