Cholesterol Changes the Mechanisms of Aβ Peptide Binding to the DMPC Bilayer

Abstract

Using isobaric-isothermal all-atom replica-exchange molecular dynamics (REMD) simulations, we investigated the equilibrium binding of Aβ10-40 monomers to the zwitterionic dimyristoylphosphatidylcholine (DMPC) bilayer containing cholesterol. Our previous REMD simulations, which studied binding of the same peptide to the cholesterol-free DMPC bilayer, served as a control, against which we measured the impact of cholesterol. Our findings are as follows. First, addition of cholesterol to the DMPC bilayer partially expels the Aβ peptide from the hydrophobic core and promotes its binding to bilayer polar headgroups. Using thermodynamic and energetics analyses, we argued that Aβ partial expulsion is not related to cholesterol-induced changes in lateral pressure within the bilayer but is caused by binding energetics, which favors Aβ binding to the surface of the densely packed cholesterol-rich bilayer. Second, cholesterol has a protective effect on the DMPC bilayer structure against perturbations caused by Aβ binding. More specifically, cholesterol reduces bilayer thinning and overall depletion of bilayer density beneath the Aβ binding footprint. Third, we found that the Aβ peptide contains a single cholesterol binding site, which involves hydrophobic C-terminal amino acids (Ile31-Val36), Phe19, and Phe20 from the central hydrophobic cluster, and cationic Lys28 from the turn region. This binding site accounts for about 76% of all Aβ-cholesterol interactions. Because cholesterol binding site in the Aβ10-40 peptide does not contain the GXXXG motif featured in cholesterol interactions with the transmembrane domain C99 of the β-amyloid precursor protein, we argued that the binding mechanisms for Aβ and C99 are distinct reflecting their different conformations and positions in the lipid bilayer. Fourth, cholesterol sharply reduces the helical propensity in the bound Aβ peptide. As a result, cholesterol largely eliminates the emergence of helical structure observed upon Aβ transition from a water environment to the cholesterol-free DMPC bilayer. We explain this effect by the formation of hydrogen bonds between cholesterol and the Aβ backbone, which prevent helix formation. Taken together, we expect that our simulations will advance understanding of a molecular-level mechanism behind the role of cholesterol in Alzheimer's disease.

Emerging Diversity in Lipid–Protein Interactions

“…412 The sensitivity to cholesterol of different Aβ peptides has also been addressed by simulations describing different cholesterol hot-spots depending on their length. 765−767 Cholesterol bound at the tandem glycine motif might compete with helix dimerization, 768 but other sites have also been proposed to promote helix–helix interactions. 769 More in general, the lipid environment and composition greatly affect helix orientation and dimerization of precursors of different lengths, 770,771 an aspect that has been addressed with MD simulations as well.…”

The Toxicity and Polymorphism of β-Amyloid Oligomers

“…The molecular docking results showed that the U-shaped oligomers inserted into the membrane and formed ion-permeable pores [ 67 ], which is consistent with the report that Aβ can insert into lipid bilayers and assemble into a β-barrel pore under optimized detergent micelle conditions [ 68 ]. Aβos can also interact with lipids and cholesterol in the membrane to exert their toxicity [ 69 , 70 , 71 , 72 , 73 ]. For example, Aβos strongly bind to GM1 ganglioside located at the external face of the cell membrane to promote LTP impairment, which requires the existence of sialic acid residues of GM1 [ 71 ].…”

“…The effect of cholesterol on the toxicity of Aβos to membrane is controversial. Cholesterol can change the structures of Aβos and facilitate the interaction between Aβ and the membrane, on the other hand, cholesterol increases the membrane rigidity and has a protective effect against Aβos-mediated damage [ 69 , 72 ].…”

The Binding of Aβ42 Peptide Monomers to Sphingomyelin/Cholesterol/Ganglioside Bilayers Assayed by Density Gradient Ultracentrifugation

“…There are also contradictory data on the role of Chol in Aβ42-binding to bilayers, from those that suggest a positive role in Aβ42 binding and aggregation [19,38] to those who propose a negative influence [39] or a dual effect depending on Chol concentration [40]. In general, Chol appears to have a negative effect on Aβ binding and aggregation particularly in the absence of sphingolipids [41,42].…”