Structure and conformation of peptides involving prolyl residue III. L-Prolyl-L-isoleucine monohydrate

The dipeptide, L-prolyl-L-isoleucine monohydrate (C₁₁ H₂₀N₂O₃· H₂O, molecular weight 246.3) crystallizes in the monoclinic space group P2₁, with a = 6.601(3)Å, b = 5.413(3) Å, c = 19.128(6) Å, β= 98.1(1)°, Z = 2, Do = 1.20g·cm^-3 and Dc = 1.208g·cm^-3. The structure was solved by MULTAN–80 and refined to a final R-factor of 0.081 for 594 reflections measured on a Enraf Nonius CAD-4 diffractometer. The peptide linkage exists in the trans conformation. The pyrrolidine ring is disordered with two alternate envelope conformations for the C^γ atom. The values of the sidechain torsion angles are: χ₁₁=– 63.6(17)°, χ₁₂= 171.1(16)° and χ₂=– 59.6(21)° for isoleucine (C-terminal). The crystal structure is stabilized by a three-dimensional network of N—H ? O, O—H ? O and C—H ? O hydrogen bonds. The dipeptide exists in the extended Conformation.     

Structure and conformation of linear peptides

L-tyrosyl-L-tyrosine crystallizes as a dihydrate in the orthorhombic system, space group C222₁, with a = 12.105(2), b = 12.789(2), c = 24.492(3) Å, Z = 8. The structure was solved by direct methods and refined to a final R-value of 0.059 for 1740 observed reflections. The molecule exists as a zwitterion, the peptide unit is trans planar, and the backbone torsion angles correspond to an extended conformation, with e₁ = 149.4°, e₂ = - 161.2°, e₂ = 158.3°. The values of the side-chain torsion angles (χ₁, χ₂) are (- 58.8°, - 63.1°) for the first tyrosine and (- 171.7°, - 116.5°) for the second. The planes of the aromatic rings are nearly parallel (dihedral angle of 6.1°), and their centers are separated by 10.9 Å. The carboxyl plane forms a dihedral angle of 23.8° with the plane of the peptide bond.     

Structure and conformation of linear peptides. IX. Structure of l-tyrosyl-l-phenylalanine

The dipeptide, l -tyrosyl-l -phenylalanine (C₁₈H₂₀N₂O₄, molecular weight = 346) crystallizes as a monohydrate in the orthorhombic system, space group P2₁2₁2₁ with a = 5.744(2), b = 8.284(2), c = 35.518(6)Å, Z = 4. The structure was solved by direct methods and refined to a final R-index of 0.060. The peptide unit is trans and planar, and makes a dihedral angle of 93° with the plane of the carboxyl group. The backbone torsion angles are given by: ø₁ = 164.7°, ω₁ = 177.0°, φ₂ = – 70.1°, ø₂ = 146.6°. The values of the side-chain torsion angles (χ₁, χ₂) are (47.3°, 79.9°) for tyrosine and (– 75.1°, 75.9°) for phenylalanine. The planes of the two (side-chain) aromatic rings make a dihedral angle of 142.6° and their centres are separated by 9.3 Å.     

Structure and conformation of linear peptides

The crystal structure of a dipeptide tert-butyloxycarbonyl-l -alanylglycine monohydrate (C₁₀H₁₈N₂O₅·H₂O), molecular weight 264, has been determined. The crystals are monoclinic, space group P2₁, with a= 10.767(1), b= 6.317(1), c= 10.981(2) Å, β= 109.15(2)°, and Z= 2, D_c= 1.24 g cm^?3. The structure was solved by direct methods and refined to 3 final R-index of 0.045 for 856 reflections (sin θ/λ < 0.55 Å^?1) with I > 2 σ. The N-terminus of the molecule blocked with the t-Boc group is uncharged and the C-terminus exists in an unionized state. The peptide unit is trans and shows slight deviations from planarity. (Δω= 3.1°). The peptide backbone is folded, with torsion angles of φ₁= -76.0(5), ψ₁= 164.3(4), ω₁= 176.9(5), φ₂= 116.1(5), ψ₂₁= - 2.8(7) and ψ₂₂= 177.8(4)°. The conformation about the urethane bond (C5–N1) is trans. The urethane group is essentially planar. The conformation of the boc group is trans–trans.     

