Peptide β-Bend and 3 10-Helix: from 3D-Structural Studies to Applications as Templates (original) (raw)
Related papers
Journal of The American Chemical Society, 1997
Insertion of achiral ω-amino acids into peptide sequences results in replacement of scissile peptide bonds by proteolytically stable C-C bonds. This provides a convenient means of creating peptidomimetics. The present study establishes the preservation of helical structures in octa-and undecapeptides with centrally located -and γ-amino acids in the sequence. X-ray diffraction analyses of single crystals and NMR studies have been used to investigate the extent of perturbations of a regular 3 10 -or R-helix by the introduction of (-CH 2 -) n groups into the backbone by the use of the -Ala-γ-Abu segment ( -Ala ) -alanine, γ-Abu ) γ-aminobutyric acid), which is formally homomorphous with a (Gly) 3 segment. In crystals, the octapeptide Boc-Leu-Aib-Val--Ala-γ-Abu-Leu-Aib-Val-OMe (1) and the undecapeptide Boc-Leu-Aib-Val--Ala-γ-Abu-Leu-Aib-Val-Ala-Leu-Aib-OMe (2) retain their helical motifs with minor bulges. Five new types of 4 f 1, 5 f 1, and 6 f 1 hydrogen bond rings are formed with up to three extra CH 2 moieties. Cell parameters for peptide 1 are space group P2 1 2 1 2 1 with a ) 11.506 (1) Å, b ) 16.600 (1) Å, c ) 27.362(1) Å, and R ) 6.1% for 2696 data measured >4σ(F); for the undecapeptide 2, the space group is P2 1 with a ) 8.605 (3) Å, b ) 22.806 (4) Å, c ) 19.014 (3) Å, ) 101.47(2)°, and R ) 7.5% for 3797 data measured >4σ(F). Helical conformations in solution are also maintained for peptide 2 as is evident from NMR studies in CDCl 3 , which suggest that the centrally positioned, flexible -Ala-γ-Abu segment can be comfortably accommodated into helical structures adopting gauche conformations about specific C-C bonds of the poly(methylene) units. Twenty structures for backbone conformations generated from MD simulations using NMR-derived contraints, superpose with a low RMSD value (0.78 ( 0.05 Å), further indicating that in these peptides the conformational flexibility of the -Ala-γ-Abu segment is limited and confined to largely helical conformations.
Journal of the American Chemical Society, 1998
The homooligopeptide series based on O,O-isopropylidene-R-hydroxymethylserine from dimer through pentamer has been synthesized to examine the conformational preferences of this new C R -tetrasubstituted R-amino acid characterized by concomitant C i R T C i R cyclization and presence of two ether oxygen atoms in the γ-positions of the six-membered ring 1,3-dioxane system. To this aim we have exploited X-ray diffraction in the crystal state and FTIR absorption and 1 H NMR techniques in solution. The results obtained are compared with those of the homooligopeptides based on the related cyclohexane-containing C R -tetrasubstituted residue. We conclude that in the former peptides a competition takes place between the classical intramolecular (peptide) CdO‚‚‚H-N (peptide) H-bonds, stabilizing the -bend/3 10 -helical structures, and the newly discovered (peptide) N i+1 -H‚‚‚O i γ (side-chain ether) intramolecular H-bonds. The extent of regular (incipient) 3 10 -helix formation, where this latter type of H-bond is absent, tends to increase as peptide main-chain length increases. As a result of this intramolecular N-H‚‚‚O γ interaction, the critical main-chain length for 3 10 -helix formation in the crystal state shifts from the shortest possible oligomer, the terminally protected trimer, in the cyclohexane series to the pentamer in the 1,3-dioxane series. Interestingly, a strict correlation has been found between the observed (peptide) N i+1 -H‚‚‚O i γ (side-chain ether) intramolecular H-bond and (i) the backbone ψ torsion angle of the i residue (extended), and (ii) the disposition of the R-amino substituent in the 1,3-dioxane ring of the i + 1 residue (axial).
