skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Fibrillar dimer formation of islet amyloid polypeptides

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.

Authors:
 [1];  [1]
  1. Univ. of Chicago, IL (United States); Argonne National Lab. (ANL), Argonne, IL (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
National Science Foundation (NSF); USDOE Office of Science (SC), Basic Energy Sciences (BES)
OSTI Identifier:
1247157
DOE Contract Number:  
AC02-06CH11357
Resource Type:
Journal Article
Journal Name:
AIP Advances
Additional Journal Information:
Journal Volume: 5; Journal Issue: 9; Journal ID: ISSN 2158-3226
Publisher:
American Institute of Physics (AIP)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Chiu, Chi-cheng, and de Pablo, Juan J. Fibrillar dimer formation of islet amyloid polypeptides. United States: N. p., 2015. Web. doi:10.1063/1.4921073.
Chiu, Chi-cheng, & de Pablo, Juan J. Fibrillar dimer formation of islet amyloid polypeptides. United States. https://doi.org/10.1063/1.4921073
Chiu, Chi-cheng, and de Pablo, Juan J. 2015. "Fibrillar dimer formation of islet amyloid polypeptides". United States. https://doi.org/10.1063/1.4921073.
@article{osti_1247157,
title = {Fibrillar dimer formation of islet amyloid polypeptides},
author = {Chiu, Chi-cheng and de Pablo, Juan J.},
abstractNote = {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.},
doi = {10.1063/1.4921073},
url = {https://www.osti.gov/biblio/1247157}, journal = {AIP Advances},
issn = {2158-3226},
number = 9,
volume = 5,
place = {United States},
year = {2015},
month = {5}
}

Works referenced in this record:

Islet Amyloid Polypeptide, Islet Amyloid, and Diabetes Mellitus
journal, July 2011


Control of energy homeostasis by amylin
journal, December 2011


Aggregation of islet amyloid polypeptide: from physical chemistry to cell biology
journal, February 2013


Amyloid fibrils formed from a segment of the pancreatic islet amyloid protein
journal, September 1988


Islet amyloid polypeptide: pinpointing amino acid residues linked to amyloid fibril formation.
journal, July 1990


Islet amyloid: From fundamental biophysics to mechanisms of cytotoxicity
journal, February 2013


Effects of Sequential Proline Substitutions on Amyloid Formation by Human Amylin 20 - 29
journal, February 1999


A Single-Point Mutation Converts the Highly Amyloidogenic Human Islet Amyloid Polypeptide into a Potent Fibrillization Inhibitor
journal, September 2007


Inhibition of Islet Amyloid Polypeptide Fibril Formation:  A Potential Role for Heteroaromatic Interactions
journal, November 2004


Design of a mimic of nonamyloidogenic and bioactive human islet amyloid polypeptide (IAPP) as nanomolar affinity inhibitor of IAPP cytotoxic fibrillogenesis
journal, February 2006


Identification of a penta- and hexapeptide of islet amyloid polypeptide (IAPP) with amyloidogenic and cytotoxic properties
journal, January 2000


Full-length Rat Amylin Forms Fibrils Following Substitution of Single Residues from Human Amylin
journal, February 2003


Pramlintide acetate
journal, November 2005


Pramlintide in the treatment of type 1 and type 2 diabetes mellitus
journal, October 2005


The Parallel Superpleated Beta-structure as a Model for Amyloid Fibrils of Human Amylin
journal, April 2005


Peptide Conformation and Supramolecular Organization in Amylin Fibrils:  Constraints from Solid-State NMR
journal, November 2007


2DIR Spectroscopy of Human Amylin Fibrils Reflects Stable β-Sheet Structure
journal, October 2011


Fibril Structure of Human Islet Amyloid Polypeptide
journal, December 2011


Atomic structure of the cross-β spine of islet amyloid polypeptide (amylin)
journal, September 2008


Comparative Molecular Dynamics Study of Human Islet Amyloid Polypeptide (IAPP) and Rat IAPP Oligomers
journal, January 2013


Human Islet Amyloid Polypeptide Monomers Form Ordered β-hairpins: A Possible Direct Amyloidogenic Precursor
journal, December 2009


