Impact of Cis ‐proline analogs on peptide conformation

The β‐turn is a common motif in both proteins and peptides and often a recognition site in protein interactions. A β‐turn of four sequential residues reverses the direction of the peptide chain and is classified by the Φ and Ψ backbone torsional angles of residues i + 1 and i + 2. The type VI turn usually contains a proline with a cis ‐amide bond at residue i + 2. Cis ‐proline analogs that constrain the peptide to adopt a type VI turn led to peptidomimetics with enhanced activity or metabolic stability. To compare the impact of different analogs on amide cis – trans isomerism and peptide conformation, the conformational preference for the cis ‐amide bond and the type VI turn was investigated at the MP2/6‐31+G ** level of theory in water (polarizable continuum water model). Analogs stabilize the cis ‐amide conformations through different mechanisms: (1) 5‐alkylproline, with bulky hydrocarbon substituent on the C δ of proline, increases the cis ‐amide population through steric hindrance between the alkyl substituent and the N ‐terminal residues; (2) oxaproline or thioproline, the oxazolidine‐ or thiazolidine‐derived proline analog, favors interactions between the dipole of the heterocyclic ring and the preceding carbonyl oxygen; and (3) azaproline, containing a nitrogen atom in place of the C α of proline, prefers the cis ‐amide bond by lone‐pair repulsion between the α‐nitrogen and the preceding carbonyl oxygen. Preference for the cis conformation was augmented by combining different modifications within a single proline. Azaproline and its derivatives are most effective in stabilizing cis ‐amide bonds without introducing additional steric bulk to compromise receptor interactions. © 2005 Wiley Periodicals, Inc. Biopolymers 81:392–406, 2006 This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com