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

Abstract
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.

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