Design of a peptide hairpin containing a central three-residue loop

The construction of a designed β-hairpin structure, containing a central three-residue loop has been successfully achieved in the synthetic nonapeptide Boc-Leu-Phe-Val-DPro-LPro-DAla-Leu-Phe-Val-OMe (2). The design is based on expanding the two-residue loop established in the peptide β-hairpin Boc-Leu-Phe-Val-DPro-LPro-Leu-Phe-Val-OMe (1). Characterization of the registered β-hairpins in peptides 1 and 2 is based on the observation of key nuclear Overhauser effects (NOEs) in CDCl3 and CD3OH. Solvent titration and temperature dependence of NH chemical shifts establish the identity of NH groups involved in interstrand hydrogen bonding. In peptide 2, the antiparallel registry is maintained, with the formation of a DPro-LPro-DAla loop, stabilized by a 5→1 hydrogen bond between Val3 CO and Leu7 NH groups (C13, β-turn) and a 3→1 hydrogen bond between dPro4 CO and DAla6 NH groups (C7, γ-turn). NMR derived structures suggest that in peptide 2, DAla(6) adopts an αL conformation. In peptide 1, the DPro-LPro segment adopts a type II' β-turn. Replacement of DAla (6) in peptide 2 by lAla in peptide 3 yields a β-hairpin conformation, with a central DPro-LPro two-residue loop. Strand slippage at the C-terminus results in altered registry of the antiparallel strands

NMR analysis of aromatic interactions in designed peptide β-hairpins

Designed octapeptide β-hairpins containing a central DPro-Gly segment have been used as a scaffold to place the aromatic residues Tyr and Trp at various positions on the antiparallel β-strands. Using a set of five peptide hairpins, aromatic interactions have been probed across antiparallel β-sheets, in the non-hydrogen bonding position (Ac-L-Y-V-DP-G-L-Y/W-V-OMe: peptides 1 and 2), diagonally across the strands (Boc-Y/W-L-V-DP-G-W-L-V-OMe: peptides 3 and 6), and along the strands at positions i and i + 2 (Boc-L-L-V-DP-G-Y-L-W-OMe: peptide 4). Two peptides served as controls (Boc-L-L-V-DP-G-Y-W-V-OMe: peptide 5; Boc-L-Y-V-DP-G-L-L-V-OMe: peptide 7) for aromatic interactions. All studies have been carried out using solution NMR methods in CDCl3 + 10% DMSO-d6 and have been additionally examined in CD3OH for peptides 1 and 2. Inter-ring proton-proton nuclear Overhauser effects (NOEs) and upfield shifted aromatic proton resonances have provided firm evidence for specific aromatic interactions. Calculated NMR structures for peptides 1 and 2, containing aromatic pairs at facing non-hydrogen bonded positions, revealed that T-shaped arrangements of the interacting pairs of rings are favored, with ring current effects leading to extremely upfield chemical shifts and temperature dependences for specific aromatic protons. Anomalous far-UV CD spectra appeared to be a characteristic feature in peptides where the two aromatic residues are spatially proximal. The observation of the close approach of aromatic rings in organic solvents suggests that interactions of an electrostatic nature may be favored. This situation may be compared to the case of aqueous solutions, where clustering of aromatic residues is driven by solvophobic (hydrophobic) forces

Design of a Peptide Hairpin Containing a Central Three-Residue Loop

The construction of a designed $\beta$-hairpin structure, containing a central three-residue loop has been successfully achieved in the synthetic nonapeptide $Boc-Leu-Phe-Val-^DPro-^LPro-^DAla-Leu-Phe-Val-OMe$ (2). The design is based on expanding the two-residue loop established in the peptide $\beta$-hairpin $Boc-Leu-Phe-Val-^DPro-^LPro-Leu-Phe-Val-OMe$ (1). Characterization of the registered $\beta$-hairpins in peptides 1 and 2 is based on the observation of key nuclear Overhauser effects (NOEs) in $CDCl_3$ and $CD_3OH$. Solvent titration and temperature dependence of NH chemical shifts establish the identity of NH groups involved in interstrand hydrogen bonding. In peptide 2, the antiparallel registry is maintained, with the formation of a $^DPro-^LPro-^DAla$ loop, stabilized by a $5\rightarrow1$ hydrogen bond between Val3 CO and Leu7 NH groups $(C_{13}, \alpha-turn)$ and a $3\rightarrow1$ hydrogen bond between $^DPro4$ CO and $^DAla6$ NH groups $(C_7, \gamma-turn)$. NMR derived structures suggest that in peptide 2, $^DAla(6)$ adopts an $\alpha_L$ conformation. In peptide 1, the $^DPro-^LPro$ segment adopts a type II' $\beta$-turn. Replacement of $^DAla (6)$ in peptide 2 by $^LAla$ in peptide 3 yields a $\beta$-hairpin conformation, with a central $^DPro-^LPro$ two-residue loop. Strand slippage at the C-terminus results in altered registry of the antiparallel strands

