Andrea Veronese

Zinc(II) as an Allosteric Regulator of Liposomal Membrane Permeability Induced by Synthetic Template‐Assembled Tripodal Polypeptides

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.

Metal ions co-operativity in the catalysis of the hydrolysis of a β-amino ester by a macrocyclic dinuclear Cu(II) complex

Abstract The macrocyclic receptor 3, featuring two diaminomethylpyridine moieties as ligand subunits and two diphenylmethane lipophilic spacers was synthesized and the crystal structure of its dinuclear Cu(II) complex, 3·2Cu, defined by X-ray analysis. From a kinetic study of the catalytic activity of 3·2Cu in the hydrolysis of the p-nitrophenyl ester of β-alanine (AlaPNP), a β-amino acid, clear evidence of co-operativity of the two metal ions was obtained. Such an allosteric effect was not observed in the hydrolysis of the p-nitrophenyl ester of leucine (LeuPNP), an α-amino acid. The reactivity of 3·2Cu was compared with that of the mononuclear complex of the acyclic ligand 4 having a single diaminomethylpyridine subunit and to that of Cu(II) alone. At pH=6.3 in a 1:1 water/DMSO mixture, being [Cu(II)]=6×10−4 M, a 80-fold acceleration was observed employing 3·2Cu compared with a 35-fold rate increase with Cu(II) alone and a 17-fold increase with 4·Cu. The crystal structure of the dinuclear Cu(II) complex gives a distance between the two Cu(II) centers of 9.9 A, suitable for the co-ordination of the β-amino ester by both Cu(II) ions with the nitrogen of the amino group and the oxygen of the C=O. Although significant, the rate accelerations observed employing 3·2Cu are rather modest and this is likely due to the orientation of the two pyridine moieties in the macrocycle which does not allow the most favorable inclusion mode of the substrate.

A zinc(II)-organized molecular receptor as a catalyst for the cleavage of amino acid esters

The ZnII complex of ligand 1a, a derivative of TREN bearing three 3-hydroxyphenyl units at the amines of its arms, acts as a transacylation catalyst of the p-nitrophenyl ester of 4-pyridinecarboxylic acid.

Control of Permeation of Ions Across Vesicles and Chemical Differentiation of Their Bilayer Membrane

Vesicles are aggregates of amphiphilic molecules (lipids), typically bearing two paraffinic tails, which self-assemble in water under proper conditions when some form of external energy is provided (like swirling or sonication)[1]. The simplest morphology is that of a sphere made of a bilayer of lipids trapping in its interior a water pool. The bilayer (membrane) is organized in such a way (Figure 1) that the hydrophilic head-groups of the lipids are exposed to the aqueous solutions and the hydrophobic portions of the molecules, the hydrocarbon chains, are tightly packed providing an effective barrier against the permeation of polar species like hydrophilic ions (organic or inorganic).