title: Membrane permeation induced by aggregates of human islet amyloid polypeptides.
abstract: Several neurodegenerative diseases such as Alzheimer's and Parkinson's diseases as well as nonneuropathic diseases such as type II diabetes and atrial amyloidosis are associated with aggregation of amyloid polypeptides into fibrillar structures, or plaques. In this study, we use molecular dynamics simulations to test the stability and orientation of membrane-embedded aggregates of the human islet amyloid polypeptide (hIAPP) implicated in type II diabetes. We find that in both monolayers and bilayers of dipalmitoylphosphatidylglycerol (DPPG) hIAPP trimers and tetramers remain inside the membranes and preserve their β-sheet secondary structure. Lipid bilayer-inserted hIAPP trimers and tetramers orient inside DPPG at 60° relative to the membrane/water interface and lead to water permeation and Na(+) intrusion, consistent with ion-toxicity in islet β-cells. In particular, hIAPP trimers form a water-filled β-sandwich that induce water permeability comparable with channel-forming proteins, such as aquaporins and gramicidin-A. The predicted disruptive orientation is consistent with the amphiphilic properties of the hIAPP aggregates and could be probed by chiral sum frequency generation (SFG) spectroscopy, as predicted by the simulated SFG spectra.
authors.affiliation: Forschungszentrum Jülich GmbH, Institute of Complex Systems: Structural Biochemistry (ICS-6), 52425 Jülich, Germany.
authors.forename: Chetan
authors.initials: C
authors.lastname: Poojari
authors.forename: Dequan
authors.initials: D
authors.lastname: Xiao
authors.forename: Victor S
authors.initials: VS
authors.lastname: Batista
authors.forename: Birgit
authors.initials: B
authors.lastname: Strodel
mesh_terms: D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism*; D002463:Cell Membrane Permeability; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000737:chemistry* / Q000378:metabolism; D008051:Lipid Bilayers / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D009995:Osmosis; D010715:Phosphatidylglycerols / Q000378:metabolism; D055503:Protein Multimerization; D055550:Protein Stability; D017433:Protein Structure, Secondary
chemical_list: D058228:Islet Amyloid Polypeptide; D008051:Lipid Bilayers; D010715:Phosphatidylglycerols; C030345:1,2-dipalmitoylphosphatidylglycerol