Structure and conformation of linear peptides

The crystal structure of t-Boc-glycyl-L-phenylalanine (C₁₄H₂₂N₂O₅, molecular weight = 298) has been determined. Crystals are monoclinic, space group P2₁, with a = 7.599(1)Å, b = 9.576(2), c = 12.841(2), β = 97.21(1)°, Z = 2, D_m = 1.149, D° = 1.168 g · cm^-3. Trial structure was obtained by direct methods and refined to a final R-index of 0.064 for 1465 reflections with I> 1s?. The peptide unit is trans planar and is nearly perpendicular to the plane containing the urethane moiety. The plane of the carboxyl group makes a dihedral angle of 16.0° with the peptide unit. The backbone torison angles are ω₀ = - 176.9°, ø₁ = - 88.0°, ψ₁ = - 14.5°, ω1 = 176.4°, ø₂ = - 164.7° and ψ2 = 170.3°. The phenylalanine side chain conformation is represented by the torsion angles χ₁ = 52.0°, χ₂ = 85.8°.     

Structure and conformation of linear peptides

The dipeptide, (DL)-alanyl-(DL)-norvaline, crystallizes in the monoclinic space group P2₁/c, with a = 12.559(2)A, b = 5.265(1), c = 16.003(3), β = 103.53(2)°, Z = 4. The structure was solved by direct methods and refined to an R-value of 0.054 for 871 reflections with I > 2. The molecule exists as a zwitterion in the crystal. The peptide unit is trans and shows significant deviations from planarity (Δω = 12.4°). The peptide backbone adopts an extended conformation. The unit cell contains D-Ala-L-norval and its enantiomer. The molecular conformation and packing features show a striking resemblance to those for D-Ala-L-Met (1), and leads to the speculation that norvaline might act as an analog of methionine.     

Structure and conformation of linear peptides

The tripeptide, L-prolyl-glycyl-glycine, crystallizes in the trigonal space group P3₂, with a = b = 8.682(2)Å, c= 12.008(2) and Z = 3. The structure was solved by direct methods and refined to an R-value of 0.07 for 727 reflections (I > 1.0s?). The molecule exists as a zwitterion in the crystal. The peptide units and trans and show significant deviations from planarity (ω₁ = 169.7^o, ω₂=-170.1^o). The peptide backbone adopts a left-handed helical conformation similar to that of polyglycine II and polyproline II.     

Structure and conformation of linear peptides

The tripeptide, glycyl-glycyl-L-isoleucine, crystallizes as a monohydrate in the monoclinic space group P2₁, with a = 12.746(2), b = 6.172(1), c = 8.643(1) Å, β = 99.77(2)°, and Z = 2. The structure was solved by direct methods and refined to an R-value of 0.039 for 917 (I > 1°) reflections. The molecule exists as a zwitterion in the crystal. The peptide units are trans and show significant deviations from planarity. The plane of peptide units and of the carboxyl group are nearly mutually perpendicular to each other. The peptide backbone torsion angles are: ø₁ = - 171.2°, ω₁ = - 176.8°, ø₂ = - 106.1°, ø₂ = - 150.7°, ø₂ = - 172.1°, ø₃ = - 70.9°, ø₃ = 136.5°. For the side-chain of isoleucine, ø₁ = - 58.1°, ø₂ = 169.7° and the system of bonds C′-C^α-C^β-C γ₁^-Cδ is trans zig-zag. The packing arrangement involves spatial segregation of polar and nonpolar moieties.     

Crystal structure and conformation of l-pyroglutamyl-l-alanine

Crystals of the dipeptide, pyroglutamyl-alanine (C₈H₁₂N₂O₄) grown from aqueous methanol are monoclin-ic, space group P2₁ with the following cell parameters: a = 4.863(2), b = 16.069(1), c = 6.534(2)Å and β= 109.9(2)°, V = 480.0ų, M_r= 200.2, D_c= 1.385 g cm^?3, and Z = 2. The crystal structure was solved by the application of direct methods and refined to an R value of 0.044 for 699 reflections with I > 2σ. The amide of the pyroglutamyl side chain is cis, ω₁= 2.6(7)°; the peptide unit is trans and appreciably non-planar (ω₂= 167.4(5)°). The backbone torsional angles are: Ψ₁= 166.1(5), φ₂=?90.3(6), and Ψ₂=?22.4(6)°. This structure contains a short (2.551(5)Å) intermolecular hydrogen bond between the carboxyl OH and the N-acyl oxygen, a feature common to most acyl amino acids and acyl peptides.     

