MODULATION OF IONOPHORE PROPERTIES BY CHEMICAL MODIFICATIONS OF SYNTHETIC ALAMETHICIN ANALOGUES

A series of analogues of alamethicin in which all Aib were replaced either by Ala or by Leu was synthesized by the solid-phase method. The influences of peptide helical length and of modifications introduced in the hydrophilic sector of the amphipathic helices on the ability to develop voltage-dependent multi-state channels were tested in planar lipid bilayers. Whilst the substitution of Aib by Ala proved unsuitable, the des-Aib-Leu analogue displayed a voltage-dependent macroscopic conductance and a single-channel conductance pattern very similar to the alamethicin behaviour. The much faster conductance fluctuations were attributed to some shortening of the molecule due to a greater α-helical character. The inclusion of an additional residue (either Leu or Ser) in the hydrophilic sector led, respectively, to even faster fluctuations or to much better resolved kinetics. These results stress the minimum requirements for the design of pertinent models for protein channels.