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

• DOI: 10.1021/acs.jpcb.3c02633
• Publication Date: 2023-06-01T18:43:49Z
• Authors: Rongmei Lin; Guoning Tang; Zhonggui Gao; Jiangtao Lei; Buyong Ma; Yuxiang Mo
• Keywords: Trimer; Oligomer; Beta sheet; Helix (gastropod)

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