Chemical and Biomolecular Engineering Faculty Research

Title

Comparative Molecular Dynamics Study of Human Iapp and Rat Iapp Oligomers

Document Type

Article

Publication Date

Fall 2012

Abstract

Human islet amyloid polypeptide (hIAPP or amylin) is a causative agent in pancreatic amyloid deposits found in patients with type 2 diabetes. The aggregation of full-length hIAPP(1-37) into small oligomeric species is increasingly believed to be responsible for cell dysfunction and death. However, rat IAPP (rIAPP(1-37)), which differs from hIAPP in only six of 37 residues, loses its aggregation ability to form toxic amyloid species. Atomic details of the effect of sequence on the structure and toxicity between the amyloidogenic, toxic hIAPP peptide and the nonamyloidogenic, nontoxic rIAPP peptide remain unclear. Here, we probe sequence-induced differences in structural stability, conformational dynamics, and driving forces between different hIAPP and rIAPP polymorphic forms from monomer to pentamer using molecular dynamics simulations. Simulations show that hIAPP forms from trimer to pentamer exhibit high structural stability with well-preserved in-register parallel β-sheet and the U-bend conformation. The hIAPP trimer appears to be a smallest minimal seed in solution. The stabilities of parallel hIAPP oligomers increase with the number of peptides. Conversely, replacement of hIAPP sequence by rIAPP sequence causes a significant loss of favorable interpeptide interactions in all rIAPP oligomers, destabilizing the C-terminal β-sheet, turn conformation, and overall stability. A less β-sheet-rich structure and a disturbed U-shaped topology exert a large energy penalty on the self-assemble of the rIAPP peptides into highly ordered, in-register β-sheet-rich protofibrils and fibrils, which explains the nonamyloidogenic activity of rIAPP. Moreover, the absence of interior water within the U-turn region in the well-packed higher-order hIAPP oligomers, not in the poorly packed rIAPP oligomers, also stabilizes peptide association. This work provides atomic details of the sequence-structure relationship between the amyloidogenic hIAPP and its analogues such as the nonamyloidogenic rIAPP and some mutants, which could help in the development of novel therapeutic agents to block the formation of toxic hIAPP oligomeric species for type 2 diabetes.

Volume

52

Issue

6

First Page

1089

Last Page

1100