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, 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.