Free Cholesterol Induces Higher β-Sheet Content in Aβ Peptide Oligomers by Aromatic Interaction with Phe19

Abstract

Accumulating experimental evidence support an enhancing effect of free cholesterol on amyloid-beta (Aβ) aggregation. To probe the mechanisms of cholesterol-mediated Aβ aggregation, we applied all-atom molecular dynamic simulations on Aβ42 peptides in presence of free cholesterol. Several control systems were also designed to examine the specificity of cholesterol-residue interactions, including mutation on aromatic residue, substitution of cholesterol with sphingomyelin (SM) and DPPC bilayer, and a mixing SM and cholesterol. Each system was performed 4 independent simulations, with a total time of 560 ns. It was found that cholesterol increased β-sheet formation by 4 folds, but the Phe19→Ser mutation on Aβ42 peptide totally eliminated cholesterol’s effect. A stable contact was recognized between the steroid group of cholesterol and the Benzyl group of Phe19. Interestingly, our simulation revealed a regular 1 ns time interval between the establishment of cholesterol-phenylalanine contact and consequent β-sheet formation, suggesting an important role of steroid-benzyl interaction in cholesterol-mediated aggregation. The presence of SM slightly increased β-sheet formation, but the mixture of cholesterol and SM had a strong induction effect. Also, the measurement of Phe19-lipid distance indicates that aromatic side chains of peptides prone to bind to cholesterol on the surface of the mixed micelle. In the DPPC system, polar chains were attracted to the surface of membrane, yielding moderate increase of β-sheet formation. These results shed light on the mechanism of cholesterol-mediated fibrillogenesis, and help to differentiate the effects of cholesterol and other lipids on β-sheet formation process.

Effects of Charged Cholesterol Derivatives on Aβ40 Amyloid Formation

“…This is similar to that of the unmodified cholesterol and DC-cholesterol, suggesting that the negatively charged sulfate moiety of cholesterol-SO 4 does not dramatically influence its function in mediating Aβ aggregation. Taken together, if non-aggregating cholesterol and the derivatives modify the aggregation of Aβ via binding with the peptide, as suggested by recent simulation studies, 30, 32 they presumably interact with Aβ peptides mainly through hydrophobic interactions. The positively or negatively charged groups in the cholesterol derivatives studied here likely are not involved in critical interactions in this process.…”

“…32 Using all-atom molecular dynamic simulations, Zhou et al reported an important role of steroid-benzyl interaction in cholesterol-mediated aggregation. 30 More specifically, the amino acid Phe19 was found to be critical for this interaction. Our experimental results are in accord with these simulation results.…”

Scaling and alpha-helix regulation of protein relaxation in a lipid bilayer

“…[24][25][26][27][28][29] Simulation of aggregation and release processes 26,30,31 are particularly relevant to the work presented here because they can compete with unfolding, penetration, and binding phenomena.…”

Lipid insertion domain unfolding regulates protein orientational transition behavior in a lipid bilayer

“…Both computer simulations and complementary experiments such as NMR and single-molecule imaging and spectroscopy are urgently needed to uncover the basic mechanisms governing these events [28]. There have been a number of recent MD simulations of Aβ peptide in or on model membranes with different starting structures [13, 14, 29–33]. Simulations of aggregation and release processes [30, 31, 33] of Aβ are relevant to this work, because they represent the future molecular events that take place after the completion of the predicted protein orientational transitions.…”

“…There have been a number of recent MD simulations of Aβ peptide in or on model membranes with different starting structures [13, 14, 29–33]. Simulations of aggregation and release processes [30, 31, 33] of Aβ are relevant to this work, because they represent the future molecular events that take place after the completion of the predicted protein orientational transitions. In addition, our predicted structures of the new protein orientational states may signal further downstream folding/unfolding, binding and self-aggregation phenomena in the complex membrane-associated amyloid cascade pathways that may contribute to the pathogenesis of Alzheimer’s.…”