Role of the English (H6R) Mutation on the Structural Properties of Aβ40 and Aβ42 Owing to the Histidine Tautomeric Effect

Abstract

As an intrinsic origin cause, histidine behaviors play a critical role in protein misfolding processes. Generally, the English (H6R) mutation will disrupt H6 interactions. However, the structural properties of Aβ40 H6R and Aβ42 H6R under the complex influence of a histidine tautomeric effect and an H6R mutation remain unclear. Therefore, we performed a replica exchange molecular dynamics simulation to unveil such structural properties. Our result showed that the H6R substitute could promote the generation of β-sheet structures in comparison to the wild type. Three β-strand structure properties were observed in Aβ40 (rδδ), Aβ42 (rεε), Aβ42 (rεδ), and Aβ42 (rδδ) with β-sheet contents of 47.5%, 37.2%, 46.9%, and 38.6%, respectively, and the dominant conformational properties of Aβ40 (rδδ), Aβ42 (rεε), Aβ42 (rεδ), and Aβ42 (rδδ) had top conformational states of 86.0%, 73.2%, 67.0%, and 56.5%, respectively. Further analysis confirmed that R6 had different mechanisms for controlling the conformational features in Aβ40 H6R and Aβ42 H6R. In the Aβ40 systems, H14 H-bond networks played a critical role in controlling the structural properties. However, in the Aβ42 systems, R6 was more important because it was directly involved in the β-strand formation and maintained the β-sheet between the N-terminus and the central hydrophobic core region. Our current study helps to elucidate the histidine tautomeric behaviors in H6R mutations, which will present opportunities to understand the correlation between with/without H6 and the Aβ40/Aβ42 H6R misfolding mechanisms.

Histidine Protonation Behaviors on Structural Properties and Aggregation Properties of Aβ(1–42) Mature Fibril: Approaching by Edge Effects

“…36 The different states of histidine play a crucial role in the structure and aggregation properties of the Aβ aggregation process. 43,44 Compared to the conformational shift from helix to coil in deprotonated Aβ(1−40), protonation of histidine in Aβ (1− 42) stimulates interactions between the N-and C-terminus, leading to an increase in β-sheet content and rapid aggregation in an acidic environment. 45 Furthermore, previous studies of the middle chain substitution with different tautomeric and/or protonated states in Aβ mature fibrils have demonstrated that histidines directly contribute to the β-strand structure and influence the N-terminus H-bonding interaction networks, 38,46,47 However, the impact of histidine protonation behavior on the edge chain of Aβ mature fibrils remains unclear and requires further investigation.…”

“…Histidine is an essential amino acid that exhibits certain effects on structural properties and aggregation properties. − The histidine behaviors include tautomerization behavior and protonation behavior as the imidazole group of histidine readily donates and accepts protons, resulting in three states for histidine, as shown in Figure a: the tautomerization states (the ε state (Nε-H) (HIE) and the δ state (Nδ-H) (HID)) and the protonation state (the (p) state (HIP), both Nε-H and Nδ-H). , The ε:δ ratio of histidine is approximately 1:0.16 in the gas phase, but this ratio can be influenced by various external factors, including pH, side chain imidazole ring, and the N atom orientation and protein amino acid position . The different states of histidine play a crucial role in the structure and aggregation properties of the Aβ aggregation process. , Compared to the conformational shift from helix to coil in deprotonated Aβ(1–40), protonation of histidine in Aβ(1–42) stimulates interactions between the N- and C-terminus, leading to an increase in β-sheet content and rapid aggregation in an acidic environment . Furthermore, previous studies of the middle chain substitution with different tautomeric and/or protonated states in Aβ mature fibrils have demonstrated that histidines directly contribute to the β-strand structure and influence the N-terminus H-bonding interaction networks, ,, However, the impact of histidine protonation behavior on the edge chain of Aβ mature fibrils remains unclear and requires further investigation.…”

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

“…34,35 Our earlier research has shown that each histidine's e, d, or p state has a unique impact on the structure of Ab fragments. 64,[70][71][72][73] Furthermore, under conditions of protonated and deprotonated norepinephrine, the various processes of degradation on Ab(1-42) protofibrils were discovered. 74 Additionally, the redox activity in the metal-Ab complex 75 can be modulated by the status of the histidine residues.…”

Monitoring early-stage β-amyloid dimer aggregation by histidine site-specific two-dimensional infrared spectroscopy in a simulation study

“…10 Recently, a novel histidine tautomerism/protonation hypothesis accounting for the pathogenesis of AD and other neurological diseases has been suggested by our research team. 11–26 We have demonstrated that different protonated states in the histidine imidazole ring are related to the conformational characteristics of diverse misfolded peptides (namely Aβ, tau, amylin, and prion) and can influence fibrillization processes in polypeptides, resulting in proteopathies. This histidine hypothesis implies that protein accumulation may occur inherently rather than as a consequence of extrinsic agents.…”