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.

Islet Amyloid Polypeptide: A Partner in Crime With Aβ in the Pathology of Alzheimer's Disease

“…Yankner, 1996), however, the current consensus is that toxicity is mostly associated with soluble oligomers and protofibrils, which may act as the trigger agents for β-cell depletion and diabetes onset (Haataja et al, 2008;Zhao et al, 2009;Zhang et al, 2016). Oligomeric IAPP species form ion-leaking pores in the cell membranes (Gurlo et al, 2010;Li et al, 2016b), leading to enhanced membrane fluidity, calcium dysregulation, and decreased cell viability (Huang et al, 2010). IAPP oligomers have also been found within disturbed mitochondrial membranes in transgenic hIAPP mice and T2DM patients (Gurlo et al, 2010).…”

Dissipative Particle Dynamics Simulations for Phospholipid Membranes Based on a Four-To-One Coarse-Grained Mapping Scheme

“…Shilcock and Lipowsky modified the Y-shape model to a λ -shape model [ 12 ], Fig 1C . We recently made a DPD-versioned MARTINI-like h-shape lipid model by mapping about four heavy atoms onto one bead [ 31 – 33 ] ( Fig 1D ), where the beads were divided into types distinguished by polarizability and hydrogen-bonding capacity. The four-to-one CG mapping was also applied to sufactants and polymer brushes in DPD simulations by Neimark’s group [ 34 – 37 ].…”

“…The four-to-one CG mapping was also applied to sufactants and polymer brushes in DPD simulations by Neimark’s group [ 34 – 37 ]. Based on these mapping schemes, various sets of force fields were assigned to the CG lipids [ 10 , 12 , 14 , 23 , 31 – 33 ]. Even for the same CG model, such as the Y-shape model in Fig 1B , at least four force parameter sets were used in the literature [ 23 ].…”

“…(C): λ -shape model by Shillcock and Lipowsky [ 12 ]. (D): h-shape MARTINI model used by us [ 31 – 33 ].…”

“…However, the DPD force field for this model, given in Ref. [ 31 – 33 ] was obtained based on the three-to-one mapping strategy. Therefore, it is essential to develop a new set of DPD force parameters for the MARTINI-like lipid model.…”