Peptide hairpins with strand segments containing α- and β-amino acid residues: Cross-strand aromatic interactions of facing Phe residues

The incporation of β-amino acid residues into the strand segments of designed β-hairpin leads to the formation of polar sheets, since in the case of β-peptide strands, all adjacent carbonyl groups point in one direction and the amide groups orient in the opposite direction. The conformational analysis of two designed peptide hairpins composed of α/β-hybrid segments are described: Boc-βLeu-βPhe-Val-D-Pro-Gly-βLeu-βPhe-Val-OMe (1) and Boc-βLeu-Phe-βVal-D-Pro-Gly-βLeu-Phe-βVal-OMe (2). A 500-MHz 1H-NMR (nuclear magnetic resonance) analysis in methanol supports a significant population of hairpin conformations in both peptides. Diagnostic nuclear Overhauser effects (NOEs) are observed in both cases. X-ray diffraction studies on single crystals of peptide 1 reveal a β-hairpin conformation in both the molecules, which constitute the crystallographic asymmetric unit. Three cross-strand hydrogen bonds and a nucleating type II′ β-turn at the D-Pro-Gly segment are observed in the two independent molecules. In peptide 1, the Phe residues at positions 2 and 7 occur at the nonhydrogen-bonding position, with the benzyl side chains pointing on opposite faces of the β-sheet. The observed aromatic centroid-to-centroid distances are 8.92 Å (molecule A) and 8.94 Å (molecule B). In peptide 2, the aromatic rings must occupy facing positions in antiparallel strands, in the NMR-derived structure. Peptide 1 yields a normal hairpin-like CD spectrum in methanol with a minimum at 224 nm. The CD spectrum of peptide 2 reveals a negative band at 234 nm and a positive band at 221 nm, suggestive of an exciton split doublet. Modeling of the facing Phe side chains at the hydrogen-bonding position of a canonical β-hairpin suggests that interring separation is 4.78 Å for the gauche+gauche- (g+g-) rotamer. A previously reported peptide β-hairpin composed of only α-amino acids, Boc-Leu-Phe-Val-D-Pro-Gly-Leu-Phe-Val-OMe also exhibited an anomalous far-UV (ultraviolet) CD (circular dichroism) spectrum, which was interpreted in terms of interactions between facing aromatic chromophores, Phe 2 and Phe

Proteolytic stability of β-peptide bonds probed using quenched fluorescent substrates incorporating a hemoglobin cleavage site

AbstractA set of designed internally quenched fluorescence peptide substrates has been used to probe the effects of insertion of β-peptide bonds into peptide sequences. The test sequence chosen corresponds to a proteolytically susceptible site in hemoglobin α-chain, residues 32–37. Fluorescence and mass spectral measurements demonstrate that the insertion of an β-residues at the potential cleavage sites completely abolishes the action of proteases; in addition, the rate of cleavage of the peptide bond preceding the site of modification is also considerably reduced

Convenient and simple homologation of Nα-​urethane protected α-​amino acids to their β-​homologues with concomitant o-​nitrophenyl esters formation

The Wolff rearrangement of α-​aminodiazoketones derived from Nα-​urethane protected α-​amino acids in presence of o-​nitrophenol catalyzed by silver acetate at low temp. is described. Reactants included [3-​diazo-​2-​oxo-​1-​(phenylmethyl)​propyl]​carbamic acid 1,​1-​dimethylethyl ester, [3-​diazo-​2-​oxo-​1-​[(phenylmethoxy)​methyl]​propyl]​carbamic acid 1,​1-​dimethylethyl ester, and [3-​diazo-​1-​methyl-​2-​oxopropyl]​carbamic acid 9H-​fluoren-​9-​ylmethyl ester, etc. The potential utility of the well-​known ketene intermediate is exploited for the synthesis of cryst., optically pure β-​amino acid active esters. Thus the homologation of Boc-​/Z-​/Fmoc-​α-​amino acids to β-​amino acids with concomitant formation of the corresponding o-​nitrophenyl esters has been achieved by this method. All the β-​amino acid active esters have been obtained in good yield and purity and fully characterized by IR and NMR spectra

Hybrid Peptides: Direct Transformation of α/α, β-Unsaturated γ-Hybrid Peptides to α/γ-Hybrid Peptide 12-Helices

A smooth transformation of unusual planar structures of α/vinylogous hybrid peptides to ordered α/γ⁴-hybrid peptide 12-helices and the stereochemical preferences of vinylogous amino acid residues in single crystals are studied

Crystal structure of a hydrophobic 19-residue peptide helix containing three centrally located d amino acids