Journal of the American Chemical Society, 2003
Amino acid oligomers composed exclusively of homochiral trans-2-aminocyclopentanecarboxylic acid (ACPC) residues and/or related pyrrolidine-based residues are known to favor a specific helical secondary structure that is defined by 12-membered ring CdO(i)--H-N(i+3) hydrogen bonds ("12-helix"). The 12-helix is structurally similar to the familiar R-helix and therefore represents a source of potential R-helix-mimics. The 12-helix will be most useful in this regard if this conformational scaffold can be employed to arrange specific sets of protein-like side chains in space. Here we examine whether the 12-helix tolerates insertion of acyclic -amino acid residues bearing a substituent in the R-position (" 2 -residues"). Seventeen homologous -peptide heptamers have been prepared in which one to four 2 -residues reside among ACPC and/or pyrrolidine residues. Circular dichroism comparisons suggest that 2 -residues have a lower 12helical propensity than do residues preorganized by a five-membered ring, as expected, but that -peptides containing 2 -residues at one or two of the seven positions retain a significant preference for 12-helix formation. These results indicate that a limited number of 2 -residues can be used to introduce side chains at specific positions along the surface of a 12-helix.
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).
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.
Protein Science, 1994
A structural transition from a 3,0-helix to an a-helix has been characterized at high resolution for an octapeptide segment located in 3 different sequences. Three synthetic peptides, decapeptide (A) Boc-Aib-Trp-(Leu-Aib-Ala)*-Phe-Aib-OMe, nonapeptide (B) B~c-Trp-(Leu-Aib-Ala)~-Phe-Aib-OMe, and octapeptide (C) Boc-(Le~-Aib-AIa)~-Phe-Aib-OMe, are completely helical in their respective crystals. At 0.9 A resolution, R factors for A, B, and C are 8.3070, 5.4070, and 7.3070, respectively. The octapeptide and nonapeptide form ideal 310-helices with average torsional angles +(N-Ca) and (Ca−C′)of−57",−26"forCand−60",−27"forB.The10−residuepeptide(A)beginsasa3,,−helixandabruptlychangestoana−helixatcarbonyl0(3),whichistheacceptorforbotha4+1hydrogenbondwithN(6)Handa5+1hydrogenwithN(7)H,eventhoughthelast8residueshavethesamesequenceinall3peptides.Theaverageq5,(Ca-C') of-57",-26" for C and-60",-27" for B. The 10-residue peptide (A) begins as a 3,,-helix and abruptly changes to an a-helix at carbonyl 0(3), which is the acceptor for both a 4 + 1 hydrogen bond with N(6)H and a 5 + 1 hydrogen with N(7)H, even though the last 8 residues have the same sequence in all 3 peptides. The average q5,(Ca−C′)of−57",−26"forCand−60",−27"forB.The10−residuepeptide(A)beginsasa3,,−helixandabruptlychangestoana−helixatcarbonyl0(3),whichistheacceptorforbotha4+1hydrogenbondwithN(6)Handa5+1hydrogenwithN(7)H,eventhoughthelast8residueshavethesamesequenceinall3peptides.Theaverageq5, angles in the decapeptide are-58",-28" for residues 1-3 and-63",-41 O for residues 4-10. The packing of helices in the crystals does not provide any obvious reason for the transition in helix type. Fourier transform infrared studies in the solid state also provide evidence for a 310-to a-helix transition with the amide I band appearing at 1,656-1,657 cm" in the 9-and 10-residue peptides, whereas in shorter sequences the band is observed at 1,667 cm-l.
