Binding Orientations and Lipid Interactions of Human Amylin at Zwitterionic and Anionic Lipid Bilayers

Zhenyu Qian,Yan Jia,Guanghong Wei

doi:10.1155/2016/1749196

Abstract

Increasing evidence suggests that the interaction of human islet amyloid polypeptide (hIAPP) with lipids may facilitate hIAPP aggregation and cause the death of pancreatic islet β-cells. However, the detailed hIAPP-membrane interactions and the influences of lipid compositions are unclear. In this study, as a first step to understand the mechanism of membrane-mediated hIAPP aggregation, we investigate the binding behaviors of hIAPP monomer at zwitterionic palmitoyloleoyl-phosphatidylcholine (POPC) bilayer by performing atomistic molecular dynamics simulations. The results are compared with those of hIAPP at anionic palmitoyloleoyl-phosphatidylglycerol (POPG) bilayers. We find that the adsorption of hIAPP to POPC bilayer is mainly initiated from the C-terminal region and the peptide adopts a helical structure with multiple binding orientations, while the adsorption to POPG bilayer is mostly initiated from the N-terminal region and hIAPP displays one preferential binding orientation, with its hydrophobic residues exposed to water. hIAPP monomer inserts into POPC lipid bilayers more readily than into POPG bilayers. Peptide-lipid interaction analyses show that the different binding features of hIAPP at POPC and POPG bilayers are attributed to different magnitudes of electrostatic and hydrogen-bonding interactions with lipids. This study provides mechanistic insights into the different interaction behaviors of hIAPP with zwitterionic and anionic lipid bilayers.

Highlights

Many human diseases, such as type II diabetes mellitus, Alzheimer’s disease, Parkinson’s disease, and Huntingdon’s disease, are associated with protein aggregation and amyloid formation [1,2,3,4]
As a first step to understand how lipid composition modulates the aggregation of full-length human islet amyloid polypeptide (hIAPP), in this study, we investigate the binding orientation and membrane interaction of hIAPP at zwitterionic palmitoyloleoyl-phosphatidylcholine (POPC) bilayer by conducting multiple atomistic MD simulations and compare the results with those obtained at anionic POPG bilayers
We observe that in 11 out of 12 MD runs, the C-terminal residues are observed to adsorb to the POPC bilayer surface prior to the N-terminal residues, namely, the adsorption of hIAPP monomer is initiated from the Cterminal residues

Summary

Introduction

Many human diseases, such as type II diabetes mellitus, Alzheimer’s disease, Parkinson’s disease, and Huntingdon’s disease, are associated with protein aggregation and amyloid formation [1,2,3,4]. Experimental studies reported that monomeric hIAPP exhibits predominantly a random coil conformation in aqueous solution, and residues 8∼19 of the peptide transiently adopt an α-helical structure [23,24,25]. As a first step to understand how lipid composition modulates the aggregation of full-length hIAPP, in this study, we investigate the binding orientation and membrane interaction of hIAPP at zwitterionic palmitoyloleoyl-phosphatidylcholine (POPC) bilayer by conducting multiple atomistic MD simulations and compare the results with those obtained at anionic POPG bilayers. A recent spectroscopic study reported that hIAPP transiently sample an α-helical structure in solution that becomes fully stabilized when bound to the surface of a membrane containing negatively charged lipids [59]. Each hIAPP-membrane system was immersed in a SPC water [65] box

Materials and Methods

Results and Discussion

A13 V17

A13 V17 L12 L16

Conclusions