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

Abstract

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.

Edge Substitution Effects of Histidine Tautomerization Behaviors on the Structural Properties and Aggregation Properties of Aβ(1–42) Mature Fibril

“…These findings indicate that the various histidine states have an impact on structural characteristics and aggregation. Our analysis of the Δ G 2 binding model confirmed that chains 1 and 6 barely interact, consistent with previous studies , that emphasize the crucial role of the main chain and adjacent chains in maintaining fibril stability.…”

“…59 Previous studies have also demonstrated that, in the substitution of middle chain of mature fibril, the H6 and H13 isomeric states directly influence the N-terminal H-bonding interaction networks, which in turn affect the interaction patterns between the various β-strands and the stability of the fibril. 56,60 However, the effect of histidine tautomerization behaviors on the edge chain of Aβ mature fibrils is not yet fully understood, although it has the potential to influence structural stability and aggregation characteristics.…”

“…Under ideal conditions, the ε:δ ratio is generally 1:0.16, − but it is influenced by various environmental factors, including pH, metal ions, and side chain interactions. − The histidine state has a significant impact on the structural and aggregation properties of Aβ peptides, including monomers, oligomers, and fibrils. − Studies on the regulation of Aβ(1–40) and Aβ(1–42) monomers have shown that different histidine combinatorial states can strongly influence their secondary structure characteristics. ,, Furthermore, investigations on homodimers and heterodimers have revealed that the Aβ(1–40) (δδδ:δδδ) dimer and (εεε:δδδ) dimer are more prone to aggregation than related homodimer and heterodimer. , Similarly, Aβ(1–40) (δδδ) and Aβ(1–42) (εδδ) have been found to accelerate pentamer aggregation . Previous studies have also demonstrated that, in the substitution of middle chain of mature fibril, the H6 and H13 isomeric states directly influence the N-terminal H-bonding interaction networks, which in turn affect the interaction patterns between the various β-strands and the stability of the fibril. , However, the effect of histidine tautomerization behaviors on the edge chain of Aβ mature fibrils is not yet fully understood, although it has the potential to influence structural stability and aggregation characteristics.…”

Effect of Histidine Behaviors on Structural Properties of Human Islet Amyloid Peptides

“…Histidine tautomeric behaviors involve isomerization between N‐ϵ (HIE, ϵ) and N‐δ (HID, δ), while protonation behaviors include both N‐ϵ (HIE, ϵ) and N‐δ (HID, δ) in a protonation state (denoted as (p) state) (Figure 1b). In an ideal vacuum, the ϵ/δ ratio is 1:0.16 [34,35] . However, histidine behaviors are highly susceptible to external factors, such as the pH environment, side chain interactions, and N/N−H atom orientation in the imidazole ring, which can result in significant fluctuations and diverse structural and aggregation features in realistic scenarios.…”

The effect of histidine behaviors on the structural properties of Aβ(1–42) peptide in protonation stage one, two, and three

“…38,39,[51][52][53][54][55][56] Histidine behavior in illnesses with misfolded proteins has been a significant problem in numerous research studies. [57][58][59][60] Owing to net charge shifts and varying N/N-H position on imidazole rings, histidine behaviors (containing tautomeric behaviors and protonation behaviors) are hypothesized to be a root cause of protein folding and/or misfolding 57,[60][61][62][63][64] (Scheme 1). In the imidazole ring, there are two intrinsically changeable isomeric forms (N-e (HIE, e) and N-d (HID, d) states) and a protonated form (both e and d states, described as p state) that play an active role in Ab misfolding.…”