Thermodynamics of lipid-protein association and the activation of lecithin:Cholesterol acyltransferase by synthetic model apolipopeptides

We have synthesized three lipid-associating peptides of 16, 20 and 24 residues (LAP-16, -20, -24, respectively) and measured their affinities for the synthetic lipid, dimyristoylphosphatidylcholine (DMPC) and their activation of the enzyme, lecithin:cholesterol acyltransferase (EC 2.3.1.43). All three, to varying degrees, have many of the physical properties of native apolipoproteins; these include the spontaneous association with DMPC with a concomitant increase in their helical content and transfer of their hydrophobic amino acid residues from the aqueous phase to the less-polar lipid phase. The free energy of association with DMPC, ΔG_a, decreases in the order LAP-24 > LAP-20 > LAP-16. Salts such as NaCl increase the lipid-peptide association but guanidine hydrochloride decreases it. These data suggest that the association is largely hydrophobic. LAP-24 self-associates but this process does not compete effectively with the lipid-peptide association. All three peptides activate lecithin:cholesterol acyltransferase if they are associated with the substrate.