Impact of azaproline on peptide conformation

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

Abstract

The amino acid analog azaproline (azPro) contains a nitrogen atom in place of the Cα of proline. Peptides containing azPro were shown to stabilize the cis-amide conformer for the acyl-azPro bond and prefer type VI β-turns both in crystals and in organic solvents by NMR. The increased stability for cis-amide conformers was relatively minor with respect to the trans-conformers. Further, their conformational preferences were depended on solvent. To elucidate the impact of azPro substitution on amide cis-trans isomerism and peptide conformation, this paper reports ab initio studies on azPro derivatives and a comparison with their cognate Pro derivatives: 1-acetyl-2methyl pyrrolidine (1), 1-acetyl-2-methyl pyrazolidine (2), Ac-Pro-NHMe (3), Ac-azPro-NHMe (4), Ac-azPro-NMe2 (5), Ac-azAzc-NHMe (6), and Ac-azPip-NHMe (7). Conformational preferences were explored at the MP2/6-31+G** level of theory in vacuo. Solvation effects for 1 and 2 were studied implicitly using the polarizable continuum model and explicitly represented by interactions with a single water molecule. An increase in the conformational preference for the cis-amide conformer of azPro was clearly seen. An intramolecular hydrogen bond occurred solely in the trans-amide conformer that reduced the preference for the cis-conformer by 2.2 kcal/mol. The larger ring homolog aza-pipecolic acid (azPip), in which this internal hydrogen bond was diminished, significantly augmented stabilization of the cis-amide conformer. In aqueous solution, the preference for the cis-amide conformers was greatly reduced, mainly as a result of interaction between water and the lone pair of the α-nitrogen in the trans-amide conformer that was 3.8 kcal/mol greater than that in the cis-conformer. In the azPro analog, the energy barrier for cis-trans amide isomerization was 6 kcal/ mol less than that in the cognate Pro derivative. Because the azPro derivatives can stabilize the cis-amide bond and mimic a type VI β-turn without incorporation of additional steric bulk, such a simple chemical modification of the peptide backbone provides a useful conformational constraint when incorporated into the structure of selected bioactive peptides. Such modifications can scan receptors for biological recognition of reverse turns containing cis-amide bonds by the incorporation of type VI β-turn scaffolds with oriented appended side chains.

Original languageEnglish
Pages (from-to)9030-9042
Number of pages13
JournalJournal of Organic Chemistry
Volume69
Issue number26
DOIs
StatePublished - Dec 24 2004

Fingerprint

Dive into the research topics of 'Impact of azaproline on peptide conformation'. Together they form a unique fingerprint.

Cite this