Transition Networks Unveil Disorder-to-Order Transformations in A β Caused by Glycosaminoglycans or Lipids.

The aggregation of amyloid- β (A β) peptides, particularly of A β 1 − 42 , has been linked to the pathogenesis of Alzheimer's disease. In this study, we focus on the conformational change of A β 1 − 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 A β 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 β 1 − 42 in solution to more compact states arising from stable β -hairpin formation when A β 1 − 42 is in the vicinity of a GAG molecule, and even more compact states characterized by a α -helix or β -sheet structures when A β 1 − 42 interacts with a POPC lipid cluster. We show that the molecular mechanisms underlying these transitions from disorder to order are different for the A β 1 − 42 /GAG and A β 1 − 42 /POPC systems. While in the latter the hydrophobicity provided by the lipid tails facilitates the folding of A β 1 − 42 , in the case of GAG there are hardly any intermolecular A β 1 − 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 A β peptide, which in turn influences its aggregation into toxic oligomers and amyloid fibrils. [ABSTRACT FROM AUTHOR]