Importance of the tryptophans of gramicidin for its lipid structure modulating activity in lysophosphatidylcholine and phosphatidylethanolamine model membranes. A comparative study employing gramicidin analogs and a synthetic alpha-helical hydrophobic polypeptide.

The importance of the tryptophan residues of gramicidin for the lipid structure modulating activity of this pentadecapeptide was investigated by studying the interaction of gramicidin analogs A, B, C (which have a tryptophan, phenylalanine and tyrosine in position 11, respectively) and tryptophan-N-formylated gramicidin (in which the four tryptophan residues have been formylated) with several phospholipid systems. In addition an alpha-helical model pentadecapeptide (P15) was studied to further test the specificity of the gramicidin-lipid interaction. DSC experiments showed that all the gramicidin analogs produced a significant decrease in the gel to liquid-crystalline transition enthalpy of dipalmitoylphosphatidylcholine. The P15 peptide was much less effective in this respect. In dielaidoylphosphatidylethanolamine the gel----liquid-crystalline transition enthalpy was much less affected by the incorporation of these molecules. In this lipid system tryptophan-N-formylated gramicidin was found to be the most ineffective. 31P-NMR and small angle X-ray diffraction experiments showed that the ability of the peptides to induce bilayer structures in palmitoyllysophosphatidylcholine and HII phase promotion in dielaidoylphosphatidylethanolamine systems follows the order: gramicidin A' (natural mixture) approximately equal to gramicidin A greater than gramicidin B approximately equal to gramicidin C greater than tryptophan-N-formylated gramicidin greater than P15. These results support the hypothesis that the shape of gramicidin and its aggregational behaviour, in which the tryptophan residues play an essential role, are major determinants in the unique lipid structure modulating activity of gramicidin.