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

Guo, Ashley Z.; Fluitt, Aaron M.; de Pablo, Juan J.

doi:10.1063/1.5033458

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

Journal Article · Fri Jul 13 00:00:00 EDT 2018 · Journal of Chemical Physics

DOI:https://doi.org/10.1063/1.5033458· OSTI ID:1498504

^[1]; Fluitt, Aaron M. ^[1]; de Pablo, Juan J. ^[2]

Univ. of Chicago, IL (United States). Inst. for Molecular Engineering
Univ. of Chicago, IL (United States). Inst. for Molecular Engineering; Argonne National Lab. (ANL), Argonne, IL (United States). Materials Science Division

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.

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Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States)

Sponsoring Organization:: National Science Foundation (NSF); USDOE

Grant/Contract Number:: AC02-06CH11357; DMR-1710357

OSTI ID:: 1498504

Alternate ID(s):: OSTI ID: 1460132

Journal Information:: Journal of Chemical Physics, Vol. 149, Issue 2; ISSN 0021-9606

Publisher:: American Institute of Physics (AIP)Copyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 16 works

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References (63)

Membrane Interactions of hIAPP Monomer and Oligomer with Lipid Membranes by Molecular Dynamics Simulations Zhang, Mingzhen; Ren, Baiping; Liu, Yonglan ACS Chemical Neuroscience, Vol. 8, Issue 8 https://doi.org/10.1021/acschemneuro.7b00160	journal	June 2017
Revisiting the finite temperature string method for the calculation of reaction tubes and free energies Vanden-Eijnden, Eric; Venturoli, Maddalena The Journal of Chemical Physics, Vol. 130, Issue 19 https://doi.org/10.1063/1.3130083	journal	May 2009
Effects of Sequential Proline Substitutions on Amyloid Formation by Human Amylin ₂₀ _- ₂₉ ^† Moriarty, Daniel F.; Raleigh, Daniel P. Biochemistry, Vol. 38, Issue 6 https://doi.org/10.1021/bi981658g	journal	February 1999
Secondary Structure of Rat and Human Amylin across Force Fields Hoffmann, Kyle Quynn; McGovern, Michael; Chiu, Chi-cheng PLOS ONE, Vol. 10, Issue 7 https://doi.org/10.1371/journal.pone.0134091	journal	July 2015
Molecular Simulations of Amyloid Structures, Toxicity, and Inhibition Zhang, Mingzhen; Ren, Baiping; Chen, Hong Israel Journal of Chemistry, Vol. 57, Issue 7-8 https://doi.org/10.1002/ijch.201600075	journal	November 2016
An Analysis of Biomolecular Force Fields for Simulations of Polyglutamine in Solution Fluitt, Aaron M.; de Pablo, Juan J. Biophysical Journal, Vol. 109, Issue 5 https://doi.org/10.1016/j.bpj.2015.07.018	journal	September 2015
A Free Energy Barrier Caused by the Refolding of an Oligomeric Intermediate Controls the Lag Time of Amyloid Formation by hIAPP Serrano, Arnaldo L.; Lomont, Justin P.; Tu, Ling-Hsien Journal of the American Chemical Society, Vol. 139, Issue 46 https://doi.org/10.1021/jacs.7b08830	journal	November 2017
Self-Assembling Pathway of HiApp Fibrils within Lipid Bilayers Scalisi, Silvia; Sciacca, Michele F. M.; Zhavnerko, Genady ChemBioChem, Vol. 11, Issue 13 https://doi.org/10.1002/cbic.201000090	journal	July 2010
GROMACS 4: Algorithms for Highly Efficient, Load-Balanced, and Scalable Molecular Simulation Hess, Berk; Kutzner, Carsten; van der Spoel, David Journal of Chemical Theory and Computation, Vol. 4, Issue 3 https://doi.org/10.1021/ct700301q	journal	February 2008
