Design of peptides with α,β-dehydro residues: pseudo-tripeptide N -benzyloxycarbonyl–ΔLeu– L -Ala– L -Leu–OCH 3 (original) (raw)
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Journal of the Chemical Society, Perkin Transactions 2, 1996
The conformational characteristics of three hexapeptides Boc-Leu-Xxx-Val-Leu-Aib-Val-OMe (Xxx = Ala 1, D-Ala 2, Gly 3; Aib = a-aminoisobutyryl) have been probed in CDCl, solution by NMR methods using solvent perturbation of chemical shifts and radical broadening of NH resonances to delineate intramolecularly hydrogen bonded NH groups. Nuclear Overhauser effects (NOEs) provide additional information on preferred backbone conformations. The substituent at position 2 acts as a major conformational determinant. While a continuous 3 1, helical conformation is favoured for the peptide with Xxx = Ala, a multiple p-turns conformation is supported by both NMR and CD data for the peptide with Xxx = D-Ala. In the peptide with Xxx = Gly CD and NMR data suggest that both 3,, helical and multiple turns conformations are simultaneously populated. The results suggest that incorporation of D-amino acids and Aib residues into all L-sequences may prove useful in generating sequences containing multiple turns.
Three-Residue Turns in α/β-Peptides and Their Application in the Design of Tertiary Structures
Chemistry – An Asian Journal, 2008
Proteins and peptides adopt compact three-dimensional structures to play myriad roles in biological processes. Details of the complex tertiary and quaternary structures in proteins, which are assembled from a limited number of secondary structures such as helices, strands, and turns, permit the understanding of their functions at the molecular level. Reverse turns [1] are often located at protein surfaces, where their structural compactness as well as the desirable orientation of the side chains permit them to participate actively in protein folding. b-Turns, the simplest defined loops, are the most frequently found reverse turns; their design principles are well-understood. On the other hand, reports on threeresidue loops are scanty, thus providing the desired impetus to design such structural elements. Recently, Balaram and co-workers designed a three-residue loop comprising d-Pro-l-Pro-d-Ala in a b-hairpin. Herein we describe the synthesis and discovery of novel three-residue turns as well as helix-turn (HT) and helix-turn-helix (HTH) motifs in a/b hybrid peptides 2-11 (Scheme 1).
Biochemistry, 2005
Recent studies have provided evidence that peptides as short as tripeptides do adopt preferred conformations. Here we report that the tripeptide Ala-Phe-Ala (AFA) in aqueous solution preferentially forms an inverse γ-turn. Circular dichroism (CD) indicated the presence of a predominant turn structure, and Fourier transform infrared (FTIR) bands suggested the presence of a γ-turn forming a bifurcated H-bond with the solvent molecules. The high-resolution structure was obtained by a combined use of NMR spectroscopy and calculations. On the basis of 30 unambiguous ROESY-derived distance restraints (including the HR-NH NOE between Ala 1 and Ala 3 and a hydrogen bond between the CO group of Ala 1 and the NH group of Ala 3 ), calculations clearly demonstrated the presence of an inverse γ-turn centered on Phe 2 . From NOE data, we estimated a mole fraction for the γ-turn of 0.65. Since for AFA an extended -strand was also reported [], we investigated the possibility that γ-turn and -strand may represent two major conformations. By using a best-fit procedure that calculated experimental NOEs as weighted averages of the effects originating from both structures, we were able to calculate with good accuracy the backbone NOEs at 280 K in terms of the two limiting conformers, yielding a mole fraction for the γ-turn and -strand conformations of 0.60 and 0.40, respectively, in good agreement with those found by NOE data. The implication of the existence of a preferred conformation by a small structural element is discussed in the context of the nucleation of protein folding events and the design of small peptide and peptidomimetic drugs.
Journal of Peptide Science, 2008
The crystal structures of two oligopeptides containing di-n-propylglycine (Dpg) residues, Boc-Gly-Dpg-Gly-Leu-OMe (1) and Boc-Val-Ala-Leu-Dpg-Val-Ala-Leu-Val-Ala-Leu-Dpg-Val-Ala-Leu-OMe (2) are presented. Peptide 1 adopts a type I βturn conformation with Dpg(2)-Gly(3) at the corner positions. The 14-residue peptide 2 crystallizes with two molecules in the asymmetric unit, both of which adopt α-helical conformations stabilized by 11 successive 5 → 1 hydrogen bonds. In addition, a single 4 → 1 hydrogen bond is also observed at the N -terminus. All five Dpg residues adopt backbone torsion angles (φ, ψ) in the helical region of conformational space. Evaluation of the available structural data on Dpg peptides confirm the correlation between backbone bond angle N-C α -C (τ ) and the observed backbone φ,ψ values. For τ > 106°, helices are observed, while fully extended structures are characterized by τ < 106°. The mean τ values for extended and folded conformations for the Dpg residue are 103.6°± 1.7°and 109.9°± 2.6°, respectively. Figure 5 (a) Superposition of peptide 2 of Molecule-A (black) with VALU15 (gray) (Backbone atom of residues 2-13 are used, RMSD = 0.21Å) (b) Superposition of peptide 2 of Molecule-B (black) with VALU15 (gray) (Backbone atom of residues 2-13 are used, RMSD = 0.19Å). VALU15: Boc-Val-Ala-Leu-Aib-Val-Ala-Leu-Val-Ala-Leu-Aib-Val-Ala-Leu-Aib-OMe.