The design of the synthetic 19-residue peptide Boc-Leu-Aib-Val-Ala-Leu(5)-Aib-Val-d-Ala-d-Leu-Leu(10)-Val-Phe-Val-Aib-d-Val(15)-Leu-Phe-Val-Val-OMe (Aib, α-aminoisobutyric acid; OMe, methyl ester) was intended to produce a crystalline peptide with independent helical and hairpin domains. The design was partially based on an octapeptide with the same sequence as residues 11–18 above, which was shown to fold into a β-hairpin in the crystal. However, the crystal structure of the present peptide provided a surprising result. The conformation is the longest characterized right-handed α-helix, with as many as three internal d residues in the sequence. The completely helical structure was also unexpected, because β-branched residues such as Val have a low propensity for helix formation in proteins. The helical peptides in the present structure assemble to form hydrophobic channels that accommodate five toluene molecules per peptide along the length of the channel. The structural results illustrate the similarity in energetics between helical and β-hairpin conformations for peptides containing Aib residues. The crystallographic parameters for C(107)H(179)N(19)O(22)·3H(2)O·2.5 toluenes are: space group C2, a = 34.679(3) Å, b = 12.866(1) Å, c = 31.915(3) Å, β = 96.511(8)°, V = 14,148 Å(3), Z = 4, d(calc) = 1.099 g/cm(3), and agreement factor R(1) = 10.2%

Infinite pleated beta-sheet formed by the beta-hairpin Boc-beta-Phe-beta-Phe-D-Pro-Gly-beta-Phe-beta-Phe-OMe

A beta-hairpin conformation and extended beta-pleated sheet assembly have been characterized by single crystal x-ray diffraction for the synthetic peptide t-butoxycarbonyl-beta-Phe-beta-Phe-D-Pro-Gly-b-Phe-b-Phe-methyl ester [b-Phe: (S)-b3 homophenylalanine]. The centrally located D-Pro-Gly segment nucleates a chain reversal in a type II’ beta-turn conformation. Two intramolecular cross-strand hydrogen bonds stabilize the peptide fold. Intermolecular NH…O=C hydrogen bonds (two on each side of the hairpin) connect the hairpins into an infinitely extended beta-sheet. The beta-residues cause all CAOgroups to point in the same direction, resulting in a ‘‘polar’’ sheet by the unidirectional alignment of NH…O=C hydrogen bonds. In contrast, beta-sheets formed by beta-residues have alternating directions for the hydrogen bonds, thus resulting in an ‘‘apolar’’ sheet. The crystallographic parameters for C53H66N6O9.CH3OH are: space group P21, a = 9.854(2) Å, b = 10.643(2) Å, c = 25.296(4) Å, beta = 100.39(2)°, Z = 2, agreement factor R1 _ 0.065 for 3,706 data observed >4_(F) and a resolution of 0.90 Å

γ- and β‑Peptide Foldamers from Common Multifaceted Building Blocks: Synthesis and Structural Characterization

Structural characterization of 3,4-disubstituted γ-peptide and 2,3-disubstituted β-peptide foldamers derived from common multifaceted β-nitromethyl γ-amino acids and the chemical transformation of the β-nitromethyl group in γ-peptides into various functional derivatives are reported. The γ^3,4-oligomers and α,γ-hybrid peptides showed characteristic C₁₄-and C₁₂-helical conformations in single crystals. Further, the new 2,3-disubstituted acyclic β-peptide showed the C₆-helical conformation despite the poor geometry of H-bonds

Peptide hybrids containing alpha- and beta-amino acids: Structure of a decapeptide beta-hairpin with two facing beta-phenylalanine residues

A beta-hairpin conformation has been characterized in crystals of the decapeptide t-butoxycarbonyl-Leu-Val-betaPhe-Val-DPro-Gly-Leub Phe-Val-Val-methyl ester [bPhe; (S)-b3 homophenylalanine] by x-ray diffraction. The polypeptide chain reversal is nucleated by the centrally positioned DPro-Gly segment, which adopts a type-I’ beta-turn conformation. Four intramolecular cross-strand hydrogen bonds stabilize the peptide fold. The betaPhe(3) and betaPhe(8) residues occupy facing positions on the hairpin, with the side chains projecting on opposite faces of the beta-sheet. At the site of insertion of beta- residues, the polarity of the peptide units along each strand reverses, as compared with the alpha-peptide segments. In this analog, a small segment of a polar sheet is observed, where adjacent CO and NH groups line up in opposite directions in each strand. In the crystal, an extended beta-sheet is formed by hydrogen bonding between strands of antiparallel pairs of beta-hairpins. The crystallographic parameters for C65H102N10O13z 3H2O are: space group P212121; a 5 19.059(8) Å, b 5 19.470(2) Å, c 5 21.077(2) Å; Z 5 4; agreement factor R1 5 9.12% for 3,984 data observed >4s(F) and a resolution of 0.90 Å

Convenient and simple homologation of N^α-urethane protected α-amino acids to their β-homologues with concomitant <i>o</i>-nitrophenylesters formation

790-795The Wolff rearrangement of α-aminodiazoketones derived from Nα-urethane protected α-amino acids in presence of o-nitrophenol catalyzed by silver acetate at low temperature is described. The potential utility of the well-known ketene intermediate is exploited for the synthesis of crystalline, optically pure β-amino acid active esters. Thus the homologation of Boc-/Z-/Fmoc-α-amino acids to β-amino acids with concomitant formation of the corresponding o-nitrophenyl esters has been achieved by this method. All the β-amino acid active esters have been obtained in good yield and purity and fully characterized by IR and NMR spectra. &nbsp