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Title: Early-stage human islet amyloid polypeptide aggregation: Mechanisms behind dimer formation

Abstract

Amyloid aggregates of human islet amyloid polypeptide (hIAPP or human amylin) have long been implicated in the development of type II diabetes. While hIAPP is known to aggregate into amyloid fibrils, it is the early-stage prefibrillar species that have been proposed to be cytotoxic. A detailed picture of the early-stage aggregation process and relevant intermediates would be valuable in the development of effective therapeutics. Here, we use atomistic molecular dynamics simulations with a combination of enhanced sampling methods to examine the formation of the hIAPP dimer in water. Bias-exchange metadynamics calculations reveal relative conformational stabilities of the hIAPP dimer. Finite temperature string method calculations identify pathways for dimer formation, along with relevant free energy barriers and intermediate structures. We show that the initial stages of dimerization involve crossing a substantial free energy barrier to form an intermediate structure exhibiting transient beta-sheet character, before proceeding to form an entropically stabilized dimer structure.

Authors:
ORCiD logo [1];  [1];  [2]
+ Show Author Affiliations
  1. Univ. of Chicago, IL (United States). Inst. for Molecular Engineering
  2. Univ. of Chicago, IL (United States). Inst. for Molecular Engineering; Argonne National Lab. (ANL), Argonne, IL (United States). Materials Science Division
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
National Science Foundation (NSF); USDOE
OSTI Identifier:
1498504
Alternate Identifier(s):
OSTI ID: 1460132
Grant/Contract Number:  
AC02-06CH11357; DMR-1710357
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Chemical Physics
Additional Journal Information:
Journal Volume: 149; Journal Issue: 2; Journal ID: ISSN 0021-9606
Publisher:
American Institute of Physics (AIP)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES

Citation Formats

Guo, Ashley Z., Fluitt, Aaron M., and de Pablo, Juan J. Early-stage human islet amyloid polypeptide aggregation: Mechanisms behind dimer formation. United States: N. p., 2018. Web. doi:10.1063/1.5033458.
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Guo, Ashley Z., Fluitt, Aaron M., & de Pablo, Juan J. Early-stage human islet amyloid polypeptide aggregation: Mechanisms behind dimer formation. United States. https://doi.org/10.1063/1.5033458
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Guo, Ashley Z., Fluitt, Aaron M., and de Pablo, Juan J. Fri . "Early-stage human islet amyloid polypeptide aggregation: Mechanisms behind dimer formation". United States. https://doi.org/10.1063/1.5033458. https://www.osti.gov/servlets/purl/1498504.
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@article{osti_1498504,
title = {Early-stage human islet amyloid polypeptide aggregation: Mechanisms behind dimer formation},
author = {Guo, Ashley Z. and Fluitt, Aaron M. and de Pablo, Juan J.},
abstractNote = {Amyloid aggregates of human islet amyloid polypeptide (hIAPP or human amylin) have long been implicated in the development of type II diabetes. While hIAPP is known to aggregate into amyloid fibrils, it is the early-stage prefibrillar species that have been proposed to be cytotoxic. A detailed picture of the early-stage aggregation process and relevant intermediates would be valuable in the development of effective therapeutics. Here, we use atomistic molecular dynamics simulations with a combination of enhanced sampling methods to examine the formation of the hIAPP dimer in water. Bias-exchange metadynamics calculations reveal relative conformational stabilities of the hIAPP dimer. Finite temperature string method calculations identify pathways for dimer formation, along with relevant free energy barriers and intermediate structures. We show that the initial stages of dimerization involve crossing a substantial free energy barrier to form an intermediate structure exhibiting transient beta-sheet character, before proceeding to form an entropically stabilized dimer structure.},
doi = {10.1063/1.5033458},
journal = {Journal of Chemical Physics},
number = 2,
volume = 149,
place = {United States},
year = {Fri Jul 13 00:00:00 EDT 2018},
month = {Fri Jul 13 00:00:00 EDT 2018}
}
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https://doi.org/10.1063/1.5033458
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Cited by: 16 works
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