Abstract
The aggregation of amyloid-β (Aβ) peptides, particularly of Aβ1-42, has been linked to the pathogenesis of Alzheimer's disease. In this study, we focus on the conformational change of Aβ1-42 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 Aβ 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 Aβ1-42 in solution to more compact states arising from stable β-hairpin formation when Aβ1-42 is in the vicinity of a GAG molecule, and even more compact states characterized by a α-helix or β-sheet structures when Aβ1-42 interacts with a POPC lipid cluster. We show that the molecular mechanisms underlying these transitions from disorder to order are different for the Aβ1-42/GAG and Aβ1-42/POPC systems. While in the latter the hydrophobicity provided by the lipid tails facilitates the folding of Aβ1-42, in the case of GAG there are hardly any intermolecular Aβ1-42-GAG interactions. Instead, GAG removes sodium ions from the peptide, allowing stronger electrostatic interactions within the peptide that stabilize a β-hairpin. Our results contribute to the growing knowledge of the role of GAGs and lipids in the conformational preferences of the Aβ peptide, which in turn influences its aggregation into toxic oligomers and amyloid fibrils.