Conformation of uncomplexed [Phe4, Val6] antamanide crystallized from nonpolar solvents

[Phe4, Val6] antamanide, a synthetic, biologically active analog of the cyclic decapeptide antitoxin isolated from Amanita phalloides, has been crystallized from a mixture of n-hexane and methyl acetate, and its conformation has been established by the direct method of x-ray diffraction analysis, i.e., without the benefit of any heavy atom. The uncomplexed molecule contains a 2-fold rotation axis and cis peptide linkages between Pro2-Pro3 and Pro7-Pro8. Otherwise, its conformation differs extensively from that of the Na+[Phe4, Val6] antamanide-C2H5OH complex. The 30-membered ring is elongated and relatively planar as compared to the folded ring in the Na+ complex. The six NH groups are directed toward the anterior of the molecule. There is one pair of intra-molecular NH---O=C bonds of the 5 leads to 1 type containing a cis peptide unit. The other four NH groups participate in hydrogen bonds to three H2O sites in the interior of the molecule. The 10 hydrophobic side groups cover the bottom and surround the perimeter of the molecule with the phenyl groups in the four Phe residues folded against the molecule. The conformation found for [Phe4, Val6] antamanide crystallized from nonpolar solvents is different from any conformations proposed for antamanide in solution based on nuclear magnetic resonance data.