Structure and conformation of linear peptides XIII. Structure of l-phenylalanyl-glycyl-glycine

The crystal structure of a tripeptide, l -phenylalanyl-glycyl-glycine (C₁₃H₁₇,N₃O₄), molecular weight = 279.3, has been determined. The crystals are orthorhombic, space group P 2₁2₁2₁, with a= 5.462(1) A, b= 15.285(5), c= 16.056(4), Z = 4 , and P(calc) = 1.384 g. cm^-3. The final R-index is 0.052 for 866 reflections with θ/λ≤ 0.55 A^-1 and 1 > σ. The molecule exists as a zwitterion, with the N-terminus protonated and the C-terminus in an ionized form. Both the peptide units are in the trans configuration and planar, though one of them shows significant deviations from planarity (|Δ| = 5.1°). The peptide backbone is folded, with the torsion angles of ψ₁= 116.2(5)°, ψ₃₁= 178.8(4), φ₂=?89.7(5), ψ₂=?28.9(6), ω₂=?174.9(4), φ₃= 134.9(5), ψ₃₁= 7.8(6), ψ₃₂=?172.6(4). The terminal glycine adopts a “d -residue” conformation. For the sidechain of phenylalanine, χ₁= 175.5(4), χ₂= - 127.0(6).     

Structure and conformation of linear peptides

The tripeptide, glycyl-glycyl-L-valine, crystallizes as a dihydrate in the monoclinic space group P₂1, with a = 5.786(1), b = 7.954(2), c = 14.420(3)A, β= 93.85(2)d?, Z = 2. The structure was solved by direct methods and refined to an R-value of 0.040 for 876 observed reflections. The molecule exists as a zwitterion in the crystal. The peptide planes show significant deviations from planarity. The chain conformation resembles a reverse turn if the orientation of the carboxyl group is also taken into account. An intramolecular water bridge links the amino and carboxyl ends of the molecule. The crystal packing involves spatial segregation of polar and nonpolar moieties.     

Structure and conformation of linear peptides VII.

The tripeptide, L-valyl-glycyl-glycine (C₉H₁₇N₃O₄, molecular weight = 231), crystallizes in the monoclinic space group C2, with a = 24.058(3)Å, b = 4.801(1), c = 10.623(2), β = 110.02(1)° and Z = 4. The structure was determined by direct methods and refined to a final R-index of 0.043 for 830 reflections (sinθ/Λ ≤ 0.53 A^-1) with I> 1.0s?. The molecule exists as a zwitterion. The peptide units are trans and one of them shows significant deviations from planarity (Δω₂ = 9.3°). The peptide chain repeat distance, 1C^α-3Cα, is 7.23Å and the molecule displays a highly extended conformation with backbone torsion angles of ψ₁ = 123.1°, ω₁ = - 179.4°, ø₂ = - 155.1°, ψ;₂ = 154.7°, ω₂ = 170.7°, ø₃ = - 146.6° and ψ₃ = 180.0°. For the valyl side chain, χ₁₁ = - 52.5°, χ₁₂ = 174.2°. The packing involves hydrogen-bonded interactions between successive molecules related by the β-translation of the lattice, giving rise to the familiar parallel β-sheet structure which appears to be the most extended one observed to date.     

Structure and conformation of linear peptides. X. Structure of glycyl-glycyl-L-phenylalanine hydrochloride

The crystal structure of a tripeptide, glycyl-glycyl-L-phenylalanine HCl (C₁₃H₁₈N₃O₄ ± HCl, molecular weight = 316.5) has been determined. The crystals are orthorhombic, space group P2₁2₁2₁, with a = 4.877 (2) Å, b = 9.956(3), c = 32.690(5) and Z = 4. The final R-index is 0.043 for 1325 reflections (sinØ/Λ ± 0.55 Å^-1) with I > 2.0 s? (I). The N-terminal of the molecule is protonated and the C-terminal exists in an un-ionised state. The peptide units are trans and one of them shows significant deviations from planarity (¶Δω₁¶ = 11.3°). The peptide backbone is folded with torsion angles of: ø₁ = 165.5°, ω₁ = — 168.7°, ø₂ = 63.6°, ø₂ = — 153.6°, ω₂ = 176.5°, ø₃ = — 72.2° and Φ₃ = 166.5°. For the side chain of phenylalanine, X₁ = — 79.5° and X₂ = 86.8°. An intramolecular water bridge links the two ends of the molecule.     

