Exploring Specific and Non-specific Membrane Binding Targets of Self-assembling Human Islet Amyloid Polypeptide Oligomers on Phase-Separated Lipid Domains Using MD Simulations

Self-aggregation of human Islet Amyloid Polypeptide (hIAPP) is linked to type 2 diabetics (T2D). Recent cellular studies indicate that the small, disordered hIAPP oligomers are more membrane-active and cytotoxic than the mature, ordered hIAPP fibrils. How hIAPP oligomers interact with the phase-separated lipid bilayers, a model of plasma membranes, is still unclear. Using coarse-grained (CG) and all-atom (AA) MD simulations, hIAPP oligomers in solution were created. By mixing phosphatidylcholine, cholesterol, ganglioside (GM1), and phosphatidylserine (PS) lipids, bilayers containing ordered (Lo), disordered (Ld), and mixed (Lod) domains on both leaflets, as well as PS- or GM1-domains on one leaflet each, were also formed. Within 10 μs of CG simulations, hIAPP oligomers bound to the Lod domains in leaflets without PS or GM1, but to PS- or GM1-domains in leaflets with PS or GM1. After a CG-to-AA mapping and a 300 ns long AA simulation, protein-induced disruptions of lipid chain orientational order in all lipids, particularly saturated lipids, and extensive beta-sheet formation in oligomers bound on Lod domains were found. Since PS and GM1 are found exclusively in the inner and outer leaflets of plasma membranes, respectively, we conclude that the PS- and GM1-domains are leaflet-specific targets while the Lod domains are non-specific membrane targets in the early progression of T2D.