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Title: Aspects of structural landscape of human islet amyloid polypeptide

The human islet amyloid polypeptide (hIAPP) co-operates with insulin to maintain glycemic balance. It also constitutes the amyloid plaques that aggregate in the pancreas of type-II diabetic patients. We have performed extensive in silico investigations to analyse the structural landscape of monomeric hIAPP, which is presumed to be intrinsically disordered. For this, we construct from first principles a highly predictive energy function that describes a monomeric hIAPP observed in a nuclear magnetic resonance experiment, as a local energy minimum. We subject our theoretical model of hIAPP to repeated heating and cooling simulations, back and forth between a high temperature regime where the conformation resembles a random walker and a low temperature limit where no thermal motions prevail. We find that the final low temperature conformations display a high level of degeneracy, in a manner which is fully in line with the presumed intrinsically disordered character of hIAPP. In particular, we identify an isolated family of α-helical conformations that might cause the transition to amyloidosis, by nucleation.
Authors:
;  [1] ;  [2] ;  [3] ;  [1] ;  [4] ;  [5]
  1. School of Physics, Beijing Institute of Technology, Beijing 100081 (China)
  2. Institute of Biopharmaceutical Research, Yangtze River Pharmaceutical Group Beijing Haiyan Pharmaceutical Co., Ltd, Beijing 102206 (China)
  3. Department of Physics and Astronomy, Uppsala University, P.O. Box 803, S-75108 Uppsala (Sweden)
  4. (Sweden)
  5. (France)
Publication Date:
OSTI Identifier:
22416060
Resource Type:
Journal Article
Resource Relation:
Journal Name: Journal of Chemical Physics; Journal Volume: 142; Journal Issue: 4; Other Information: (c) 2015 AIP Publishing LLC; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL AND ANALYTICAL CHEMISTRY; COMPUTERIZED SIMULATION; HEATING; INSULIN; MONOMERS; NUCLEAR MAGNETIC RESONANCE; NUCLEATION; POLYPEPTIDES; TEMPERATURE DEPENDENCE