Molecular Insights into the Self-Assembly of a Full-Length hIAPP Trimer: ß-Protofibril Formed by ß-Hairpin Lateral or Longitudinal Association.

The fibrillar protein deposits of the human islet amyloid polypeptide (hIAPP) in the pancreatic islet of Langerhans are pathological hallmark of type II diabetes. Extensive experimental studies have revealed that the oligomeric formations of the hIAPP are more toxic than the mature fibrils. Exploring the oligomeric conformations in the early aggregation state is valuable for effective therapeutics. In this work, using the all-atom explicit-solvent replica exchange molecular dynamic (REMD) simulations, we investigated the structural features and the assembly mechanisms of the full-length hIAPP trimer in solution. The hIAPP trimer adopted more ß-sheets than a-helix conformations, and three types of ordered conformations including open ß-barrel, single-layer, and double-layer U-shaped ß-sheet structures with five ß-strands were captured in our simulations. A representative single-layer ß-sheet conformation with a CCS value of 1400 Å2 in our simulations matches exactly the experimentally ESI-IMS-MS-derived hIAPP trimer sample. These five ß-strand conformations formed via the ß-hairpin lateral and longitudinal association, respectively, showing two ß-protofibril formation models. To the best of our knowledge, it is the first time to reveal two routes to ß-sheet formation in the hIAPP trimers on the atomic level. The contact probabilities between pairs of the ß-stranded residue show that the hydrophobic interactions between the residues F15 ∼ V17 and A25 ∼ L27 are responsible for the inter- and intra-peptide ß-hairpin formations. All of these results indicate that the ß-sheet formation is the first step in the conformational changes toward pathological aggregation and provides evidence of the ß-sheet assembly mechanism into hIAPP aggregation.