Interaction of enkephalin peptides with anionic model membranes

Marek Romanowski, Xiaoyun Zhu, Kathy Kim, Victor J. Hruby, David F. O'Brien

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


According to the model for passive transport across the membranes, the total flow of permeant molecules is related to the product of the water-membrane partition coefficient and the diffusion coefficient, and to the water-membrane interfacial barrier. The effect of membrane surface charge on the permeability and interaction of analgesic peptide ligands with model membranes was investigated. A mixture of zwitterionic phospholipids with cholesterol was used as a model membrane. The lipid membrane charge density was controlled by the addition of anionic 1-palmitoyl-2-oleoylphosphatidylserine. Two classes of highly potent analgesic peptides were studied, c[D-Pen2,D-Pen5]enkephalin (DPDPE) and biphalin, a dimeric analog of enkephalin. The effect of increased surface charge on the permeability of the zwitterionic DPDPE is a relatively modest decrease, that appears to be due to a diminished partition coefficient. On the other hand the binding of the dicationic biphalin ligands to membranes increases proportionally with increased negative surface charge. This effect translates into a significant reduction of biphalin permeability by reducing the diffusion of the peptide across the bilayer. These experiments show the importance of electrostatic effects on the peptide-membrane interactions and suggest that the negative charge naturally present in cell membranes may hamper the membrane transport of some peptide drugs, especially cationic ones, unless there are cationic transporters present.

Original languageEnglish (US)
Pages (from-to)45-53
Number of pages9
JournalBiochimica et Biophysica Acta - Biomembranes
Issue number1
StatePublished - Jan 2 2002


  • Electrostatic effect
  • Partition coefficient
  • Peptide-membrane
  • Permeability coefficient

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Cell Biology


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