Protein aggregation: Mechanisms and functional consequences Invernizzi, Gaetano; Papaleo, Elena; Sabate, Raimon The International Journal of Biochemistry & Cell Biology, Vol. 44, Issue 9 https://doi.org/10.1016/j.biocel.2012.05.023	journal	September 2012
A biomolecular force field based on the free enthalpy of hydration and solvation: The GROMOS force-field parameter sets 53A5 and 53A6 Oostenbrink, Chris; Villa, Alessandra; Mark, Alan E. Journal of Computational Chemistry, Vol. 25, Issue 13 https://doi.org/10.1002/jcc.20090	journal	January 2004
Improved side-chain torsion potentials for the Amber ff99SB protein force field Lindorff-Larsen, Kresten; Piana, Stefano; Palmo, Kim Proteins: Structure, Function, and Bioinformatics https://doi.org/10.1002/prot.22711	journal	January 2010
2DIR Spectroscopy of Human Amylin Fibrils Reflects Stable β-Sheet Structure Wang, Lu; Middleton, Chris T.; Singh, Sadanand Journal of the American Chemical Society, Vol. 133, Issue 40 https://doi.org/10.1021/ja204035k	journal	October 2011
METAGUI. A VMD interface for analyzing metadynamics and molecular dynamics simulations Biarnés, Xevi; Pietrucci, Fabio; Marinelli, Fabrizio Computer Physics Communications, Vol. 183, Issue 1 https://doi.org/10.1016/j.cpc.2011.08.020	journal	January 2012
Interplay Between Membrane Composition and Structural Stability of Membrane-Bound hIAPP Dignon, Gregory L.; Zerze, Gül H.; Mittal, Jeetain The Journal of Physical Chemistry B, Vol. 121, Issue 37 https://doi.org/10.1021/acs.jpcb.7b05689	journal	September 2017
Free Energy and Kinetics of Conformational Transitions from Voronoi Tessellated Milestoning with Restraining Potentials Maragliano, Luca; Vanden-Eijnden, Eric; Roux, Benoît Journal of Chemical Theory and Computation, Vol. 5, Issue 10 https://doi.org/10.1021/ct900279z	journal	August 2009
Islet Amyloid Polypeptide, Islet Amyloid, and Diabetes Mellitus Westermark, Per; Andersson, Arne; Westermark, Gunilla T. Physiological Reviews, Vol. 91, Issue 3 https://doi.org/10.1152/physrev.00042.2009	journal	July 2011
Amyloid Fiber Formation and Membrane Disruption are Separate Processes Localized in Two Distinct Regions of IAPP, the Type-2-Diabetes-Related Peptide Brender, Jeffrey R.; Lee, Edgar L.; Cavitt, Marchello A. Journal of the American Chemical Society, Vol. 130, Issue 20 https://doi.org/10.1021/ja710484d	journal	May 2008
Comparison of simple potential functions for simulating liquid water Jorgensen, William L.; Chandrasekhar, Jayaraman; Madura, Jeffry D. The Journal of Chemical Physics, Vol. 79, Issue 2 https://doi.org/10.1063/1.445869	journal	July 1983
Islet amyloid polypeptide: pinpointing amino acid residues linked to amyloid fibril formation. Westermark, P.; Engstrom, U.; Johnson, K. H. Proceedings of the National Academy of Sciences, Vol. 87, Issue 13 https://doi.org/10.1073/pnas.87.13.5036	journal	July 1990
Folding dynamics with nonadditive forces: A simulation study of a designed helical protein and a random heteropolymer Takada, Shoji; Luthey-Schulten, Zaida; Wolynes, Peter G. The Journal of Chemical Physics, Vol. 110, Issue 23 https://doi.org/10.1063/1.479101	journal	June 1999
