Structural Chemistry of Peptides Containing Backbone Expanded Amino Acid Residues: Conformational Features of β, γ, and Hybrid Peptides

Vasudev, Prema G.; Chatterjee, Sunanda; Shamala, Narayanaswamy; Balaram, Padmanabhan

doi:10.1021/cr100100x

Cited by 305 publications

(163 citation statements)

References 336 publications

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“…Nearest-neighbor C9 H bonding has commonly been observed for gabapentin residues in peptidic oligomers for which crystal structures have been determined. 5,6,43 In contrast, other types of γ-amino acid residues seem to prefer longer range H-bonding patterns, especially CdO(i)ÀHÀN(i+3), when embedded in peptidic oligomers. 43À46 These preferences for longer range H bonding support formation of helical secondary structures.…”

Section: Discussionmentioning

confidence: 99%

Competition between Amide Stacking and Intramolecular H Bonds in γ-Peptide Derivatives: Controlling Nearest-Neighbor Preferences

James

Buchanan

et al. 2011

J. Phys. Chem. A

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Resonant two-photon ionization (R2PI), IR-UV holeburning (IR-UV), and resonant ion-dip infrared spectroscopy (RIDIRS) have been used to record mass-selected, single-conformation ultraviolet and infrared spectra of three simple diamide derivatives of γ-amino acids as isolated molecules cooled in a supersonic expansion. This work builds on an earlier study of Ac-γ(2)-hPhe-NHMe (James, W. H., III, et al. J. Am. Chem. Soc. 2009, 131, 14243), which showed that this methyl-capped γ-peptide forms amide-stacked conformations that are similar in stability to H-bonded conformations containing a C9 ring and more stable than C7 H-bonded ring structures. Among the γ-peptides discussed here, Ac-γ(2)-hPhe-N(Me)(2) contains an additional methyl group relative to the previously studied Ac-γ(2)-hPhe-NHMe and therefore lacks the amide NH group responsible for C9 ring formation. Three conformations of Ac-γ(2)-hPhe-N(Me)(2) are observed, all of which are amide-stacked structures. In a second new molecule, Ac-γ(2)-hPhe-NH(iPr), the C-terminal NHMe group of Ac-γ(2)-hPhe-NHMe is replaced with an NH(iPr) group. Three conformations of Ac-γ(2)-hPhe-NH(iPr) are observed, all of which are C9 H-bonded structures. The dramatic difference between C-terminal NHMe and NH(iPr) reveals the delicate balance of noncovalent forces within these γ-peptides. The third molecule we examined is a gabapentin-derived diamide (designated 1), which contains a phenylacyl group at the N-terminus and an N(Me)(2) group at the C-terminus; the latter precludes C9 H bonding. Comparison of 1 with Ac-γ(2)-hPhe-N(Me)(2) allows us to examine the impact of the backbone substitution pattern (monosubstitution at carbon-2 vs disubstitution at carbon-3) on the competition between the C7 H-bonded and the amide-stacked conformation. In this case, only C7 rings are observed. The different gas-phase behaviors observed among the molecules analyzed here offer insight on the intrinsic conformational propensities of the γ-peptide backbone, information that provides a foundation for future foldamer design efforts.

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Section: Discussionmentioning

confidence: 99%

Competition between Amide Stacking and Intramolecular H Bonds in γ-Peptide Derivatives: Controlling Nearest-Neighbor Preferences

James

Buchanan

et al. 2011

J. Phys. Chem. A

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“…[1][2][3][4] Like natural a-peptides, oligomers of b-or g-amino acid residues (i.e., b-or g-peptides) as well as their hybrids with a-amino acid residues (a-peptides) have been known to adopt various secondary structures, including a-helix, b-sheet, b-turn, or b-hairpin structures. [5][6][7][8][9][10][11][12] b-and g-peptides can stabilize the helix foldamer domain by folding into helices with a short chain length of four to six residues; this compares with approximately 10-12 residues for natural a-peptides in organic solvents. 4,5 The handedness of the helix, the helix type, and the direction of the helix macrodipole (i.e., the orientation of H-bonds) can be controlled by the substitution pattern and/or the stereochemistry of the residues.…”

Section: Introductionmentioning

confidence: 99%

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

Kang

Lee

2015

New J. Chem.

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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.

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“…[17] This purely local gabapentin folding pattern does not necessarily lead to a regular secondary structure, as illustrated by the crystal structure of a gabapentin tetramer, in which the torsion angles within the C 9 rings vary irregularly along the sequence. [8g] In contrast, NMR analysis of γ-peptide oligomers containing γ 4 -amino acid residues bearing a bulky side chain suggest formation of a regular 9-helix.…”

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confidence: 99%

Characteristic Structural Parameters for the γ‐Peptide 14‐Helix: Importance of Subunit Preorganization

Zhang

Reidenbach

et al. 2011

Angew Chem Int Ed

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We report crystallographic data for a set of homologous γ-peptides that contain a Boc-protected residue derived from the flexible gabapentin monomer at the N-terminus and cyclically constrained γ-residues at all other positions. The crystallized γ-peptides range in length from 3 to 7 residues. Previously only one atomic-resolution structure had been available for a short γ-peptide 14-helix. The new data provided here allow derivation of characteristic parameters for the γ-peptide 14-helix, and establish guidelines for characterizing 14-helical folding in solution via 2D NMR. In addition, the results suggest that the substitution pattern of a γ-residue has a profound effect on the propensity for 14-helical folding.

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Structural Chemistry of Peptides Containing Backbone Expanded Amino Acid Residues: Conformational Features of β, γ, and Hybrid Peptides

Cited by 305 publications

References 336 publications

Competition between Amide Stacking and Intramolecular H Bonds in γ-Peptide Derivatives: Controlling Nearest-Neighbor Preferences

Competition between Amide Stacking and Intramolecular H Bonds in γ-Peptide Derivatives: Controlling Nearest-Neighbor Preferences

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

Characteristic Structural Parameters for the γ‐Peptide 14‐Helix: Importance of Subunit Preorganization

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