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Histidine tautomerism is considered a crucial component that affects the constitutional and accumulation characteristics of the tau 267−312 monomer in the neutral condition, which are connected with the pathobiology of Alzheimer's disease (AD). Interpreting the organizational characteristics and accumulation procedure is a challenging task because two tautomeric conformations (the N ε −H or N δ −H tautomer) can occur in the open neutral condition. In the current work, replica-exchange molecular dynamics (REMD) simulations were performed to investigate the structural properties of the tau 267−312 monomer considering the histidine tautomeric effect. Based on the simulation outcomes, the histidine 268 (H268) (δ)− H299 (δ) (δδ) isomer had the highest β-sheet content with a value of 26.2%, which acquires a sheet-governing toxic conformer with the first abundant conformational state of 22.6%. In addition, δδ displayed notable antiparallel βsheets between lysine 8 (K8)−asparagine 13 (N13) and valine 40 (V40)−tyrosine 44 (Y44) as well as between K32−H33 and V40−Y44 (β-meander supersecondary structure), indicating this tautomeric isomer may exist to stimulate tau oligomerization. Furthermore, H299 was found to play an essential role in the structural stabilization of the δδ isomer compared with H268. The present research will aid in obtaining insight into the organizational and accumulation properties of tau protein in the presence of histidine tautomerism to control AD.

The accumulation of ΔK280 tau mutant resulting in neurotoxic oligomeric aggregates is an important but yet mysterious procedure in Alzheimer’s disease (AD) development. Recently, we proposed a histidine tautomerization hypothesis...

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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.