Comparison of the interaction of methionine and norleucine‐containing peptides with phospholipid bilayers Journal Articles uri icon

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abstract

  • Norleucine is a structural analog of methionine with a methylene group replacing the thio ether. Despite the close structural similarity of these two amino acids, norleucine‐containing peptides have markedly different behaviour with phospholipids compared with methionine‐containing peptides. For example, HCO‐L‐Ahx‐L‐Leu‐L‐Phe‐OMe behaves as a hydrophobic peptide when mixed with dimyristoylphosphatidylcholine. This peptide lowers the enthalpy of the lipid phase transition. The effect is independent of the rate of heating. With the homologous peptide, HCO‐L‐Met‐L‐Leu‐L‐Phe‐OMe, the results are markedly dependent on scan rate with a higher enthalpy observed at faster scan rates. Only at a scan rate of 0.2 K min‐1 do the two peptides approach similar behaviour. The higher enthalpy observed for samples with the methionine peptide at higher scan rates can be explained assuming that the peptide aggregates at low temperature. As the phase transition temperature is approached, the more hydrophilic methionine peptide partitions more slowly into the membrane than the norleucine peptide. Partitioning of the peptides between aqueous and lipid phases was measured at 37° by centrifuging down the lipid‐bound fraction. At a peptide concentration of 15 μM and a lipid concentration of 1.4 mM, 89% of the HCO‐L‐Ahx‐L‐Leu‐L‐PheOMe and 97% of the HCO‐L‐Met‐L‐Leu‐L‐PheOMe remained in the supernate, indicating a greater tendency of the norleucine‐containing peptide to partition into the lipid phase. The peptides Ac‐L‐Phe‐L‐Met‐L‐Arg‐L‐Phe‐NH2 and Ac‐L‐Phe‐L‐Ahx‐L‐Arg‐L‐Phe‐NH2 are readily soluble in water. These peptides were deposited with the lipid from a solution in chloroform/methanol. After repeated scanning and/or incubation at the phase transition temperature the effect of the peptide in raising the phase transition temperature of the lipid was lost. Thus these peptides were no longer incorporated into the bilayer after these treatments. The loss of the alterations of the phase transitions caused by these peptides was observed upon immediate rescanning of the methionine‐containing samples while for the norleucine‐containing ones, incubation for several hours at the phase transition was required. Our results demonstrate that norleucine‐containing peptides partition more rapidly into the lipid phase while the methionine peptides are more rapidly extracted from the lipid into the aqueous phase. The results emphasize the importance of determining the effect of scan rate as a criterion of the attainment of equilibrium in lipid‐peptide mixtures. We demonstrate how relatively minor changes in structure can alter the behaviour of peptides with lipids. Our results suggest that the pharmacodynamics of peptides in which norleucine has replaced methionine will be altered.

publication date

  • October 1987