Glycosaminoglycans Recruit IAPP Oligomers on Lipid Bilayers

Glycosaminoglycans (GAGs) are anionic polysaccharides that coexist with cell membranes in the extracellular matrix and have been shown to cooperatively enhance the aggregation of islet amyloid polypeptide (IAPP) at zwitterionic lipid surfaces─a process implicated in β-cell death in type 2 diabetes. However, the molecular mechanisms by which GAGs and lipids concertedly promote IAPP aggregation remain poorly understood. Here, we develop a coarse-grained model for the GAG chondroitin-4-sulfate (CS) and employ molecular dynamics simulations to investigate the aggregation of the IAPP11-29 fragment in environments containing CS, a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayer, or both. By comparing simultaneous and sequential assembly pathways, we show that the order of molecular encounters reshapes the aggregation landscape. CS drives rapid peptide consolidation at the bilayer surface through GAG-chain flexion and peptide crawling on the GAG chain, yielding ternary aggregates in which hydrophobic residues anchor into the bilayer, a globular peptide body extends above the membrane plane, while the CS chain forms a corona. CS further stabilizes helical intermediates through dipole-charge interactions, with helix half-lives four- to five-fold greater than in the bilayer-only system. When introduced to dispersed, bilayer-bound oligomers, CS recruits them into larger, more orientationally ordered aggregates that may serve as superior seeds for downstream fibrillation. Together, these results provide a molecular basis for the experimentally observed cooperative enhancement of IAPP aggregation by GAGs and zwitterionic lipids.