A Link Between Peptide Lipidation and Membrane Curvature Modulus

Peptides and drugs are subject to lipidation reactions in membranes, and in some cases appear to additionally facilitate lipid hydrolysis. Lipidation reactions involve acyl transfer from membrane lipids to reactive sites on a bound peptide or drug. For peptides, an amphiphilic structure, typical of peptides such as melittin, appears to favor lipidation, where as for drugs, the depth of bilayer partitioning appears to be a crucial factor. In membranes with saturated lipids such as DPPC or DMPC, melittin undergoes little or no lipidation, whereas with unsaturated lipids such as POPC, modest lipidation is found. Cholesterol incorporation into all membrane types leads to striking increases in lipidation activity, alongside changes in the chemical selectivity of the transfer process. For some POPC/cholesterol mixtures, less than 50% of the original unmodified melittin is present after 24 hours. The level of activity does not correlate with the affinity of melittin for each membrane type. Rather the curvature modulus of the membrane is a better predictor of membrane activity. We hypothesise that the qualitative relationship between curvature modulus and lipidation activity is a consequence of changes in the penetration depth of melittin. Access of water to lipidation intermediates may also influence lipidation rates.