Effect of Sequence on Peptide Geometry in 5-tert-Butylprolyl Type VI β-Turn Mimics

Abstract

The influence of sequence on turn geometry was examined by incorporating (2S,5R)-5-tert-butylproline (5-(t)BuPro) into a series of dipeptides and tetrapeptides. (2S,5R)-5-tert-Butylproline and proline were respectively introduced at the C-terminal residue of N-acetyl dipeptide N'-methylamides 1 and 2. The conformational analysis of these analogues was performed using NMR and CD spectroscopy as well as X-ray diffraction to examine the factors that control the prolyl amide (in this text, the term "prolyl amide" refers to the tertiary amide composed of the pyrrolidine nitrogen of the prolyl residue and the carbonyl of the N-terminal residue) equilibrium and stabilize type VI beta-turn conformation. The high cis-isomer population with aromatic residues N-terminal to proline was shown to result from a stacking interaction between the partial positive charged prolyl amide nitrogen and the aromatic pi-system as seen in the crystal structure of 1c. The effect of sequence on the prolyl amide equilibrium of 5-(t)BuPro-tetrapeptides (Ac-Xaa-Yaa-5-(t)BuPro-Zaa-XMe, 13 and 14) was studied by varying the amino acids at the Xaa, Yaa, and Zaa positions. High (>80%) cis-isomer populations were obtained with alkyl groups at the Xaa position, an aromatic residue at the Yaa position, and either an alanine or a lysine residue at the Zaa position of the 5-(t)BuPro-tetrapeptide methyl esters in water. Tetrapeptides Ac-Ala-Phe-5-(t)BuPro-Zaa-OMe (Zaa = Ala, Lys), 14d and 14f, with high cis-isomer content adopted type VIa beta-turn conformations as shown by their NMR and CD spectra. Although a pattern of amide proton temperature coefficient values indicative of a hairpin geometry was observed in peptides 14d and 14f, the value magnitudes did not indicate strong hydrogen bonding in water.

Amino‐Acid‐Based Block Copolymers by RAFT Polymerization

“…A variety of polymers based on hydroxyproline have been reported, including polyester,144–146 polyester copolymer,147–149 polyamide,150, 151 and polyacrylate25 derivatives. L ‐Proline is also responsible for various functions and ordered structures, such as a turn inducer in natural peptides and proteins,152, 153 and the helical structure of oligoprolines 154, 155. The attractive features of L ‐proline have prompted a number of studies of derivatives,156, 157 polymeric materials,158 and their biorelated phenomena and applications 159, 160…”

Aromatic–Proline Interactions: Electronically Tunable CH/π Interactions

“…4 In model peptides and in proteins in the PDB, proline-proline, aromatic-proline, and proline-aromatic sequences have the highest propensities to adopt a cis prolyl amide bond, suggestive of specific favorable interactions between aromatic residues and proline. 1,2,5–14 Local structural preferences inform on the relative strengths of long-range interactions, and thus data on local aromatic-proline interactions provide a basis for understanding these interactions in long-range intramolecular and intermolecular contexts. Consistent with this idea, aromatic-proline interactions appear to play a special role in stabilizing small proteins and in specific protein-protein interactions.…”

Effects of i and i+3 residue identity on Cis–Trans isomerism of the aromatici+1–prolyli+2 amide bond: Implications for type VI β‐turn formation

“…Aromatic–prolyl residue pairs are relatively more likely to exhibit cis amide bonds, with favorable interactions between the aromatic and proline rings stabilizing the cis conformation (Figure 1a) 11, 14, 18, 20–35. In the PDB, 9.7% of tyrosine–proline residue pairs exhibit a cis amide bond, indicating that both local and global interactions are important in determining cis – trans isomerization state.…”