Conformational study of cyclosporin A in acetone at low temperature.
The conformation of cyclosporin A (CsA), an undecapeptide with seven N-methylated amino acids, was studied in acetone at 193 K. Previous studies of the conformation of CsA in different solvents, in the cyclosporin-cyclophilin complex and in complexes with LiCl showed that the conformation of the free and the bound CsA are different. Differences were observed at the conformation of the MeLeu9-MeLeu10 peptide bond, which is cis in solution and trans in the complex, and in the orientation of the amide protons and the N-Me groups. By using acetone, which is a proton acceptor, we wanted to influence the orientation of the amide protons. In the conditions used in this study a new conformation is found, which differs as well from the one previously observed in solution as from the conformation observed in the complex. This conformation has a cis peptide bond between MeLeu9 and MeLeu10. The trans conformation of the peptide bond MeLeu9-MeLeu10, which is necessary for biological activity, was not induced. One of the amide protons is involved in an intramolecular H-bridge stabilising a beta-turn around Sar3MeLeu4, and three of the seven NMe groups are oriented to the centre of the molecule.
Verheyden
P
P
Department of Organic Chemistry, Free University of Brussels, Belgium.
Jaspers
H
H
De Wolf
E
E
Van Binst
G
G
D000096:Acetone / Q000737:chemistry*; D000595:Amino Acid Sequence; D003080:Cold Temperature; D016572:Cyclosporine / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D011487:Protein Conformation; D012995:Solubility; D013816:Thermodynamics
D000096:Acetone; D016572:Cyclosporine