Pseudo-Prolines as a Molecular Hinge:  Reversible Induction of<i>cis</i>Amide Bonds into Peptide Backbones

Abstract

Serine, threonine-derived (4 S )-oxazolidine-4-carboxylic acid, and cysteine-derived (4 R )-thiazolidinecarboxylic acid, denoted pseudo-proline (Xaa[Ψ R 1,R 2 pro]), serve as structure disrupting, solubilizing building blocks in peptide synthesis. Variation of the 2-C substituents within the heterocyclic system results in different physicochemical and conformational properties. NMR studies of a series of pseudo-proline (ΨPro)-containing peptides reveal a pronounced effect of the 2-C substituents upon the cis to trans ratio of the adjacent amide bond in solution. 2-C unsubstituted systems show a preference similar to that of the proline residue for the trans form, whereas 2,2-dimethylated derivatives adopt the cis amide conformation in high content. For 2-monosubstituted ΨPro, the cis − trans distribution depends on the 2-C chirality. For the 2-( S )-diastereoisomer, both forms are similarly populated in solution, whereas the 2-( R )-epimer adopts preferentially the trans form. The results are supported by conformational energy calculations and suggest that, by tailoring the degree of substitution, pseudo-prolines may serve as a temporary proline mimetic or as a hinge in peptide backbones.