Stabilities and structures of islet amyloid polypeptide (IAPP22-28) oligomers: from dimer to 16-mer.

ABSTRACT

BACKGROUND: The formation of amyloid fibrils is associated with many age-related degenerative diseases. Nevertheless, the molecular mechanism that directs the nucleation of these fibrils is not fully understood. METHODS: Here, we performed MD simulations for the NFGAILS motif of hIAPP associated with the type II diabetes to estimate the stabilities of hIAPP22-28 protofibrils with different sizes from 2 to 16 chains. In addition, to study the initial self-assembly stage, 4 and 8 IAPP22-28 chains in explicit solvent were also simulated. RESULTS: Our results indicate that the ordered protofibrils with no more than 16 hIAPP22-28 chains will be structurally stable in two layers, while one-layer or three-layer models are not stable as expected. Furthermore, the oligomerization simulations show that the initial coil structures of peptides can quickly aggregate and convert to partially ordered ß-sheet-rich oligomers. CONCLUSIONS: Based on the obtained results, we found that the stability of an IAPP22-28 oligomer was not only related with its size but also with its morphology. The driving forces to form and stabilize an oligomer are the hydrophobic effects and backbone H-bond interaction. Our simulations also indicate that IAPP22-28 peptides tend to form an antiparallel strand orientation within the sheet. GENERAL SIGNIFICANCE: Our finding can not only enhance the understanding about potential mechanisms of hIAPP nuclei formation and the extensive structural polymorphisms of oligomers, but also provide valuable information to develop potential ß-sheet formation inhibitors against type II diabetes.