Interaction of human islet amyloid polypeptide (hIAPP) peptides, particularly small oligomers, with cell membrane is crucial for the understanding of amyloid toxicity associated with Type II diabetes (T2D). The exact mechanisms of hIAPP-oligomer-induced toxicity remain unclear, because characterization of the conformations of hIAPP oligomers and their interactions with cell membranes at the atomic level still presents a daunting challenge. Herein, we proposed multiscale molecular modeling and simulations to study different hIAPP-induced membrane disruption scenarios, including (1) membrane adsorption models by hIAPP monomer and oligomers and (2) ion channel models by hIAPP oligomers. The presence of different lipid components and hIAPP aggregates allows to investigate the combinatorial effects of lipid compositions/structures/dynamics and hIAPP sizes/conformations on the adsorption, orientation, and interactions of hIAPP on lipid bilayers. Simulation results show that (1) hIAPP monomer and pentamer could stably associate with both POPC and POPC/POPE bilayers, but via specific N-terminal residues to interact with the lipids. Moreover, hIAPP aggregates interacted more strongly with and located more closely to mixed POPC/POPG lipids than pure POPC lipids, resulting from cooperative hIAPP-lipid interactions from hydrogen bonds and salt bridges. (2) hIAPP peptides can also form ion-channels with different ion channel conformations, sizes, and orientations. The resultant hIAPP channels fragment into three to five oligomeric units that are loosely associated, but remain open, channel-like structures in the bilayer, similar to other amyloid channels by Aβ and K3. The hIAPP channels exhibit relatively high ion binding selectivity and ion conductivity of Cl- over cations. Complement to experimental studies, our computational works provide a more complete picture about the mechanism of amyloid peptide−membrane interactions that are central to the toxicity of amyloid peptides.<br/>

Computational studies of membrane interaction of hIAPP aggregates: Implication of different membrane-disruption mechanisms

255th National Meeting (2018)

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