Fibrillar dimer formation of islet amyloid polypeptides

Chi-Cheng Chiu,Juan J De Pablo

doi:10.1063/1.4921073

Abstract

Amyloid deposits of human islet amyloid polypeptide (hIAPP), a 37-residue hormone co-produced with insulin, have been implicated in the development of type 2 diabetes. Residues 20 – 29 of hIAPP have been proposed to constitute the amyloidogenic core for the aggregation process, yet the segment is mostly unstructured in the mature fibril, according to solid-state NMR data. Here we use molecular simulations combined with bias-exchange metadynamics to characterize the conformational free energies of hIAPP fibrillar dimer and its derivative, pramlintide. We show that residues 20 – 29 are involved in an intermediate that exhibits transient β-sheets, consistent with recent experimental and simulation results. By comparing the aggregation of hIAPP and pramlintide, we illustrate the effects of proline residues on inhibition of the dimerization of IAPP. The mechanistic insights presented here could be useful for development of therapeutic inhibitors of hIAPP amyloid formation.

Highlights

Residues 20 – 29 of human islet amyloid polypeptide (hIAPP) have been proposed to constitute the amyloidogenic core for the aggregation process, yet the segment is mostly unstructured in the mature fibril, according to solid-state NMR data
To characterize the free energies of hIAPP fibrillar dimer conformations, we performed BEMeta simulations with the five collective variable (CV) described in the Methods section
As can be appreciated in the map, hIAPP forms multiple intermediates during the fibrillar dimer formation characterized by distinct free energy minima