INFLUENCE OF THE SECONDARY STRUCTURE ON THE PORE-FORMING PROPERTIES OF SYNTHETIC ALAMETHICIN ANALOGS - NMR AND MOLECULAR MODELING STUDIES

Synthetic alamethicin analogs, in which all Aib residues had been repl aced by Leu (L2) then proline 14 replaced by an alanine (L5), were stu died in SDS micelles using circular dichroism and NMR spectroscopy. Nu clear Overhauser effects were used as constraints for molecular modell ing. The structures determined for both peptides in SDS micelles were compared with those previously obtained in methanol in order to establ ish a secondary structure:ionophore activity relationship. Our results indicated that a shortening of peptide helices could be responsible f or the observed decrease in ion channel lifetimes. However, the length of helices may not by itself explain the drastic destabilization of c hannels when Pro14 of alamethicin is replaced by Ala in L5. indeed ana lysis of the helical wheel of L5 reveals heterogeneity in the amphipat hicity depending on the medium. Thus, loss of amphipathicity seems to underly the observed destabilization of channels. (C) 1998 European Pe ptide Society and John Wiley & Sons, Ltd.