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Title: Interplay Between Membrane Composition and Structural Stability of Membrane-Bound hIAPP

Abstract

Amyloid aggregates are characteristic of many serious diseases such as Alzheimer’s disease, Parkinson’s, and type 2 diabetes and commonly involve intrinsically disordered proteins (IDPs), those that populate an ensemble of conformations rather than a single folded structure. Human islet amyloid polypeptide (hIAPP or amylin) is an amyloidogenic IDP implicated in pancreatic β-cell death during the pathogenesis of type 2 diabetes. The target of amylin’s toxic activity is thought to be the cell’s lipid membrane, which may also act as a catalyst for aggregation. Since amylin is intrinsically disordered, differing environments can have a large impact on its equilibrium conformational ensemble. We apply atomistic molecular dynamics simulations on multiple systems containing a full-length amylin monomer and a lipid bilayer to study the changes induced by the membrane. Here, we observe stabilized helical conformations structurally similar to those determined by NMR experiments conducted in similar environments. We also find that bilayers of different compositions result in greatly different equilibrium ensembles of amylin. Finally, we discuss how a mixed bilayer containing zwitterionic and anionic lipid headgroups can allow for greater preference toward conformations which are adsorbed below the membrane surface through rearrangement of lipids for more favorable protein–lipid interactions.

Authors:
 [1];  [1]; ORCiD logo [1]
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  1. Lehigh Univ., Bethlehem, PA (United States). Dept. of Chemical and Biomolecular Engineering
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
OSTI Identifier:
1480289
Grant/Contract Number:  
SC0013979; AC02-05CH11231
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Physical Chemistry. B, Condensed Matter, Materials, Surfaces, Interfaces and Biophysical Chemistry
Additional Journal Information:
Journal Volume: 121; Journal Issue: 37; Journal ID: ISSN 1520-6106
Publisher:
American Chemical Society
Country of Publication:
United States
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY

Citation Formats

Dignon, Gregory L., Zerze, Gül H., and Mittal, Jeetain. Interplay Between Membrane Composition and Structural Stability of Membrane-Bound hIAPP. United States: N. p., 2017. Web. doi:10.1021/acs.jpcb.7b05689.
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Dignon, Gregory L., Zerze, Gül H., & Mittal, Jeetain. Interplay Between Membrane Composition and Structural Stability of Membrane-Bound hIAPP. United States. https://doi.org/10.1021/acs.jpcb.7b05689
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Dignon, Gregory L., Zerze, Gül H., and Mittal, Jeetain. Tue . "Interplay Between Membrane Composition and Structural Stability of Membrane-Bound hIAPP". United States. https://doi.org/10.1021/acs.jpcb.7b05689. https://www.osti.gov/servlets/purl/1480289.
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@article{osti_1480289,
title = {Interplay Between Membrane Composition and Structural Stability of Membrane-Bound hIAPP},
author = {Dignon, Gregory L. and Zerze, Gül H. and Mittal, Jeetain},
abstractNote = {Amyloid aggregates are characteristic of many serious diseases such as Alzheimer’s disease, Parkinson’s, and type 2 diabetes and commonly involve intrinsically disordered proteins (IDPs), those that populate an ensemble of conformations rather than a single folded structure. Human islet amyloid polypeptide (hIAPP or amylin) is an amyloidogenic IDP implicated in pancreatic β-cell death during the pathogenesis of type 2 diabetes. The target of amylin’s toxic activity is thought to be the cell’s lipid membrane, which may also act as a catalyst for aggregation. Since amylin is intrinsically disordered, differing environments can have a large impact on its equilibrium conformational ensemble. We apply atomistic molecular dynamics simulations on multiple systems containing a full-length amylin monomer and a lipid bilayer to study the changes induced by the membrane. Here, we observe stabilized helical conformations structurally similar to those determined by NMR experiments conducted in similar environments. We also find that bilayers of different compositions result in greatly different equilibrium ensembles of amylin. Finally, we discuss how a mixed bilayer containing zwitterionic and anionic lipid headgroups can allow for greater preference toward conformations which are adsorbed below the membrane surface through rearrangement of lipids for more favorable protein–lipid interactions.},
doi = {10.1021/acs.jpcb.7b05689},
journal = {Journal of Physical Chemistry. B, Condensed Matter, Materials, Surfaces, Interfaces and Biophysical Chemistry},
number = 37,
volume = 121,
place = {United States},
year = {Tue Aug 22 00:00:00 EDT 2017},
month = {Tue Aug 22 00:00:00 EDT 2017}
}
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https://doi.org/10.1021/acs.jpcb.7b05689
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    Works referencing / citing this record:

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