Histidine Tautomerism Driving Human Islet Amyloid Polypeptide Aggregation in the Early Stages of Diabetes Mellitus Progression: Insight at the Atomistic Level

Abstract

Early oligomerization of human islet amyloid polypeptide (hIAPP), which is accountable for β‐cell death, has been implicated in the progression of type 2 diabetes mellitus. Some researches have shown the connection between hIAPP and Alzheimer's disease as well. However, the mechanism of peptide accumulation and associated cytotoxicity remains unclear. Due to the unique properties and significant role of histidine in protein sequences, here for the first time, the tautomeric effect of histidine at the early stages of amylin misfolding was investigated via molecular dynamics simulations. Considering Tau and Pi tautomeric forms of histidine (Tau and Pi tautomers are denoted as ϵ and δ, respectively), simulations were performed on two possible isomers of amylin. Our analysis revealed a higher probability of transient α‐helix generation in the δ isomer in monomeric form. In dimeric forms, the δδ and δϵ conformations showed an elevated amount of α‐helix and lower coil in comparison to the ϵϵ dimer. Due to the significant role of α‐helix in membrane disruption and transition to β‐sheet structure, these results may imply a noticeable contribution of the δ isomer and the δδ and δϵ dimers rather than ϵ and ϵϵ conformations in the early stages of diabetes initiation. Our results may aid in elucidating the hIAPP self‐association process in the etiology of amyloidosis.

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

“…[36] The results of the study indicate that the δ isomer and δδ/δɛ dimer configurations exhibit a greater degree of significance when compared to the ɛ and ɛɛ conformations. [37] The results show that the protein structure rearrangement during aggregation can affect the population and dynamics of toxic oligomerized species. [38] Although previous research has shown that the tautomeric behavior of histidine can rapidly promote oligomer aggregation, [39] the specific histidine behaviors of hIAPP, including tautomerism and protonation, remain poorly understood.…”

“…Studies on artificial rat islet amyloid polypeptide (rIAPP) have indicated that H18 plays a crucial role in regulating hIAPP fibril formation [36] . The results of the study indicate that the δ isomer and δδ/δϵ dimer configurations exhibit a greater degree of significance when compared to the ϵ and ϵϵ conformations [37] . The results show that the protein structure rearrangement during aggregation can affect the population and dynamics of toxic oligomerized species [38] .…”

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][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] We have demonstrated that different protonated states in the histidine imidazole ring are related to the conformational characteristics of diverse misfolded peptides (namely Ab, 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.…”