Web Release Date: November 13,
Impact of Azaproline on Peptide Conformation
and
Center for Computational Biology and Department of Biochemistry and Molecular Biophysics, Washington University, St. Louis, Missouri 63110
Received July 23, 2004
Abstract:
The amino acid analog azaproline (azPro) contains a nitrogen atom in place of the C
of proline.
Peptides containing azPro were shown to stabilize the cis-amide conformer for the acyl-azPro bond
and prefer type VI 
-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 -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 -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 -turn scaffolds with oriented appended side chains.
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