title: Zinc(II) as an allosteric regulator of liposomal membrane permeability induced by synthetic template-assembled tripodal polypeptides.
abstract: Three copies of peptide sequences from the peptaibol family, known to affect the permeability of the lipid bilayer of membranes, were connected to tris(2-aminoethyl)amine (TREN), a tripodal metal ion ligand, to prepare functional peptides capable of modifying the permeability of liposomal membranes. Some of the resulting tripodal polypeptide derivatives are very effective in promoting carboxyfluorescein (CF) leakage from CF-loaded unilamellar vesicles composed of a 70:30 phosphatidylcholine/cholesterol blend. The activity of these novel compounds was shown to be tunable upon metal ion coordination of the TREN subunit; the tripodal apopeptide was far more effective than its ZnII complex. Leakage experiments showed that a minimum number of five amino acids per peptide chain is required to form active systems. A mechanism is proposed in which the ZnII ion changes the conformation of the template from extended to globular and thus acts as an allosteric regulator of the activity of the systems. Molecular modeling studies indicate that when the three peptide chains are connected to the template in the extended conformation, the resulting tripodal polypeptide is able to span across the membrane, thus allowing the formation of permeable channels made of a cluster of molecules. The same change of conformation induces, to some extent, fusion of the membranes of different liposomes.
authors.affiliation: Dipartimento di Chimica Organica and CNR-CMRO, Università di Padova, Via Marzolo, 1 35131 Padova, Italy. paolo.scrimin@unipd.it, umberto.tonellato@unipd.it
authors.forename: Paolo
authors.initials: P
authors.lastname: Scrimin
authors.forename: Paolo
authors.initials: P
authors.lastname: Tecilla
authors.forename: Umberto
authors.initials: U
authors.lastname: Tonellato
authors.forename: Andrea
authors.initials: A
authors.lastname: Veronese
authors.forename: Marco
authors.initials: M
authors.lastname: Crisma
authors.forename: Fernando
authors.initials: F
authors.lastname: Formaggio
authors.forename: Claudio
authors.initials: C
authors.lastname: Toniolo
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000595:Amino Acid Sequence; D002463:Cell Membrane Permeability / Q000187:drug effects; D002784:Cholesterol; D005452:Fluoresceins / Q000032:analysis; D008024:Ligands; D008081:Liposomes / Q000737:chemistry*; D008954:Models, Biological; D008958:Models, Molecular; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry*; D010713:Phosphatidylcholines; D011487:Protein Conformation / Q000187:drug effects; D013050:Spectrometry, Fluorescence; D017550:Spectroscopy, Fourier Transform Infrared; D015032:Zinc / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D005452:Fluoresceins; D008024:Ligands; D008081:Liposomes; D010455:Peptides; D010713:Phosphatidylcholines; C024098:6-carboxyfluorescein; D002784:Cholesterol; D015032:Zinc