Aspects of structural landscape of human islet amyloid polypeptide

• Published in: The Journal of chemical physics Vol. 142; no. 4; p. 045102
• Main Authors: He, Jianfeng, Dai, Jin, Li, Jing, Peng, Xubiao, Niemi, Antti J.
• Format: Journal Article
• Language: English
• Published: United States American Institute of Physics 28.01.2015
• Subjects: Biological Physics; Computer simulation; COMPUTERIZED SIMULATION; First principles; HEATING; Humans; INORGANIC, ORGANIC, PHYSICAL AND ANALYTICAL CHEMISTRY; INSULIN; Islet Amyloid Polypeptide - chemistry; Models, Molecular; MONOMERS; NMR; NUCLEAR MAGNETIC RESONANCE; NUCLEATION; Pancreas; Physics; POLYPEPTIDES; Protein Structure, Secondary; Temperature; TEMPERATURE DEPENDENCE
• ISSN: 0021-9606; 1089-7690; 1089-7690
• DOI: 10.1063/1.4905586

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.