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

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 e 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 δe conformations showed an elevated amount of α-helix and lower coil in comparison to the ee 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 δe dimers rather than e and ee conformations in the early stages of diabetes initiation. Our results may aid in elucidating the hIAPP self-association process in the etiology of amyloidosis.