The Interplay of Catalysis and Toxicity by Amyloid Intermediates on Lipid Bilayers: Insights from Type II Diabetes Hebda, James A.; Miranker, Andrew D. Annual Review of Biophysics, Vol. 38, Issue 1 https://doi.org/10.1146/annurev.biophys.050708.133622	journal	June 2009
Seed-Induced Heterogeneous Cross-Seeding Self-Assembly of Human and Rat Islet Polypeptides Hu, Rundong; Ren, Baiping; Zhang, Mingzhen ACS Omega, Vol. 2, Issue 3 https://doi.org/10.1021/acsomega.6b00559	journal	March 2017
Early aggregation preceding the nucleation of insulin amyloid fibrils as monitored by small angle X-ray scattering Chatani, Eri; Inoue, Rintaro; Imamura, Hiroshi Scientific Reports, Vol. 5, Issue 1 https://doi.org/10.1038/srep15485	journal	October 2015
A Single-Point Mutation Converts the Highly Amyloidogenic Human Islet Amyloid Polypeptide into a Potent Fibrillization Inhibitor Abedini, Andisheh; Meng, Fanling; Raleigh, Daniel P. Journal of the American Chemical Society, Vol. 129, Issue 37 https://doi.org/10.1021/ja072157y	journal	September 2007
Mechanism of IAPP amyloid fibril formation involves an intermediate with a transient -sheet Buchanan, L. E.; Dunkelberger, E. B.; Tran, H. Q. Proceedings of the National Academy of Sciences, Vol. 110, Issue 48 https://doi.org/10.1073/pnas.1314481110	journal	November 2013
A unified formulation of the constant temperature molecular dynamics methods Nosé, Shuichi The Journal of Chemical Physics, Vol. 81, Issue 1 https://doi.org/10.1063/1.447334	journal	July 1984
PLUMED: A portable plugin for free-energy calculations with molecular dynamics Bonomi, Massimiliano; Branduardi, Davide; Bussi, Giovanni Computer Physics Communications, Vol. 180, Issue 10 https://doi.org/10.1016/j.cpc.2009.05.011	journal	October 2009
Fibrillar dimer formation of islet amyloid polypeptides Chiu, Chi-cheng; de Pablo, Juan J. AIP Advances, Vol. 5, Issue 9 https://doi.org/10.1063/1.4921073	journal	September 2015
Control of energy homeostasis by amylin Lutz, Thomas A. Cellular and Molecular Life Sciences, Vol. 69, Issue 12 https://doi.org/10.1007/s00018-011-0905-1	journal	December 2011
Identification of Key Interactions in the Initial Self-Assembly of Amylin in a Membrane Environment Christensen, Mikkel; Skeby, Katrine K.; Schiøtt, Birgit Biochemistry, Vol. 56, Issue 36 https://doi.org/10.1021/acs.biochem.7b00344	journal	August 2017
Protein folding kinetics and thermodynamics from atomistic simulation Piana, S.; Lindorff-Larsen, K.; Shaw, D. E. Proceedings of the National Academy of Sciences, Vol. 109, Issue 44 https://doi.org/10.1073/pnas.1201811109	journal	July 2012
Membrane Permeation versus Amyloidogenicity: A Multitechnique Study of Islet Amyloid Polypeptide Interaction with Model Membranes Martel, Anne; Antony, Lucas; Gerelli, Yuri Journal of the American Chemical Society, Vol. 139, Issue 1 https://doi.org/10.1021/jacs.6b06985	journal	December 2016
Structural Properties of Human IAPP Dimer in Membrane Environment Studied by All-Atom Molecular Dynamics Simulations Liu, Na; Duan, Mojie; Yang, Minghui Scientific Reports, Vol. 7, Issue 1 https://doi.org/10.1038/s41598-017-08504-x	journal	August 2017
Particle mesh Ewald: An N ⋅log( N ) method for Ewald sums in large systems Darden, Tom; York, Darrin; Pedersen, Lee The Journal of Chemical Physics, Vol. 98, Issue 12 https://doi.org/10.1063/1.464397	journal	June 1993
