Aspects of structural landscape of human islet amyloid polypeptide

TL;DR

This study uses in silico methods to explore the structural landscape of monomeric human islet amyloid polypeptide, revealing high conformational degeneracy and identifying alpha-helical conformations potentially involved in amyloid formation.

Contribution

It introduces a first-principles energy model and simulation approach to analyze the disordered structure of hIAPP, providing insights into its conformational diversity and amyloid nucleation.

Findings

High degeneracy of low-temperature conformations.

Identification of alpha-helical conformations linked to amyloid nucleation.

Model aligns with intrinsically disordered nature of hIAPP.

Abstract

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.