STRUCTURE OF CYCLIC-PEPTIDES - THE CRYSTAL AND SOLUTION CONFORMATION OF CYCLO(PHE-PHE-AIB-LEU-PRO)

A solid-state and solution conformation analyses of the cyclopentapept ide cyclo(Phe-Phe-Aib-Leu-Pro) has been carried out by X-ray diffracti on and nuclear magnetic resonance techniques. The structure of the hex agonal crystals, grown from a methanol solution [a = b = 16.530(4) Ang strom, c = 21.356(9) Angstrom, space group P6(5), Z = 6], shows the pr esence of one intramolecular N-H ... O=C hydrogen bond with the format ion of a gamma-turn (C-7). The Aib(3) residue, at the center of the ga mma-turn, presents unexpected values of the torsion angles [phi = 70.5 degrees and psi = -73.8 degrees], which have been observed only once before for this helicogenic residue. A cis peptide bond occurs between Leu(4) and Pro(5); all other peptide bonds are trans. The overall con formation for the cyclopentapeptide with one cis-peptide bond on one s ide and an intramolecular gamma-turn on the opposite side results in a n equatorial topology of the side-chains of the Phe(1), Phe(2) and Leu (4) residues. Indeed, the C-alpha-C-beta and C-beta-C-gamma bonds of t hese residues lie approximately in the mean plane of the cyclic ring s ystem. The structure is compared with data in the literature on cyclic pentapeptides. In addition the Pro-Phe-Phe moiety shows a conformatio n similar to that observed in other larger cyclic bioactive peptides, which indicates a reduced number of conformations for this sequence. T he solution study was carried out in three different solvent systems c hloroform, acetonitrile and methanol in the temperature interval 220-3 00 K, In all three solvents the room temperature spectra show that the peptide is conformationally nonhomogeneous. In acetonitrile at low te mperatures it is possible to reduce the conformational equilibrium to two predominant conformers which differ for the cis-trans isomerism of the Leu(4)-Pro(5) peptide bond. (C) Munksgaard 1998.