title: Effects of cholesterol on pore formation in lipid bilayers induced by human islet amyloid polypeptide fragments: a coarse-grained molecular dynamics study.
abstract: Disruption of the cellular membrane by the amyloidogenic peptide, islet amyloid polypeptide (IAPP), has been considered as one of the mechanisms of β-cell death during type 2 diabetes. The N-terminal region (residues 1-19) of the human version of IAPP is suggested to be primarily responsible for the membrane-disrupting effect of the full-length hIAPP peptide. However, the detailed assembly mode of hIAPP1-19 with membrane remains unclear. To gain insight into the interactions of hIAPP1-19 oligomer with the model membrane, we have employed coarse-grained molecular dynamics self-assembly simulations to study the aggregation of hIAPP1-19 fragments in the binary lipid made of zwitterionic dipalmitoylphosphatidylcholine (DPPC) and anionic dipalmitoylphosphatidylserine (DPPS) in the presence and absence of different levels of cholesterol content. The membrane-destabilizing effect of hIAPP1-19 is found to be modulated by the presence of cholesterol. In the absence of cholesterol, hIAPP1-19 aggregates prefer to locate inside the bilayer, forming pore-like assemblies. While in the presence of cholesterol molecules, the lipid bilayer becomes more ordered and stiff, and the hIAPP1-19 aggregates are dominantly positioned at the bilayer-water interface. The action of cholesterol may suggest a possible way to maintain the membrane integrity by small molecule interference.
authors.affiliation: State Key Laboratory of Precision Spectroscopy, Institutes for Advanced Interdisciplinary Research, East China Normal University, Shanghai, China.
authors.forename: Weixin
authors.initials: W
authors.lastname: Xu
authors.forename: Guanghong
authors.initials: G
authors.lastname: Wei
authors.forename: Haibin
authors.initials: H
authors.lastname: Su
authors.forename: Lars
authors.initials: L
authors.lastname: Nordenskiöld
authors.forename: Yuguang
authors.initials: Y
authors.lastname: Mu
mesh_terms: D000595:Amino Acid Sequence; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000737:chemistry* / Q000378:metabolism; D008051:Lipid Bilayers / Q000737:chemistry* / Q000378:metabolism*; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism*; D016062:Porosity; D055503:Protein Multimerization; D014867:Water / Q000737:chemistry
chemical_list: D058228:Islet Amyloid Polypeptide; D008051:Lipid Bilayers; D010446:Peptide Fragments; D014867:Water; D002784:Cholesterol