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

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.

Zn2+ Binding Increases Parallel Structure in the Aβ(16–22) Oligomer by Disrupting Salt Bridge in Antiparallel Structure

“…Given the abundance of Zn 2+ in Aβ aggregated structures, our study highlights the role of Zn 2+ playing in the assembled structure of Aβ 16–22 and gives a clue on modulating the assemble process by the addition of Zn 2+ ions. We note that other metal ions have also shown a similar effect for the disruption of the salt bridge. , Using the same force field CHARMM36m, Strodel et al found that Ca 2+ can bind to Glu22 of Aβ 16–22 and inhibit peptide aggregation by disrupting the Lys16-Glu22 salt bridge . Another study on the full-length Aβ showed that Na + aggregate near Glu22 and Asp23, thus screening the electrostatic interaction between Glu22/Asp23 and Lys28 .…”

“…46 Another study on the full-length Aβ showed that Na + aggregate near Glu22 and Asp23, thus screening the electrostatic interaction between Glu22/Asp23 and Lys28. 49 Taken together, this suggests that the disruptive effect of cations on salt bridges may be a common occurrence in biomolecules.…”

“…We note that other metal ions have also shown a similar effect for the disruption of the salt bridge. , Using the same force field CHARMM36m, Strodel et al found that Ca 2+ can bind to Glu22 of Aβ 16–22 and inhibit peptide aggregation by disrupting the Lys16-Glu22 salt bridge . Another study on the full-length Aβ showed that Na + aggregate near Glu22 and Asp23, thus screening the electrostatic interaction between Glu22/Asp23 and Lys28 . Taken together, this suggests that the disruptive effect of cations on salt bridges may be a common occurrence in biomolecules.…”

A brief history of amyloid aggregation simulations

“…To understand what the problem is and whether there are force fields capable of reliably modeling the intrinsic disorder of peptides such as $$$ \mathrm{A}\upbeta $$$ while also modeling their folding, either through interaction with other molecules or through self‐interactions leading to amyloid aggregation, she and her team performed several force field benchmark tests for both monomeric $$$ \mathrm{A}\upbeta $$$ 194,195 and for amyloid aggregation 196–198 . This work has largely benefited from the work of others who have developed force fields better suited for IDPs, 199,200 and the current conclusion of the Strodel group is that Charmm36m 200 provides the best balance between representing the fully unfolded state of $$$ \mathrm{A}\upbeta $$$, 195 modeling it is folding into α‐helical or β‐sheet structures in molecular interactions, 201,202 and reproducing kinetic and thermodynamic aspects of amyloid aggregation 196 …”