Adsorption and Orientation of Human Islet Amyloid Polypeptide (hIAPP) Monomer at Anionic Lipid Bilayers: Implications for Membrane-Mediated Aggregation

International Journal of Molecular Sciences

Yan Jia¹  Zhenyu Qian¹  Yun Zhang¹ 

[1]State Key Laboratory of Surface Physics, Key Laboratory for Computational Physical Sciences (MOE), Department of Physics, Fudan University, 220 Handan Road, Shanghai 200433, China

关键词: type 2 diabetes;    human islet amyloid polypeptide;    anionic palmitoyl oleolyohosphatidyl glycerol (POPG) bilayer;    adsorption dynamics;    binding orientation;    peptide-lipid interaction;    molecular dynamics simulations;   

DOI  :  10.3390/ijms14036241

来源: mdpi

【 摘 要 】

Protein misfolding and aggregation cause serious degenerative diseases, such as Alzheimer’s and type II diabetes. 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 the cellular membrane, which accelerates peptide aggregation. 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 POPG lipid bilayer by performing all-atom molecular dynamics simulations. We found that hIAPP monomer is quickly adsorbed to bilayer surface, and the adsorption is initiated from the N-terminal residues driven by strong electrostatic interactions of the positively-charged residues K1 and R11 with negatively-charged lipid headgroups. hIAPP binds parallel to the lipid bilayer surface as a stable helix through residues 7–22, consistent with previous experimental study. Remarkably, different simulations lead to the same binding orientation stabilized by electrostatic and H-bonding interactions, with residues R11, F15 and S19 oriented towards membrane and hydrophobic residues L12, A13, L16 and V17 exposed to solvent. Implications for membrane-mediated hIAPP aggregation are discussed.

【 授权许可】

CC BY   
© 2013 by the authors; licensee MDPI, Basel, Switzerland.