Helix foldamers of γ-peptides based on 2-aminocyclopentylacetic acid

Abstract

The conformational preferences of helix foldamers have been studied in oligo-g-peptides composed of 2-aminocyclopentylacetic acid (gAc 5 a) with a cyclopentyl constraint on the C b -C g bond using density functional methods. Although the gAc 5 a (1) dipeptide with homochiral (1S,2S) configurations exhibits a strong preference for the right-handed (P) 9-membered helix foldamer in chloroform and water, oligopeptides composed of gAc 5 a (1) preferentially adopt (P)-2.5 14 -helices due to the favored conformational energy produced as the peptide sequence becomes longer and as solvent polarity increases. The calculated mean backbone torsion angles and helical parameters for 14-helical foldamers composed of gAc 5 a (1) are consistent with those measured in the X-ray structures of penta-and hexapeptides composed of C a -ethyl-gAc 6 a and 14-helical foldamers composed of gAc 6 a (1) with cyclohexyl constraints.However, the substitution of cyclopentane constraints in the backbone differentially changed the conformational preference and/or handedness for helix foldamers when compared with other oligo-g-peptides with different cycloalkane positions or size constraints. The conformational preferences of the oligo-gAc 5 a peptides obtained here are expected to provide useful information for the structure-based design of biologically active g-peptides with specific functions.

Exploring helix structures of γ‐peptides based on 2‐(aminomethyl)cyclopentanecarboxylic acid

“…Four helix types with different sizes of H-bonded pseudocycles were assessed for oligomers composed of γAmc 5 residues in this study (Figure 2), as in earlier works. [24,25] The H-14 and H-9 helices are characterized by 14-and 9-membered H-bonded pseudocycles in the backward direction along the sequence between C O(iÀ3) and NÀH(i) and between C O(iÀ2) and NÀH(i),…”

“…[24] Oligo-γ-peptides of 2-aminocyclopentylacetic acid (γAc 5 a; Figure 1d), with a cyclopentyl constraint on the C β ÀC γ bond, preferentially adopted (P)-2.5 14 -helices due to the favored conformational energy produced as the peptide sequence becomes longer and as solvent polarity increases. [25] In particular, Gellmann and co-workers reported that α/γ-peptides composed of (1R, 2R)-2-(aminomethyl)cyclopentanecarboxylic acid (γAmc 5 ; Figure 1e), with a cyclopentyl constraint on the C α ÀC β bond, displayed a tendency to adopt partially 12/10-helical structures, even in nonpolar solvent. [26] The hexameric γ/α-peptide composed of (1S, 2R)-γAmc 5 and L-Ala residues formed a well-ordered 10/12-helix in CDCl 3.…”

Exploring Helical Folding in Oligomers of Cyclopentane‐Based ϵ‐Amino Acids: A Computational Study

“…It has been known that oligomers of β‐, γ‐, or δ‐amino acid residues as well as their hybrids with α‐amino acid residues can adopt various secondary structures as found in structures of peptides and proteins [1–9] . In particular, peptide foldamers can stabilize various helical structures, of which the type, handedness, and macrodipole direction of helices can be controlled by the substitutions and/or stereochemistry of the residues [1–20] . Helical peptide foldamers have been used to design (a) antimicrobial peptides (AMPs) with cationic groups [3,4,21–24] and (b) catalysts for various organic reactions by incorporating catalytic functional groups [25–31] …”

“…[1][2][3][4][5][6][7][8][9] In particular, peptide foldamers can stabilize various helical structures, of which the type, handedness, and macrodipole direction of helices can be controlled by the substitutions and/or stereochemistry of the residues. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] Helical peptide foldamers have been used to design (a) antimicrobial peptides (AMPs) with cationic groups [3,4,[21][22][23][24] and (b) catalysts for various organic reactions by incorporating catalytic functional groups. [25][26][27][28][29][30][31] It is well known that the polymer nylon 6 of the ɛ-amino caproic acid (6-aminohexanoic acid, Ahx; Figure 1a) forms fibrils composed of β-sheet-like chain structures.…”

Conformational preferences of β-sheet structures in cyclopropane-containing γ-peptides

“…[38][39][40] These dipeptides exhibited a strong tendency to adopt a g-turn structure with a seven-membered H-bond despite the differences in conformational preferences depending on the stereochemistry, position, and number of substituents. Although several quantum mechanical studies have explored the conformational preferences of helix, [41][42][43][44][45][46][47][48] turn, 49,50 and hairpin 49 foldamers composed of g-peptides, no computational studies have yet examined the conformational preferences of b-sheets in g-peptides. Here, we report the conformational preferences of parallel and antiparallel b-sheets of oligo-gAmc 3peptides obtained by DFT calculations in the gas phase and in solution (chloroform and water).…”