Molecular Dynamics Simulation Of Adsorption And Orientation Of Human Amyloid Pancreatic Peptide On Phospholipid Bilayer

Protein misfolding and aggregation cause serious degenerative diseases such as Alzheimer’s and type2diabetes. Human islet amyloid polypeptide (hIAPP) is the major component of amyloid deposits found in the pancreas of type II diabetic patients. Increasing evidence suggests that β-cell death is related to the interaction of hIAPP with cellular membrane which accelerates peptide aggregation. However, the molecular mechanism of interaction and subsequent membrane perturbation at atomic level remains poorly understood. In this study, as a first step towards understanding the membrane-mediated hIAPP aggregation, we investigate the atomic details of the initial step of hIAPP-membrane interaction, including the adsorption, orientation, and conformation of hIAPP monomer at an anionic lipid bilayer by performing all-atom molecular dynamics (MD) simulations. We found that hIAPP monomer is quickly adsorbed to bilayer surface. For the POPG system, the adsorption is initiated from the N-terminal residues driven by strong electrostatic interactions of the positively-charged residues Kl and R11with negatively-charged lipid headgroups. For the POPC system, N-terminal and C-terminal can both first adsorb to the POPC. hIAPP binds parallel to lipid bilayer surface as a stable helix through residues7-22, consistent with previous experimental study. Remarkably, both systems lead to the same binding orientation separately. Residues R11, F15and S19oriented towards membrane for the POPG system, while residues T9, N14and H18towards membrane in the POPC system.