Interplay Between Membrane Composition and Structural Stability of Membrane-Bound hIAPP.
Gregory L DignonGül H ZerzeJeetain MittalPublished in: The journal of physical chemistry. B (2017)
Amyloid aggregates are characteristic of many serious diseases such as Alzheimer's disease, Parkinson's, and type 2 diabetes and commonly involve intrinsically disordered proteins (IDPs), those that populate an ensemble of conformations rather than a single folded structure. Human islet amyloid polypeptide (hIAPP or amylin) is an amyloidogenic IDP implicated in pancreatic β-cell death during the pathogenesis of type 2 diabetes. The target of amylin's toxic activity is thought to be the cell's lipid membrane, which may also act as a catalyst for aggregation. Since amylin is intrinsically disordered, differing environments can have a large impact on its equilibrium conformational ensemble. We apply atomistic molecular dynamics simulations on multiple systems containing a full-length amylin monomer and a lipid bilayer to study the changes induced by the membrane. We observe stabilized helical conformations structurally similar to those determined by NMR experiments conducted in similar environments. We also find that bilayers of different compositions result in greatly different equilibrium ensembles of amylin. Finally, we discuss how a mixed bilayer containing zwitterionic and anionic lipid headgroups can allow for greater preference toward conformations which are adsorbed below the membrane surface through rearrangement of lipids for more favorable protein-lipid interactions.
Keyphrases
- molecular dynamics simulations
- type diabetes
- molecular docking
- cell death
- fatty acid
- molecular dynamics
- endothelial cells
- stem cells
- high resolution
- cardiovascular disease
- signaling pathway
- small molecule
- single cell
- skeletal muscle
- insulin resistance
- mesenchymal stem cells
- gold nanoparticles
- cell therapy
- bone marrow
- pi k akt
- amino acid
- glycemic control
- protein protein
- weight loss
- carbon dioxide