Interplay between human islet amyloid polypeptide aggregates and micro-heterogeneous membranes

Area of Science:

• Biophysics
• Molecular Biology
• Computational Chemistry

Background:

• Human islet amyloid polypeptides (hIAPP) aggregate in pancreatic islets, contributing to beta-cell loss in type 2 diabetes.
• The molecular mechanisms of hIAPP aggregate interaction with raft-containing membranes remain poorly understood, despite known membrane disruption effects.

Purpose of the Study:

• To investigate the impact of hIAPP aggregate insertion on lipid segregation in raft-containing membranes using molecular dynamics simulations.
• To elucidate the molecular details of the interplay between hIAPP aggregates and membrane lipid domains.

Main Methods:

• All-atom molecular dynamics simulations were employed to model hIAPP aggregate interactions with lipid bilayers.
• Simulations focused on lipid segregation, domain restoration, membrane thickness, fluidity, and acyl chain packing.

Main Results:

• hIAPP insertion enhanced lipid domain separation (DOPC/DPPC) in cholesterol-free membranes.
• Lipid domains rapidly restored spontaneously in the presence of hIAPP aggregates.
• hIAPP insertion increased membrane fluidity, disrupted acyl chain packing, and affected membrane thickness; cholesterol modulated these effects and hIAPP aggregate structure.

Conclusions:

• hIAPP aggregates significantly alter the structure and dynamics of raft-containing membranes.
• These findings provide insights into the mechanisms of hIAPP-induced amyloid cytotoxicity.
• Cholesterol plays a crucial role in modulating hIAPP-membrane interactions.