Article ID Journal Published Year Pages File Type
443521 Journal of Molecular Graphics and Modelling 2011 11 Pages PDF
Abstract

The amyloidogenic peptide apolipoprotein C-II(60–70) is known to exhibit lipid-dependent aggregation behaviour. While the peptide rapidly forms amyloid fibrils in solution, fibrillisation is completely inhibited in the presence of lipids. In order to obtain molecular-level insights into the mechanism of lipid-dependent fibril inhibition, we have employed molecular dynamics simulations in conjunction with a coarse-grained model to study the aggregation of an amyloidogenic peptide, apoC-II(60–70), in the absence and presence of a short-chained lipid, dihexanoylphosphatidylcholine (DHPC). Simulation of a solution of initially dispersed peptides predicts the rapid formation of an elongated aggregate with an internal hydrophobic core, while charged sidechains and termini are solvent-exposed. Inter-peptide interactions between aromatic residues serve as the principal driving force for aggregation. In contrast, simulation of a mixed peptide–DHPC solution predicts markedly reduced peptide aggregation kinetics, with subsequent formation of a suspension of aggregates composed of smaller peptide oligomers partially inserted into lipid micelles. Both effects are caused by strong interactions between the aromatic residues of the peptide with the lipid hydrophobic tails. This suggests that lipid-induced aggregate inhibition is partly due to the preferential binding of peptide aromatic sidechains with lipid hydrophobic tails, reducing inter-peptide hydrophobic interactions. Furthermore, our simulations suggest that the morphology of peptide aggregates is strongly dependent on their local lipid environment, with greater contacts with lipids resulting in the formation of more elongated aggregates. Finally, we find that peptides disrupt lipid self-assembly, which has possible implications for explaining the cytotoxicity of peptide oligomers.

Graphical abstractFigure optionsDownload full-size imageDownload high-quality image (252 K)Download as PowerPoint slideResearch highlights▶ Coarse-grained molecular simulations were performed to study amyloidogenic peptide aggregation under lipid-rich and lipid-depleted conditions. ▶ Rapid formation of an elongated aggregate predicted in water, while mixed peptide–lipid solution results in markedly reduced peptide aggregation kinetics, with subsequent formation of a suspension of aggregates composed of smaller peptide oligomers partially inserted into lipid micelles. ▶ Both effects are caused by strong interactions between the aromatic residues of the peptide with the lipid hydrophobic tails. ▶ This suggests that lipid-induced aggregate inhibition is partly due to the preferential binding of peptide aromatic sidechains with lipid hydrophobic tails, reducing inter-peptide hydrophobic interactions.

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Physical Sciences and Engineering Chemistry Physical and Theoretical Chemistry
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