Molecular Dynamics Simulations of Human Islet Amyloid Polypeptide (IAPP) Oligomers and their Interactions with Lipid Bilayers

Abstract

Human islet amyloid polypeptide (hIAPP) is a main component of amyloid plaques found in the pancreas of approximately 90% of typeII diabetes patients and hIAPP oligomers are major toxic species responsible for pancreatic islet β-cell dysfunction. But, molecular structures of these oligomers remain elusive. In this work, base on recent solid-state NMR, mass-per-length, and AFM data, we modeled series of hIAPP oligomers with different β-layers (one, two, and three-layers), morphologies (linear-like and annular-like), symmetries (symmetry and asymmetry), and associated interfaces using molecular dynamics simulations. For linear-like structures, three distinct interfaces formed by C-terminal-C-terminal β-sheet (CC), N-terminal-N-terminal β-sheet (NN), and C-terminal-N-terminal β-sheet (CN) are identified to drive multiple cross-β-layers laterally associated together to form different amyloid organizations via different intermolecular interactions, in which the CC interface is dominated by polar interactions, the NN interface by hydrophobic interactions, and the CN interface by mixed polar and hydrophobic interactions. Overall structural stability of the proposed hIAPP oligomers is a result of delicate balance between maximization of favorable peptide-peptide interactions at the interfaces and optimization of solvation energy with globular structure. Different hIAPP oligomeric models indicate a general and intrinsic nature of amyloid polymorphism, driven by different interfacial sidechain interactions. Furthermore, we propose two annular hIAPP structures (CNpNC and NCpCN) embedded in the DMPC lipid bilayers to examine the ion-channel mechanism. The CNpNC model is well maintained in the lipid bilayer with high selectivity of chlorine ions, while the pore structure of the NCpCN model is completed blocked in the lipid bilayers, leading to no selectivity of any ions. This result suggests a preferential conformation for hIAPP ion-channel related to their neurotoxicity. All proposed models are compatible with experimental data in overall size, cross-section area, and molecular weight.