Stable and Metastable States of Human Amylin in Solution
journal, October 2010


The Amyloid Formation Mechanism in Human IAPP: Dimers Have β-Strand Monomer−Monomer Interfaces
journal, May 2011


α-helix to β-hairpin transition of human amylin monomer
journal, April 2013


Effect of Proline Mutations on the Monomer Conformations of Amylin
journal, September 2013


Two-dimensional infrared spectroscopy reveals the complex behaviour of an amyloid fibril inhibitor
journal, March 2012


Conserved and Cooperative Assembly of Membrane-Bound α-Helical States of Islet Amyloid Polypeptide
journal, August 2006


Three-Dimensional Structure and Orientation of Rat Islet Amyloid Polypeptide Protein in a Membrane Environment by Solution NMR Spectroscopy
journal, June 2009


Dynamic α-Helix Structure of Micelle-bound Human Amylin
journal, February 2009


Direct detection of transient α-helical states in islet amyloid polypeptide
journal, January 2007


Solution state structures of human pancreatic amylin and pramlintide
journal, July 2009


Mechanism of IAPP amyloid fibril formation involves an intermediate with a transient  -sheet
journal, November 2013


A Bias-Exchange Approach to Protein Folding
journal, May 2007


A biomolecular force field based on the free enthalpy of hydration and solvation: The GROMOS force-field parameter sets 53A5 and 53A6
journal, January 2004


Structure and Dynamics of the TIP3P, SPC, and SPC/E Water Models at 298 K
journal, November 2001


Solution Structures of Rat Amylin Peptide: Simulation, Theory, and Experiment
journal, February 2010


Are Current Atomistic Force Fields Accurate Enough to Study Proteins in Crowded Environments?
journal, May 2014


Particle mesh Ewald: An N ⋅log( N ) method for Ewald sums in large systems
journal, June 1993


A smooth particle mesh Ewald method
journal, November 1995


LINCS: A linear constraint solver for molecular simulations
journal, September 1997


A molecular dynamics method for simulations in the canonical ensemble
journal, June 1984


A unified formulation of the constant temperature molecular dynamics methods
journal, July 1984


Canonical dynamics: Equilibrium phase-space distributions
journal, March 1985


GROMACS 4:  Algorithms for Highly Efficient, Load-Balanced, and Scalable Molecular Simulation
journal, February 2008


A Kinetic Model of Trp-Cage Folding from Multiple Biased Molecular Dynamics Simulations
journal, August 2009


Multidimensional View of Amyloid Fibril Nucleation in Atomistic Detail
journal, February 2012


Nucleation Process of a Fibril Precursor in the C-Terminal Segment of Amyloid- β
journal, April 2013


Escaping free-energy minima
journal, September 2002


Multicanonical ensemble: A new approach to simulate first-order phase transitions
journal, January 1992


Hyperparallel tempering Monte Carlo simulation of polymeric systems
journal, July 2000


Density of States–Based Molecular Simulations
journal, July 2012


Metadynamics: a method to simulate rare events and reconstruct the free energy in biophysics, chemistry and material science
journal, November 2008


METAGUI. A VMD interface for analyzing metadynamics and molecular dynamics simulations
journal, January 2012


THE weighted histogram analysis method for free-energy calculations on biomolecules. I. The method
journal, October 1992


PLUMED: A portable plugin for free-energy calculations with molecular dynamics
journal, October 2009


VMD: Visual molecular dynamics
journal, February 1996


Folding dynamics with nonadditive forces: A simulation study of a designed helical protein and a random heteropolymer
journal, June 1999


A Collective Variable for the Efficient Exploration of Protein Beta-Sheet Structures: Application to SH3 and GB1
journal, August 2009


Two-dimensional IR spectroscopy and isotope labeling defines the pathway of amyloid formation with residue-specific resolution
journal, April 2009


Knowledge-based protein secondary structure assignment
journal, December 1995


Works referencing / citing this record:

Synergistic long-range effects of mutations underlie aggregation propensities of amylin analogues
journal, August 2019


Early-stage human islet amyloid polypeptide aggregation: Mechanisms behind dimer formation
journal, July 2018