Surface-induced protein folding of human islet amyloid polypeptide on neuronal membrane domains.

Abstract

Aggregated human islet amyloid polypeptide (hIAPP) has been associated with the development of type II diabetes. However, recent evidence suggests that disordered hIAPP aggregates, or hIAPP oligomers, may also bind to the neurons in the brain causing membrane damage and thereby contributing to the cognitive decline of people with Alzheimer's Disease (AD). At present, the detailed membrane damage mechanisms of disordered hIAPP oligomers on neuronal membranes are unknown. Using both coarse-grained (CG) and all-atom (AA) molecular dynamics (MD) simulations, binding of disordered hIAPP oligomers (monomer, dimer, and tetramer) to phase-separated lipid bilayers (raft membranes), a model of neuronal plasma membrane domains, was investigated. We observed membrane binding of hIAPP oligomers to raft membranes containing mixed liquid-ordered (Lo) and liquid-disordered (Ld) boundary or Lod domains on both lipid leaflets of the lipid bilayer. However, much stronger binding to ganglioside (GM1) clusters embedded in the Lo domains and phosphatidylserine (PS) clusters embedded in the Lo and Lod domains, located in only one leaflet of the lipid bilayer, was evident. All oligomers binding events occurred within 10 μs. Our results suggest that the Lod domains represent the non-specific targets in both lipid leaflets, while the PS-clusters and GM1-clusters represent the specific targets in the inner lipid leaflet and outer lipid leaflet, respectively, of the plasma membranes of neurons. After a CG-to-AA resolution transformation and a 200 ns-long AA MD simulation, surface-induced protein folding, particularly the formation of localized inter-chain and intra-chain beta-sheets, in several hIAPP-raft complexes, especially those involving Lod domains, was evident. We propose that these localized beta-sheets may act as nucleation seeds to attract nearby hIAPP or non-hIAPP oligomers to form larger surface-bound amyloid aggregates and create membrane damage to the neurons that leads to the pathogenesis of AD.