Conformational studies on alamethicin

A conformational analysis has been carried out for the cyclic peptide antibiotic alamethicin. Unlikely structures were first eliminated by constructing van der Waals' energy maps for near‐neighbor contacts and using these maps to generate forty complete alamethicin structures free of steric overlaps. The energies of the forty conformations were minimized; optimizing all dihedral angles first in sets and then simultaneously, to give a family of five low‐energy structures. In the conformation of lowest energy three of the seven α‐amino isobutyric acid residues occur in a six‐residue α‐helix and three at the two chain reversals. Judged by the change in conformational energy as a function of the change in dihedral angle, the flexibility of the chain is determined by both the type of peptide unit and its position in the molecule. The model has features consistent with reported circular dichorism and surface balance measurements and has two polar centers separated by a lipophilic region. It does not contain the large central pore required by some theories for the action of alamethicin on cell membrances. It therefore probably acts by altering membrance structres rather than by shuttling ions through a pore in the membrance.