Fibril Structure of Human Islet Amyloid Polypeptide Bedrood, Sahar; Li, Yiyu; Isas, J. Mario Journal of Biological Chemistry, Vol. 287, Issue 8 https://doi.org/10.1074/jbc.m111.327817	journal	December 2011
Insight into a New Binding Site of Zinc Ions in Fibrillar Amylin Wineman-Fisher, Vered; Miller, Yifat ACS Chemical Neuroscience, Vol. 8, Issue 9 https://doi.org/10.1021/acschemneuro.7b00221	journal	July 2017
Site-specific detection of protein secondary structure using 2D IR dihedral indexing: a proposed assembly mechanism of oligomeric hIAPP Maj, Michał; Lomont, Justin P.; Rich, Kacie L. Chemical Science, Vol. 9, Issue 2 https://doi.org/10.1039/c7sc03789a	journal	January 2018
The Human Islet Amyloid Polypeptide Forms Transient Membrane-Active Prefibrillar Assemblies ^† Porat, Yair; Kolusheva, Sofiya; Jelinek, Raz Biochemistry, Vol. 42, Issue 37 https://doi.org/10.1021/bi034889i	journal	September 2003
Dictionary of protein secondary structure: Pattern recognition of hydrogen-bonded and geometrical features Kabsch, Wolfgang; Sander, Christian Biopolymers, Vol. 22, Issue 12 https://doi.org/10.1002/bip.360221211	journal	December 1983
THE weighted histogram analysis method for free-energy calculations on biomolecules. I. The method Kumar, Shankar; Rosenberg, John M.; Bouzida, Djamal Journal of Computational Chemistry, Vol. 13, Issue 8 https://doi.org/10.1002/jcc.540130812	journal	October 1992
Pancreatic islet cell toxicity of amylin associated with type-2 diabetes mellitus Lorenzo, Alfredo; Razzaboni, Bronwyn; Weir, Gordon C. Nature, Vol. 368, Issue 6473 https://doi.org/10.1038/368756a0	journal	April 1994
Cross-Seeding Interaction between β-Amyloid and Human Islet Amyloid Polypeptide Hu, Rundong; Zhang, Mingzhen; Chen, Hong ACS Chemical Neuroscience, Vol. 6, Issue 10 https://doi.org/10.1021/acschemneuro.5b00192	journal	August 2015
Folding proteins in fatal ways Selkoe, Dennis J. Nature, Vol. 426, Issue 6968 https://doi.org/10.1038/nature02264	journal	December 2003
Pore Formation by the Cytotoxic Islet Amyloid Peptide Amylin Mirzabekov, Tajib A.; Lin, Meng-chin; Kagan, Bruce L. Journal of Biological Chemistry, Vol. 271, Issue 4 https://doi.org/10.1074/jbc.271.4.1988	journal	January 1996
Fluorescence as a method to reveal structures and membrane-interactions of amyloidogenic proteins Munishkina, Larissa A.; Fink, Anthony L. Biochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 1768, Issue 8 https://doi.org/10.1016/j.bbamem.2007.03.015	journal	August 2007
Peptide Conformation and Supramolecular Organization in Amylin Fibrils: Constraints from Solid-State NMR ^† Luca, Sorin; Yau, Wai-Ming; Leapman, Richard Biochemistry, Vol. 46, Issue 47 https://doi.org/10.1021/bi701427q	journal	November 2007
Graphene oxide inhibits hIAPP amyloid fibrillation and toxicity in insulin-producing NIT-1 cells Nedumpully-Govindan, Praveen; Gurzov, Esteban N.; Chen, Pengyu Physical Chemistry Chemical Physics, Vol. 18, Issue 1 https://doi.org/10.1039/c5cp05924k	journal	January 2016
Systematic Validation of Protein Force Fields against Experimental Data Lindorff-Larsen, Kresten; Maragakis, Paul; Piana, Stefano PLoS ONE, Vol. 7, Issue 2 https://doi.org/10.1371/journal.pone.0032131	journal	February 2012