Synthesis of 2-deoxy cyclic and linear oligosaccharides by oligomerization of monomers

Cyclic and linear oligosaccharides constituted with 2-deoxy sugar units are synthesized by an oligomerization reaction involving activated thioglycoside monomers, consisting of a 2-deoxy sugar unit. The oligomerization promoter plays an important role in the formation of either the cyclic- or the linear oligosaccharides. Encapsulation abilities of a 2-deoxy cyclic hexamer with p-nitrophenot, by a H-1 NMR method, showed complexation of the guest molecule with the host molecule

Stabilizing effect of electrostatic vs. aromatic interactions in diproline nucleated peptide beta-hairpins

The contribution of Tyr-His vs. Cys-His interacting pairs to the scaffold stability of (D)Pro-(L)Pro nucleated peptide beta-hairpins has been examined. We present direct evidence for the superiority of the Cys-His pairs, mediated by sulphur-imidazole interactions, as added stabilizing agents of the beta-hairpin scaffold

C12-Helix development in ()n sequences - spectroscopic characterization of Boc-Aib-4(R)Val]-OMe oligomers

The solution conformations of the -hybrid oligopeptides Boc-Aib-4(R)Val]n-OMe (n = 1-8) in organic solvents have been probed by NMR, IR, and CD spectroscopic methods. In the solid state, this peptide series favors C12-helical conformations, which are backbone-expanded analogues of 310 helices in -peptide sequences. NMR studies of the six- (n = 3) and 16-residue (n = 8) peptides reveal that only two NH protons attached the N-terminus residues Aib(1) and 4(R)Val(2) are solvent-exposed. Sequential NiH-Ni+1H NOEs characteristic of local helical conformations are also observed at the residues. IR studies establish that chain extension leads to a large enhancement in the intensities of the hydrogen-bonded NH stretching bands (3343-3280 cm-1), which suggest elongation of intramolecularly hydrogen-bonded structures. The development of C12-helical structures upon lengthening of the sequence is supported by the NMR and IR observations. The CD spectra of the ()n peptides reveal a negative maximum at ca. 206 nm and a positive maximum at ca. 192 nm, spectral feature that are distinct from those of 310 helices in -peptides

Conformational properties and aggregation of homo-oligomeric beta(3)(R)-valine peptides in organic solvents

The conformational characteristics of protected homo-oligomeric Boc-beta(3)(R) Val](n)-OMe, n = 1, 2, 3, 4, 6, 9, and 12 have been investigated in organic solvents using nuclear magnetic resonance (NMR), Fourier transform infrared (FTIR) absorption spectroscopy and circular dichroism (CD) methods. The detailed H-1 NMR analysis of Boc-beta(3)(R)Val](12)-OMe reveals that the peptide aggregates extensively in CDCl3, but is disaggregated in 20%, (v/v) dimethyl sulfoxide (DMSO) in CDCl3 and in CD3OH. Limited assignment of the N-terminus NH groups, together with solvent dependence of NH chemical shifts and temperature coefficients provides evidence for 14-helix conformation in the 12-residue peptide. FTIR analysis in CHCl3 establishes that the onset of folding and aggregation, as evidenced by NH stretching bands at 3375 cm(-1) (intramolecular) and 3285 cm(-1) (intermolecular), begins at the level of the tetrapeptide. The observed CD bands, 214 nm (negative) and 198 nm (positive), support 14-helix formation in the 9 and 12 residue sequences. The folding and aggregation tendencies of homo-oligomeric alpha-, beta-, and gamma-residues is compared in the model peptides Boc-omega Val] omega-NHMe, omega = alpha, beta, and gamma and n = 1, 2, and 3. Analysis of the FTIR spectra in CHCl3, establish that the tendency to aggregate at the di and tripeptide level follows the order beta > alpha similar to gamma, while the tendency to fold follows the order gamma > beta > alpha

C11/C9 Helical Folding in ab Hybrid Peptides Containing 1-Aminocyclohexane acetic acid (b3,3-Ac6c)

The present study describes the solid-state conformation of ab hybrid peptides, Boc-Leu-b3,3-Ac6c-OH, P1; Boc-Leu-b3,3-Ac6c-Leu-b3,3-Ac6c-OMe, P2; and Boc-Leub 3,3-Ac6c-Leu-b3,3-Ac6c-Leu-OMe, P3. The dipeptide P1 adopts extended conformations, whereas tetrapeptide P2 and pentapeptide P3 favor a helical conformation stabilized by mixed types of C11/C9 intramolecular hydrogen bonds. In peptide P3, the amino group of b3,3-Ac6c(2) and b3,3-Ac6c(4) residues occupies axial orientation, whereas in P2 it occupies axial and equatorial orientations for residues b3,3-Ac6c(2) and b3,3-Ac6c(4), respectively. The self-assembly of P3 forms channels filled with solvent molecules that present interesting patterns