title: Mechanism of Inhibition of Human Islet Amyloid Polypeptide-Induced Membrane Damage by a Small Organic Fluorogen.
abstract: Human islet amyloid polypeptide (hIAPP) is believed to be responsible for the death of insulin-producing β-cells. However, the mechanism of membrane damage at the molecular level has not been fully elucidated. In this article, we employ coarse- grained dissipative particle dynamics simulations to study the interactions between a lipid bilayer membrane composed of 70% zwitterionic lipids and 30% anionic lipids and hIAPPs with α-helical structures. We demonstrated that the key factor controlling pore formation is the combination of peptide charge-induced electroporation and peptide hydrophobicity-induced lipid disordering and membrane thinning. According to these mechanisms, we suggest that a water-miscible tetraphenylethene BSPOTPE is a potent inhibitor to rescue hIAPP-induced cytotoxicity. Our simulations predict that BSPOTPE molecules can bind directly to the helical regions of hIAPP and form oligomers with separated hydrophobic cores and hydrophilic shells. The micelle-like hIAPP-BSPOTPE clusters tend to be retained in the water/membrane interface and aggregate therein rather than penetrate into the membrane. Electrostatic attraction between BSPOTPE and hIAPP also reduces the extent of hIAPP binding to the anionic lipid bilayer. These two modes work together and efficiently prevent membrane poration.
authors.affiliation: Key Laboratory of Theoretical and Computational Photochemistry, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China.
authors.forename: Xiaoxu
authors.initials: X
authors.lastname: Li
authors.affiliation: Key Laboratory of Theoretical and Computational Photochemistry, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China.
authors.forename: Mingwei
authors.initials: M
authors.lastname: Wan
authors.affiliation: Key Laboratory of Theoretical and Computational Photochemistry, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China.
authors.forename: Lianghui
authors.initials: L
authors.lastname: Gao
authors.affiliation: Key Laboratory of Theoretical and Computational Photochemistry, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China.
authors.forename: Weihai
authors.initials: W
authors.lastname: Fang
mesh_terms: D002462:Cell Membrane / Q000378:metabolism*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000648:ultrastructure*; D058228:Islet Amyloid Polypeptide / Q000737:chemistry / Q000378:metabolism*; D008051:Lipid Bilayers / Q000378:metabolism*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011485:Protein Binding / Q000187:drug effects; D013267:Stilbenes / Q000494:pharmacology
chemical_list: D058228:Islet Amyloid Polypeptide; D008051:Lipid Bilayers; D013267:Stilbenes; C554024:sodium 1,2-bis(4-(3-sulfonatopropoxyl)phenyl)-1,2-diphenylethene