Abstract
The aggregation of human islet amyloid polypeptide (hIAPP) can damage the membrane of the β-cells in the pancreatic islets and induce type 2 diabetes (T2D). Growing evidences indicated that the major toxic species are small oligomers of IAPP. Due to the fast aggregation nature, it is hard to characterize the structures of IAPP oligomers by experiments, especially in the complex membrane environment. On the other side, molecular dynamics simulation can provide atomic details of the structure and dynamics of the aggregation of IAPP. In this study, all-atom bias-exchange metadynamics (BE-Meta) and unbiased molecular dynamics simulations were employed to study the structural properties of IAPP dimer in the membranes environments. A number of intermediates, including α-helical states, β-sheet states, and fully disordered states, are identified. The formation of N-terminal β-sheet structure is prior to the C-terminal β-sheet structure towards the final fibril-like structures. The α-helical intermediates have lower propensity in the dimeric hIAPP and are off-pathway intermediates. The simulations also demonstrate that the β-sheet intermediates induce more perturbation on the membrane than the α-helical and disordered states and thus pose higher disruption ability.
Highlights
Growing evidences have demonstrated that the prefibrillar oligomers rather than the mature fibrils are the main toxic species for many amyloidosis peptides[13, 14] including IAPP15–19
The initially orientation and position of human islet amyloid polypeptide (hIAPP) dimer in the membranes were set according to the SFG spectrum results[40], i.e. the central U-shaped regions were immersed into the membrane and the terminus were outside the membrane surface, the initial tilt angle between the β-strand of residue 8 to 16 was set to be 48°, residues R11 and S28 were located on the membrane-water interface
The results further demonstrate that the N-terminal β-sheets are formed prior to the C-terminus in the assembly process of hIAPP dimer to the fibril structure in membrane environment
Summary
Growing evidences have demonstrated that the prefibrillar oligomers rather than the mature fibrils are the main toxic species for many amyloidosis peptides[13, 14] including IAPP15–19. Realization of the assembly mechanism of hIAPP on membrane environment and the interactions between the early stages oligomers with the membranes is very important to understand the toxicology of IAPP. Extensive studies, both experimentally[23, 32, 35,36,37,38,39,40,41,42,43] and computationally[44,45,46,47,48,49,50,51], have investigated the structure properties of IAPP monomer, oligomers and assembly of fibrils in the membrane environments. The β-sheet rich intermediates are found to pose higher disruption ability to the lipid bilayers and these toxic oligomers could be potential targets in the development of novel drugs to treat T2D
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