Helical conformations of hexapeptides containing N‐terminus diproline segments

Abstract

The role of N-terminus diproline segments in facilitating helical folding in short peptides has been investigated in a set of model hexapeptides of the type Piv-Xxx-Yyy-Aib-Leu-Aib-Phe-OMe (Piv, pivaloyl). Nine sequences have been investigated with the following N-terminus dipeptide segments: (D)Pro-Ala (4) and Pro-PsiPro (5, Psi, pseudoproline), Ala-Ala (6), Ala-Pro (7), Pro-Ala (8), Aib-Ala (9), Ala-Aib (10). The analog sequences Piv-Pro-Pro-Ala-Leu-Aib-Phe-OMe (2) and Piv-Pro-Pro-Ala-Aib-Ala-Aib-OMe (3) have also been studied. Solid state conformations have been determined by X-ray crystallography for peptides 4, 6, and 8 and compared with the previously determined crystal structure of peptide 1 (Boc-Pro-Pro-Aib-Leu-Aib-Val-OMe); (Rai et al., JACS 2006, 128, 7916-7928). Peptides 1 and 6 adopt almost identical helical conformations with unfolding of the helix at the N-terminus Pro (1) residue. Peptide 4 reveals the anticipated (D)Pro-Ala type II' beta-turn, followed by a stretch of 3(10)-helix. Peptide 8 adopts a folded conformation stabilized by four successive 4-->1 intramolecular hydrogen bonds. Ala (2) adopts an alpha(L) conformation, resulting in a type II beta-turn conformation followed by a stretch of 3(10)-helix. Conformational properties in solution were probed using solvent perturbation of NH chemical shifts which permit delineation of hydrogen bonded NH groups and nuclear Overhauser effects (NOEs) between backbone protons, which are diagnostic of local residue conformations. The results suggest that, continuous helical conformations are indeed significantly populated for peptides 2 and 3. Comparison of the results for peptides 1 and 2, suggest that there is a significant influence of the residue that follows diproline segments in influencing backbone folding.

Chain length effects on helix‐hairpin distribution in short peptides with Aib‐DAla and Aib‐Aib Segments

“…The structure of tetrapeptide Dnp‐Val‐Aib‐Gly‐Leu‐Pna constitutes an example of a type‐II′ β‐turn conformation followed by an α L residue 34. This results in a consecutive type‐II′‐III β‐turn structure, which has been widely observed in short peptidescontaining the constrained α,α‐dialkylated amino acids 11, 35–38. In this case, the C 13 hydrogen bond (3.3 Å) is appreciably longer than the two C 10 hydrogen bonds (2.98 Å and 3.13 Å).…”

N‐terminal diproline and charge group effects on the stabilization of helical conformation in alanine‐based short peptides: CD studies with water and methanol as solvent

“…The N‐terminal dialanine is substituted with a diproline segment of homochiral and heterochiral structure for possible inducement of helical conformation. The diproline segment, covalently constrained diproline surrogate, has been employed as potential nuclei for inducing helical conformations in peptides . Thus, a combination of charge‐group effect over side chains and stereochemical effect of the N‐terminal structure is examined for possible inducement of helical folds.…”

“…The folding simulations of all-alanine peptides and a number of short alanine-based helical peptides with positively or negatively charged residues have highlighted the role of hydrophobic interaction and charged side chains in the folding of α-helical peptides [35]. The diproline segments, covalently constrained diproline surrogate, have been reported as potential nuclei for initiating helical folding in peptides [36][37][38]. The present study addresses nonapeptide composed of L-amino acids for the effect in N-terminal diproline and charge-group effect over side chains that are capable of ordering the peptide as a helical fold.…”

Scrutiny of chain-length and N-terminal effects in α-helix folding: a molecular dynamics study on polyalanine peptides

“…The folding simulations of all-alanine peptides and a number of short alanine-based helical peptides with positively or negatively charged residues have highlighted the role of hydrophobic interaction and charged side chains in the folding of α-helical peptides [35]. The diproline segments, covalently constrained diproline surrogate have been reported as potential nuclei for initiating helical folding in peptides [36][37][38] [42,43].…”