Fibrillar dimer formation of islet amyloid polypeptides

Chi Cheng Chiu, Juan J. De Pablo

研究成果: Article同行評審

18 引文 斯高帕斯(Scopus)

摘要

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.

原文English
文章編號092501
期刊AIP Advances
5
發行號9
DOIs
出版狀態Published - 2015 9月 1

All Science Journal Classification (ASJC) codes

  • 一般物理與天文學

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