title: 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 β-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.
  
  
  CONCLUSIONS
  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 β-sheet formation inhibitors against type II diabetes.
authors.affiliation: School of Pharmacy, Lanzhou University, Lanzhou 730000, China; State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China; Department of Chemistry, Lanzhou University, Lanzhou 730000, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Guo
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Lulu
authors.initials: L
authors.lastname: Ning
authors.forename: Pingzu
authors.initials: P
authors.lastname: Jiao
authors.forename: Huanxiang
authors.initials: H
authors.lastname: Liu
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Yao
mesh_terms: D000682:Amyloid / Q000737:chemistry*; D001067:Appetite Depressants / Q000737:chemistry*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D058228:Islet Amyloid Polypeptide / Q000737:chemistry*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D055550:Protein Stability; D017433:Protein Structure, Secondary
chemical_list: D000682:Amyloid; D001067:Appetite Depressants; D058228:Islet Amyloid Polypeptide
keywords: Amyloid fibril; Islet amyloid polypeptide (residues 22-28); MD; Molecular dynamics simulation; Nucleation; Type II diabetes; hIAPP; human islet amyloid polypeptide; molecular dynamics