Crystal-state 3D-structural characterization of novel, Aib-based, turn and helical peptides
Journal of Peptide Science, 2007
The crystal-state conformations of the hexapeptide amide Pht-(Aib)6-NH-C(CH3)2-O-OtBu (7), the hexapeptide Ac-L-aIle-(Aib)5-OtBu (6), the pentapeptide Z-(Aib)3-L-Glu(OtBu)-Aib-O-(CH2)2-(1)Nap (5), the tetrapeptides Z-(Aib)2-L-His(Nτ-Trt)-Aib-OMe (4 I) and Z-(Aib)2-L-Nva-Aib-OtBu (4 II), the tripeptide Pyr-(Aib)3-OtBu (3 I), the dipeptide amides Pyr-(Aib)2-(4)NH-TEMPO (3 II) and Piv-(Aib)2-NH-C(CH3)2-O-OtBu (3 III), and the dipeptides Pht-Aib-βAc6c-OtBu (2 I), Pht-Aib-NH-C(CH3)2-O-OtBu (2 II) and Boc-gGly-mAib-OH (2 III) have been determined by X-ray diffraction analyses. All peptides investigated are characterized by one or more turn/helix forming Aib residues. Except the three short dipeptides, all are folded into CO···HN intramolecularly H-bonded 310-helices, or into various types of β-turns. In the structure of 6, two independent molecules of opposite screw sense were observed in the asymmetric unit, generating diastereomeric 310-helices. Copyright © 2007 European Peptide Society and John Wiley & Sons, Ltd.
Peptide design. Helix–helix motifs in synthetic sequences
Journal of the Chemical Society, Perkin Transactions 2, 1997
Two centrally positioned -aminoisobutyryl (Aib) residues have been used to stabilize distinct heptapeptide helical segments in the 15-residue synthetic sequence Boc-Met-Ala-Leu-Aib-Val-Ala-Leu-Acp-Val-Ala-Leu-Aib-Val-Ala-Phe-OMe. The helices are connected by the flexible linker -aminocaproic acid (Acp). NMR studies in CDCl 3 establish helical conformations for both independent segments as evidenced by NH-NH nuclear Overhauser effects (NOEs). The peptide strongly aggregates in CDCl 3 with the NH groups of Met(1) and Ala(2) participating in intermolecular hydrogen bonds. In (CD 3 ) 2 SO two solvated helical segments are supported by NMR results. Solvent dependent breakdown of aggregates on addition of (CD 3 ) 2 SO to CDCl 3 solutions is suggested by analysis of chemical shifts and temperature coefficients of NH protons. The observation of several interhelical NOEs in CDCl 3 , relatively few NOEs in 10% (CD 3 ) 2 SO-CDCl 3 and their absence in (CD 3 ) 2 SO provides a means of inferring helix orientations. While an antiparallel arrangement resulting in closed aggregate formation is suggested in CDCl 3 , a parallel solvated arrangement is favoured in (CD 3 ) 2 SO.
Helvetica Chimica Acta, 2012
Dedicated to Prof. Dieter Seebach on the occasion of his 75th birthday Backbone alkylation has been shown to result in a dramatic reduction in the conformational space that is sterically accessible to a-amino acid residues in peptides. By extension, the presence of geminal dialkyl substituents at backbone atoms also restricts available conformational space for b and g residues. Five peptides containing the achiral b 2,2 -disubstituted b-amino acid residue, 1-(aminomethyl)cyclohexanecarboxylic acid (b 2,2 Ac 6 c), have been structurally characterized in crystals by X-ray diffraction. The tripeptide Boc-Aib-b 2,2 Ac 6 c-Aib-OMe (1) adopts a novel fold stabilized by two intramolecular H-bonds (C 11 and C 9 ) of opposite directionality. The tetrapeptide Boc-[Aib-b 2,2 Ac 6 c] 2 -OMe (2) and pentapeptide Boc-[Aib-b 2,2 Ac 6 c] 2 -Aib-OMe (3) form short stretches of a hybrid ab C 11 helix stabilized by two and three intramolecular H-bonds, respectively. The structure of the dipeptide Boc-Aib-b 2,2 Ac 6 c-OMe does not reveal any intramolecular H-bond. The aggregation pattern in the crystal provides an example of an extended conformation of the b 2,2 Ac 6 c residue, forming a polar sheet like H-bond. The protected derivative Ac-b 2,2 Ac 6 c-NHMe (4) adopts a locally folded gauche conformation about the C b ÀC a bonds (q ¼ À 55.78). Of the seven examples of b 2,2 Ac 6 c residues reported here, six adopt gauche conformations, a feature which promotes local folding when incorporated into peptides. A comparison between the conformational properties of b 2,2 Ac 6 c and b 3,3 Ac 6 c residues, in peptides, is presented. Backbone torsional parameters of H-bonded ab/ba turns are derived from the structures presented in this study and earlier reports.