Impact of cis-proline analogs on peptide conformation.
The beta-turn is a common motif in both proteins and peptides and often a recognition site in protein interactions. A beta-turn of four sequential residues reverses the direction of the peptide chain and is classified by the phi and psi 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(delta) 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(alpha) of proline, prefers the cis-amide bond by lone-pair repulsion between the alpha-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.
Che
Ye
Y
Center for Computational Biology and Department of Biochemistry and Molecular Biophysics, Washington University, St. Louis, MO 63110, USA.
Marshall
Garland R
GR
D001665:Binding Sites; D001704:Biopolymers / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D008958:Models, Molecular; D015233:Models, Statistical; D008962:Models, Theoretical; D008968:Molecular Conformation; D009584:Nitrogen / Q000737:chemistry; D016011:Normal Distribution; D010455:Peptides / Q000737:chemistry*; D011392:Proline / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013696:Temperature; D013777:Tetrazoles / Q000737:chemistry; D013816:Thermodynamics; D013844:Thiazoles / Q000737:chemistry; D053778:Thiazolidines
D001704:Biopolymers; D010455:Peptides; D013777:Tetrazoles; D013844:Thiazoles; D053778:Thiazolidines; C045574:1H-tetrazole; D011392:Proline; C003438:thiazolidine-4-carboxylic acid; D009584:Nitrogen