Inhibition of peptide aggregation by lipids: insights from coarse-grained molecular simulations.

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, fibrillization 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.