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Crystallographic characterization of 12-helical secondary structure in ?-peptides containing side chain groups.

ABSTRACT: Helices are the most extensively studied secondary structures formed by ?-peptide foldamers. Among the five known ?-peptide helices, the 12-helix is particularly interesting because the internal hydrogen bond orientation and macrodipole are analogous to those of ?-peptide helices (?-helix and 3(10)-helix). The ?-peptide 12-helix is defined by i, i+3 C?O···H-N backbone hydrogen bonds and promoted by ?-residues with a five-membered ring constraint. The 12-helical scaffold has been used to generate ?-peptides with specific biological functions, for which diverse side chains must be properly placed along the backbone and, upon folding, properly arranged in space. Only two crystal structures of 12-helical ?-peptides have previously been reported, both for homooligomers of trans-2-aminocyclopentanecarboxylic acid (ACPC). Here we report five additional crystal structures of 12-helical ?-peptides, all containing residues that bear side chains. Four of the crystallized ?-peptides include trans-4,4-dimethyl-2-aminocyclopentanecarboxylic acid (dm-ACPC) residues, and the fifth contains a ?(3)-hPhe residue. These five ?-peptides adopt fully folded 12-helical conformations in the solid state. The new crystal structures, along with previously reported data, allow a detailed characterization of the 12-helical conformation; average backbone torsion angles of ?-residues and helical parameters are derived. These structural parameters are found to be similar to those for i, i+3 C?O···H-N hydrogen-bonded helices formed by other peptide backbones generated from ?- and/or ?-amino acids. The similarity between the conformational behavior of dm-ACPC and ACPC is consistent with previous NMR-based conclusions that 4,4-disubstituted ACPC derivatives are compatible with 12-helical folding. In addition, our data show how a ?(3)-residue is accommodated in the 12-helix, thus enhancing understanding of the diverse conformational behavior of this flexible class of ?-amino acids.

SUBMITTER: Choi SH

PROVIDER: S-EPMC2976582 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Crystallographic characterization of 12-helical secondary structure in β-peptides containing side chain groups.

Choi Soo Hyuk SH Guzei Ilia A IA Spencer Lara C LC Gellman Samuel H SH

Journal of the American Chemical Society 20101001 39

Helices are the most extensively studied secondary structures formed by β-peptide foldamers. Among the five known β-peptide helices, the 12-helix is particularly interesting because the internal hydrogen bond orientation and macrodipole are analogous to those of α-peptide helices (α-helix and 3(10)-helix). The β-peptide 12-helix is defined by i, i+3 C═O···H-N backbone hydrogen bonds and promoted by β-residues with a five-membered ring constraint. The 12-helical scaffold has been used to generate ...[more]

PMID: 20828159

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Project description:Understanding the structure and dynamics of membrane proteins in their native, hydrophobic environment is important to understanding how these proteins function. EPR spectroscopy in combination with site-directed spin labeling (SDSL) can measure dynamics and structure of membrane proteins in their native lipid environment; however, until now the dynamics measured have been qualitative due to limited knowledge of the nitroxide spin label's intramolecular motion in the hydrophobic environment. Although several studies have elucidated the structural origins of EPR line shapes of water-soluble proteins, EPR spectra of nitroxide spin-labeled proteins in detergents or lipids have characteristic differences from their water-soluble counterparts, suggesting significant differences in the underlying molecular motion of the spin label between the two environments. To elucidate these differences, membrane-exposed ?-helical sites of the leucine transporter, LeuT, from Aquifex aeolicus, were investigated using X-ray crystallography, mutational analysis, nitroxide side chain derivatives, and spectral simulations in order to obtain a motional model of the nitroxide. For each crystal structure, the nitroxide ring of a disulfide-linked spin label side chain (R1) is resolved and makes contacts with hydrophobic residues on the protein surface. The spin label at site I204 on LeuT makes a nontraditional hydrogen bond with the ortho-hydrogen on its nearest neighbor F208, whereas the spin label at site F177 makes multiple van der Waals contacts with a hydrophobic pocket formed with an adjacent helix. These results coupled with the spectral effect of mutating the i ± 3, 4 residues suggest that the spin label has a greater affinity for its local protein environment in the low dielectric than on a water-soluble protein surface. The simulations of the EPR spectra presented here suggest the spin label oscillates about the terminal bond nearest the ring while maintaining weak contact with the protein surface. Combined, the results provide a starting point for determining a motional model for R1 on membrane proteins, allowing quantification of nitroxide dynamics in the aliphatic environment of detergent and lipids. In addition, initial contributions to a rotamer library of R1 on membrane proteins are provided, which will assist in reliably modeling the R1 conformational space for pulsed dipolar EPR and NMR paramagnetic relaxation enhancement distance determination.

Dataset Information

Crystallographic characterization of 12-helical secondary structure in ?-peptides containing side chain groups.

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Crystallographic characterization of 12-helical secondary structure in β-peptides containing side chain groups.

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