Solvent and side-chain contributions to the two-cis ⇄ all-trans equilibria of cyclic hexapeptides,cyclo(Xxx-Pro-D-Yyy)2

Cyclic hexapeptides of the type cyclo(L -Xxx-L -Pro-D -Yyy)₂ or cyclo(L -Xxx-L -Pro-Gly)₂ exist in solution predominantly in two forms of C₂ average symmetry, one with all-trans peptide bonds and generally well-established conformation, and another with both Xxx-Pro peptide bonds cis. We have been measuring the thermodynamic parameters of this equilibrium using carbon and proton nmr spectroscopy. Data have been obtained for peptides in which Yyy = Gly, D -Ala, or D -Phe, and Xxx = Gly, L -Ala, L -Leu, and L -Val. In a given solvent, stability of the all-trans form decreases (ΔG⁰ increases) as Xxx is changed through the series Gly, L -Ala-, L -Leu, and L -Val, consistent with expected increasing repulsion between the Xxx side chain and the proline δ methylene across the trnas Xxx-Pro bond. Also, for a given set of side chains, the stability of the all-trnas form increases as the polarity of the solvent decreases, consistent with models in which all C?O and N? H groups are accessible for solvation in the two-cis form, but two C?O and two N? H groups are somewhat sequestered in the all-trans form. With the available data it is not possible to identify pure intramolecular (solvent-independent) or pure peptide-bond solvation (side chain-independent) terms in ΔH° or ΔS°, although trends are discernible.