Unraveling the Histidine Tautomerism Effect on the Initial Stages of Prion Misfolding: New Insights from a Computational Perspective

Abstract

The aggregation and structural conversion of normal prion peptide (PrP C ) into the pathogenic scrapie form (PrP Sc ), which can act as a seed to enhance prion amyloid fiber formation, is believed to be a crucial event in prionopathies. Previous research suggests that the prion monomer may play an important role in oligomer generation during disease pathogenesis. In the present study, extensive replica-exchange molecular dynamics (REMD) simulations were conducted to explore the conformational characteristics of the huPrP (125−160) monomer under the histidine tautomerism effect. Investigating the structural characteristics and fibrilization process is challenging because two histidine tautomers [N ε2 -H (ε) and N δ1 -H (δ)] can occur in the open neutral state. Molecular dynamics (MD) simulation outcomes have shown that the toxic εδ and δδ isomer (containing several and broader local minima) had the highest α-helix structures, with contents of 21.11% and 21.01%, respectively, and may have a strong influence on the organizational behavior of a monomeric prion. The amino acids aspartate 20 (D20)−asparagine 29 (N29) and isoleucine 15 (I15)−histidine 16 (H16), D20−arginine 27 (R27) as well as N29 formed α-helix with the highest probabilities in the δδ and εδ isomer, accordingly. On the basis of our findings, we propose the histidine tautomerization hypothesis as a new prion accumulation mechanism, which may exist to induce the formation of prion accumulates. Overall, our tautomerism hypothesis constitutes a promising perspective for enhancing understanding of prion disease pathobiology and may help in the design of a good inhibitor.

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.…”

Solid-state separation of hypoxanthine tautomers through a doping strategy

“…An in-depth understanding of tautomers is of great significance for the study of organic reaction mechanisms, base pairing and replication, and optical rotation of sugars. [1][2][3] Different from being in dynamic equilibrium in the gas and liquid phases, tautomers exist in a relatively stable form in the solid phase. 4 Solid-state separation provides an opportunity to study the physical and chemical properties of different tautomers.…”

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.…”