Abstract
The human islet amyloid polypeptide (hIAPP) is an intrinsically disordered protein that can self-assemble into fibrillar aggregates that play a key role in the pathogenesis of the type II diabetes mellitus. hIAPP can transiently adopt -helix and -strand conformations that could be important intermediate species on the fibrillization pathway. However, experimental studies of the monomeric peptide conformations are limited due to its high aggregation propensity, and the early steps of the hIAPP association are not clearly characterized. In particular, the question of whether the aggregation-prone conformation is -helical or -strand-rich is still debated. In this study, combining extensive all-atom molecular dynamics (MD) and replica exchange molecular dynamics (REMD) simulations in explicit water, we shed some light on the differences between the amidated and non-amidated hIAPP conformational ensembles. Our study shows that, when compared to the amidated monomer, the non-amidation of hIAPP induces a significantly lower propensity to form -strands, especially aggregation-prone -hairpins. Since the fibrillization of the non-amidated hIAPP is significantly slower than that of the amidated peptide, this indicates that the early steps of the peptide oligomerization involve the association of -hairpins or -strands structures.
Highlights
Cosecreted with the insulin by the islet β-cells in the pancreas, the human islet amyloid polypeptide is a normally soluble hormone that plays a role in regulating the blood glucose level
The amidated and non-amidated human islet amyloid polypeptide (hIAPP) monomer structures were resolved by NMR experiments in the presence of sodium dodecyl sulfate (SDS) micelles, and, overall, both peptides have helical conformations [25,26]
We investigated the differences between the amidated and non-amidated hIAPP conformational ensembles, by performing extensive all-atom molecular dynamics (MD) and replica exchange molecular dynamics (REMD) simulations
Summary
Cosecreted with the insulin by the islet β-cells in the pancreas, the human islet amyloid polypeptide (hIAPP) is a normally soluble hormone that plays a role in regulating the blood glucose level. HIAPP modulates the rate of insulin-stimulated glucose uptake by inhibiting the synthesis of glycogen in skeletal muscle [1,2]. Like an increasing number of proteins [3,4], hIAPP can self-aggregate into oligomers and insoluble amyloid fibrils that are found in the pancreatic tissues of most of type II diabetes patients [5,6,7]. Despite various extensive studies, the detailed mechanism of hIAPP aggregation and the structure of the early oligomers are not clearly characterized yet [11]. Different studies indicated different intermolecular interfaces in the low order oligomers [12], including helix–helix interactions [13,14,15] and β-strand associations [16,17,18]
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