International Journal of Biological Macromolecules, 1996
The dehydropeptide Boc--L--VaI--APhe--L--VaI--OC H 3 was synthesized by azlactone method in solution phase. The peptide crystallized from its solution in a methanol/water mixture (70:30) in space group P2~2~2~ with a=13.638(l)A, b = 22.864(3)A, c = 27.600(2)A, V= 8606(1)A 3. The structure was determined by direct methods and refined to an R value of 0.089 for 3326 observed I 1 > 20(I)] reflections. The structure contains three crystallographically independent molecules. Two molecules (A and B) adopt identical conformations with 41(A)=-130(1), ~(B)=-139(1), ~bl(A)= 153(1), ~bj(B)= 145(1), 42(A) = 62(1), 42(B)= 56(1), ~2(A)= 33(1), ~2(B) = 33(1), 43(A)=-75(1), 43(8)=-77(1) ~3T(A)= 152(1) and ~3T(B)= 163(1) °.
Crystal-state conformation of C?,?-dialkylated peptides containing chiral ?-homo-residues
Journal of Peptide Science, 2001
Secondary structure formation and stability are essential features in the knowledge of complex folding topology of biomolecules. To better understand the relationships between preferred conformations and functional properties of i-homo-amino acids, the synthesis and conformational characterization by X-ray diffraction analysis of peptides containing conformationally constrained C h,h -dialkylated amino acid residues, such as h-aminoisobutyric acid or 1-aminocyclohexane-1-carboxylic acid and a single i-homoamino acid, differently displaced along the peptide sequence have been carried out. The peptides investigated are: Boc-iHLeu-(Ac 6 c) 2 -OMe, Boc-Ac 6 c-iHLeu-(Ac 6 c) 2 -OMe and Boc-iHVal-(Aib) 5 -OtBu, together with the C-protected i-homo-residue HCl·H-iHVal-OMe. The results indicate that the insertion of a iH-residue at position 1 or 2 of peptides containing strong helix-inducing, bulky C h,h -disubstituted amino acid residues does not induce any specific conformational preferences. In the crystal state, most of the NH groups of i-homo residues of tri-and tetrapeptides are not involved in intramolecular hydrogen bonds, thus failing to achieve helical structures similar to those of peptides exclusively constituted of C h,h -disubstituted amino acid residues. However, by repeating the structural motifs observed in the molecules investigated, a i-pleated sheet secondary structure, and a new helical structure, named (14/15)-helix, were generated, corresponding to calculated minimum-energy conformations. Our findings, as well as literature data, strongly indicate that conformations of iH-residues, with the v torsion angle equal to −60°, are very unlikely.
Preferred conformation of peptides rich in Ac8c, a medium-ring alicyclic Cα,α-disubstituted glycine
Journal of Peptide Science, 1996
A complete series of terminally blocked, monodispersed homo-oligopeptides (to the pentamer level) from the sterically demanding, medium-ring alicyclic C"'"-disubstituted glycine 1 -aminocyclooctane-1 -earboxylic acid (Acec), and two Ala/Ac8c Mpeptides, were synthesized by solution methods and fully characterfied. The preferred conformation of all the oligopeptides was determined in deuterochloroform solution by IR absorption and 'H-NMR The molecular structures of the amino acid derivative Z-Ac8c-OH. the dipeptide pBrBz-(Ac&-OH and the tripeptide pBrBz-(Acec)3-OtBu were assessed in the crystal state by X-ray diikction. Conformational energy computations were performed on the monopeptide Ac-Ac8c-NHMe. Taken together, the results obtained strongly support the view that the Acsc residue is an effective B-turn and helix former. A comparison is also made with the conformational preferences of a-aminoisobutyric acid, the prototype of C"'"-disubstituted &cines. and of the other members of the family of 1 -aminocycloakane-1 -earboxylic acids (Ac,,c, with n = 3, $7) investigated so far. The implications for the use of the Acsc residue in peptide conformational design are considered.
Preferred Conformation of Peptides Rich in Ac8c, a Medium-ring Alicyclic C,-disubstituted Glycine
J Pept Sci, 1996
A complete series of terminally blocked, monodispersed homo-oligopeptides (to the pentamer level) from the sterically demanding, medium-ring alicyclic C"'"-disubstituted glycine 1-aminocyclooctane-1-earboxylic acid (Acec), and two Ala/Ac8c Mpeptides, were synthesized by solution methods and fully characterfied. The preferred conformation of all the oligopeptides was determined in deuterochloroform solution by IR absorption and 'H-NMR The molecular structures of the amino acid derivative Z-Ac8c-OH. the dipeptide pBrBz-(Ac&-OH and the tripeptide pBrBz-(Acec)3-OtBu were assessed in the crystal state by X-ray diikction. Conformational energy computations were performed on the monopeptide Ac-Ac8c-NHMe. Taken together, the results obtained strongly support the view that the Acsc residue is an effective B-turn and helix former. A comparison is also made with the conformational preferences of a-aminoisobutyric acid, the prototype of C"'"-disubstituted &cines. and of the other members of the family of 1-aminocycloakane-1-earboxylic acids (Ac,,c, with n = 3, $7) investigated so far. The implications for the use of the Acsc residue in peptide conformational design are considered.