A Collective Variable for the Efficient Exploration of Protein Beta-Sheet Structures: Application to SH3 and GB1 Pietrucci, Fabio; Laio, Alessandro Journal of Chemical Theory and Computation, Vol. 5, Issue 9 https://doi.org/10.1021/ct900202f	journal	August 2009
Equilibrium Free Energies from Nonequilibrium Metadynamics Bussi, Giovanni; Laio, Alessandro; Parrinello, Michele Physical Review Letters, Vol. 96, Issue 9 https://doi.org/10.1103/physrevlett.96.090601	journal	March 2006
Full length amylin oligomer aggregation: insights from molecular dynamics simulations and implications for design of aggregation inhibitors Berhanu, Workalemahu Mikre; Masunov, Artëm E. Journal of Biomolecular Structure and Dynamics, Vol. 32, Issue 10 https://doi.org/10.1080/07391102.2013.832635	journal	September 2013
A smooth particle mesh Ewald method Essmann, Ulrich; Perera, Lalith; Berkowitz, Max L. The Journal of Chemical Physics, Vol. 103, Issue 19 https://doi.org/10.1063/1.470117	journal	November 1995
Inhibition of Islet Amyloid Polypeptide Fibril Formation: A Potential Role for Heteroaromatic Interactions ^† Porat, Yair; Mazor, Yariv; Efrat, Shimon Biochemistry, Vol. 43, Issue 45 https://doi.org/10.1021/bi048582a	journal	November 2004
Escaping free-energy minima Laio, A.; Parrinello, M. Proceedings of the National Academy of Sciences, Vol. 99, Issue 20 https://doi.org/10.1073/pnas.202427399	journal	September 2002
A Bias-Exchange Approach to Protein Folding Piana, Stefano; Laio, Alessandro The Journal of Physical Chemistry B, Vol. 111, Issue 17 https://doi.org/10.1021/jp067873l	journal	May 2007
VMD: Visual molecular dynamics Humphrey, William; Dalke, Andrew; Schulten, Klaus Journal of Molecular Graphics, Vol. 14, Issue 1 https://doi.org/10.1016/0263-7855(96)00018-5	journal	February 1996
Full length amylin oligomer aggregation: insights from molecular dynamics simulations and implications for design of aggregation inhibitors Berhanu, Workalemahu Mikre; Masunov, Artëm E. Taylor & Francis https://doi.org/10.6084/m9.figshare.825930.v1	text	January 2014
Improving the specificity of organophosphorus hydrolase to acephate by mutagenesis at its binding site: a computational study Badakhshan, Reza; Mohammadi, Mozafar; Farnoosh, Gholamreza Journal of Molecular Modeling, Vol. 27, Issue 6 https://doi.org/10.1007/s00894-021-04749-6	journal	May 2021
Amorphization-induced surface electronic states modulation of cobaltous oxide nanosheets for lithium-sulfur batteries Li, Ruilong; Rao, Dewei; Zhou, Jianbin Nature Communications, Vol. 12, Issue 1 https://doi.org/10.1038/s41467-021-23349-9	journal	May 2021
Full length amylin oligomer aggregation: insights from molecular dynamics simulations and implications for design of aggregation inhibitors Berhanu, Workalemahu Mikre; Masunov, Artëm E. Taylor & Francis https://doi.org/10.6084/m9.figshare.825930.v2	text	January 2014
Control of energy homeostasis by amylin Lutz, T. A. Springer https://doi.org/10.5167/uzh-56281	text	January 2012
PLUMED: a portable plugin for free-energy calculations with molecular dynamics Bonomi, M.; Branduardi, D.; Bussi, G. arXiv https://doi.org/10.48550/arxiv.0902.0874	text	January 2009

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