Impact of azaproline on amide cis-trans isomerism: Conformational analyses and NMR studies of model peptides including TRH analogues

Wei Jun Zhang, Anders Berglund, Jeff L.F. Kao, Jean Pierre Couty, Marvin C. Gershengorn, Garland R. Marshall

Research output: Contribution to journalArticle

56 Scopus citations

Abstract

The β-turn is a well-studied motif in both proteins and peptides. Four residues, making almost a complete 180°-turn in the direction of the peptide chain, define the β-turn. Several types of the β-turn are defined according to Φ and Ψ torsional angles of the backbone for residues i + 1 and i + 2. One special type of β-turn, the type VI-turn, usually contains a proline with a cis-amide bond at residue i + 2. In an aza-amino acid, the α-carbon of the amino acid is changed to nitrogen. Peptides containing azaproline (azPro) have been shown to prefer the type VI β-turn both in crystals and in organic solvents by NMR studies. MC/MD simulations using the GB/SA solvation model for water explored the conformational preferences of azPro-containing peptides in aqueous systems. An increase in the conformational preference for the cis-amide conformer of azPro was clearly seen, but the increased stability was relatively minor with respect to the trans-conformer as compared to previous suggestions. To test the validity of the calculations in view of the experimental data from crystal structures and NMR in organic solvents, [azPro3]-TRH and [Phe2, azPro3]-TRH were synthesized, and their conformational preferences were determined by NMR in polar solvents as well as the impact of the azPro substitution on their biological activities.

Original languageEnglish
Pages (from-to)1221-1235
Number of pages15
JournalJournal of the American Chemical Society
Volume125
Issue number5
DOIs
StatePublished - Feb 5 2003

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