  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 NMR 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 alpha-helical conformations that might cause the
transition to amyloidosis, by nucleation.
