Pseudo-prolines as a molecular hinge: Reversible induction of cis amide bonds into peptide backbones

Serine, threonine-derived (4S)-oxazolidine-4-carboxylic acid, and cysteine-derived (4R)-thiazolidinecarboxylic acid, denoted pseudo-proline (Xaa[Psi(R1,R2)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 (Psi Pro)-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 Psi Pro, 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.

Published in:
J. Am. Chem. Soc., 119, 5, 918-925

 Record created 2006-02-09, last modified 2018-01-27

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