Syntheses, conformation, and reactions of cyclic peptides

SynopsisThe side-chain conformations of D-or L-Thr, D-or L-Ser, L-As~, and L-His residues in cyclic and linear dipeptides in DzO or in DMSO-ds are deduced from vicinal ('H,'H) and (13C,1H) coupling constants. Vicinal (13C,13C) coupling constants strongly depend on substituents and cannot be used without a more sound analysis. In cyclic dipeptides, the Thr and Ser side chains are folded above the DKP ring, with x' near 60". The L -A s~ side chain interacts more specifically with peptide bonds ( X I near 300"). The L-His side chain is more flexible and its conformation depends on the proximity of a second side chain and on solute-solvent interactions. In all cases, this side chain is not completely folded. In linear dipeptides, the conformation of a C-terminal L-His residue is mainly influenced by the end carboxylic group. On the other hand, a N-terminal L-His residue interacts more easily with a neighboring L-ASP residue. In aqueous solution, the imidazole pK, depends on the proximity of terminal and lateral charged groups but does not reveal any specific interaction in cyclic dipeptides. A comparison between the conformations of cyclic peptides observed in solution, in the crystalline state and calculated by empirical methods, allows one to point out the discriminating role of the packing in crystals, and of solute-solvent interactions in solution.

¹H and ¹³C nmr studies of cyclic and linear dipeptides containing threonyl, seryl, aspartyl, and histidyl residues

Ptak¹,

Heitz²,

Dreux³

1978

Cation binding cyclic peptides composed of imino acid residues

Shimizu

Fujishige

1980

SynopsisCyclo(L-Pro-Sar), (n = 2-4) with moderate flexibility and hydrophobicity of molecular structure was synthesized, and the characteristics of these cyclic peptides and their metal complexes in acetonitrile were investigated in connection with the residual properties using 13C-nmr measurements. The cyclic tetrapeptide cyclo(~-Pro-Sar)z showed a sterically hindered phenomenon in acetonitrile in which the amide backbone adopted a cis-trans-cis-trans sequence. The cyclic hexapeptide cyclo(~-Pro-Sar)~ existed as a mixture of several conformers whose interconversion is slow on the nmr time scale, including cis-cis-trans and/or cistrans-trans arrangement of the Sar-Pro bond. Finally, it was demonstrated that the cyclic octapeptide cyclo(L-Pro-Sar)4 behaved as a mixture of multiple conformers which allowed for cis-trans isomerism about the Pro-Sar peptide bond, of which 20-30% had the all-cis Sar-Pro bond isomer and the remaining 7040% had one (or more) cis Sar-Pro bond isomer. 13C-nmr spectra also demonstrated that cyclo(L-Pro-Sar), (n = 3,4) formed a 1:l ion complex whose conformation was characterized by an all-trans peptide bond in the presence of excess metal salt. Cation binding studies, using CD measurements, established that the ion selectivity of cyclo(L-Pro-Sar)4 in acetonitrile decreased in the order, Ba2+ > Ca2+ > Na+ > Mg2+ > Li+.

Crystal structure and conformation of a cyclic tetrapeptide cyclo(L‐Pro‐Sar)₂ containing all‐cis peptide units

Ueno

Shimizu

1983

SynopsisThe crystal structure and conformation of the synthetic cyclic tetrapeptide, cyclo(L-Pro-Sar)z, was determined by x-ray analysis. The peptide crystallizes in the orthorhombic space group P21212~ with cell parameters a = 9.277(1), b = 12.884(1), and c = 15.581(2) A. The crystal structure was solved by the symbolic addition procedure for direct phase determination and least-squares refinement using 1796 reflections, which led to the final R value of 0.043. This structure provides the first example observed in a crystal of a cyclic tetrapeptide in which all four peptide units have been found in the cis conformation with w angles deviating slightly by 2"-10" from the ideal value of 0". It was also found that the two Pro C"-CO single bonds assumed a trans' ($ = 159.6" and 158.4") conformation. Adjoining average planes of the peptide groups fall at nearly right angles to each other. The pyrrolidine ring conformations of the two prolyl residues are in the envelope form, with Cr carbon out of the least-squares planes for the remaining four atoms.