Transition Networks Unveil Disorder-to-Order Transformations in Aβ Caused by Glycosaminoglycans or Lipids

The aggregation of amyloid- [Formula: see text] (A [Formula: see text]) peptides, particularly of A [Formula: see text] , has been linked to the pathogenesis of Alzheimer’s disease. In this study, we focus on the conformational change of A [Formula: see text] in the presence of glycosaminoglycans (GAGs) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipids using molecular dynamics simulations. We analyze the conformational changes that occur in A [Formula: see text] by extracting the key structural features that are then used to generate transition networks. Using the same three features per network highlights the transitions from intrinsically disordered states ubiquitous in A [Formula: see text] in solution to more compact states arising from stable [Formula: see text]-hairpin formation when A [Formula: see text] is in the vicinity of a GAG molecule, and even more compact states characterized by a [Formula: see text]-helix or [Formula: see text]-sheet structures when A [Formula: see text] interacts with a POPC lipid cluster. We show that the molecular mechanisms underlying these transitions from disorder to order are different for the A [Formula: see text] /GAG and A [Formula: see text] /POPC systems. While in the latter the hydrophobicity provided by the lipid tails facilitates the folding of A [Formula: see text] , in the case of GAG there are hardly any intermolecular A [Formula: see text] –GAG interactions. Instead, GAG removes sodium ions from the peptide, allowing stronger electrostatic interactions within the peptide that stabilize a [Formula: see text]-hairpin. Our results contribute to the growing knowledge of the role of GAGs and lipids in the conformational preferences of the A [Formula: see text] peptide, which in turn influences its aggregation into toxic oligomers and amyloid fibrils.