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

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.