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.
Highlights
To search for therapeutic agents that can rescue Human islet amyloid polypeptide (hIAPP)-induced cytotoxicity, it is necessary to uncover the mechanism of amyloidal self-assembly and monitor the kinetic conformation change induced by inhibitors
Like antimicrobial peptides (AMPs)[36,37], the amphipathic nature of hIAPP drives its hydrophobic face to penetrate into the membrane interior, while the hydrophilic face extends into the water solvent
Revealing the process and mechanism of membrane damage by hIAPP at a molecular level is essential before design and synthesis of potent inhibitors
Summary
Human islet amyloid polypeptide (hIAPP) is believed to be responsible for the death of insulin-producing β-cells. Snapshots of (a) 16, (b) 36, (c) 64, (d) 81, (e) 100, and (f) 121 α-helical hIAPP molecules interacting with a bilayer membrane composed of 1600 lipids at a simulation time of 1.144 μs Both top and intersectional views of the complexes are given at low peptide concentrations in (a), (b), and (c) to illustrate the binding states of hIAPP. The calculations show that when more than 81 hIAPP molecules (P/L > 5/100) bind to the surface of the membrane, the induced electric field exceeds the critical value of 0.4 V/nm at which pore formation by an external electric field can be induced[39] These results suggest that peptide-induced electric and mechanical tension work together to propel lipid head groups and hIAPPs themselves to insert into the membrane and form permeable pores to release this tension. The consistence between CG simulations, AAMD simulations, and experiments demonstrates the validation of the inhibition mode of BSPOTPE proposed here
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