Structure and conformation of linear peptides XII. Structure of tryptophanyl-glycyl-glycine dihydrate

The crystal structure of a tripeptide, tryptophanyl-glycyl-glycine dihydrate (C₁₅H₁₈N₄O₄·2H₂O, molecular weight = 354) has been determined. The crystals are orthorhombic, space group P2₁2₁2₁ with a= 7.875 (1) A,b= 9.009(1), c= 24.307(1) and Z = 4. The final R-index is 0.058 for 1488 reflections ((sin θ/λ≤ 0.6 A^?1) with I < 2σ(I). The molecule exists as a zwitterion, with terminal NH⁺₃ and COO^? groups. The peptide units are trans and nearly perpendicular to the plane of the carboxyl group. The backbone torsion angles are: ψ₁= 132.7°, ω₁= 174.2°, φ₂ 88.2°, ψ= 8.6°, ω₂ - 179.8°, φ= - 85.2°, ψ₃₁, = - 178.1°, ψ₃₂ 5.0°. For the sidechain of tryptophan, χ₁= - 171.6°, χ₂ 101.0°.     

Structure and conformation of peptides containing the sulphonamide junction

The insertion of the (S)-lactyl residue into the cyclodipeptide cyclo (-Tau-Pro-) 3 leads in good yields to the first example of a stable tetrahedral adduct (oxa-cyclol) 5 containing the sulphonamide junction. Compound 5 does not show a significant tendency towards tautomeric equilibria and possesses an unexpected syn-orientation involving the hydroxyl group and the Pro-H_α. The crystal structure and molecular conformation of 5 has been determined. Crystals are orthorhombic, s.g. P2₁2₁2₁, with a = 6.607, b = 12.297, c = 16.622 Å. The cisoidal conformation around the S-N bond is very similar to that found in the previously studied linear and cyclic peptides containing a sulphonamide junction. The taurine nitrogen is practically planar whereas the proline nitrogen, bound to the SO₂ group, is highly pyramidal. In the tricyclic system of 5 the seven-membered ring adopts a twist-chair conformation while the pyrrolidine and oxazolidinone rings show an envelope conformation. The crystal packing is characterized by three hydrogen bonds all formed by means of a water molecule.     

Structure and conformation of peptides containing the sulphonamide junction

N-acetyl-tauryl-l -phenylalanine methyl ester 1 has been synthesized. The crystal structure and molecular conformation of 1 have been determined. Crystals are monoclinic, space group P2₁ with a = 5.088(2), b = 17.112(17), c = 9.581(6) Å, β= 92.34(4)^M-0, Z = 2. The structure has been solved by direct methods and refined to R = 0.043 for 2279 reflections with I < 1.5σ(I). The sulphonamide junction maintains the peptide backbone folded with Tau and Phe C^α atoms in a cisoidal arrangement, the torsion angle around the S-N bond being 65.4^M-0. In this conformation the p-orbital of the sulphonamide nitrogen lies in the region of the plane bisecting the O-S-O angle, thus favouring dα-pα interactions between nitrogen and sulphur atoms. The S-N bond with a length of 1.618 Å has significant α-bond character. The CO-NH is planar and adopts trans conformation. The Tau residue is extended with the Tau-C^α₁-C^β_a bond anti-periplanar to the S-N bond. The Phe side chain conformation corresponds to the statistically most favoured g^- rotamer and exhibits a χ¹ torsion angle of –67.5^M-0. The packing is characterized by intermolecular H-bonds which the Tau and Phe NH groups form with the acetyl carbonyl and one of the two sulphonamide oxygens, respectively.     

Structure and conformation of peptides containing the sulfonamide junction II. Synthesis and conformation of cyclo[-MeTau-Phe-DPro-]

By applying the method of amino-acyl incorporation to sulfonamido peptides, cyclo(-MeTau-Phe-DPro-) 3 has been synthesized in high yield starting from Z-MeTau-Phe-Pro-OH. The crystal structure and the molecular conformation of 3 have been determined. Crystals are orthorhombic, s.g. P2₁2₁2₁, with a = 5.454, b = 13.486, c = 24.025 Å. The structure has been solved by direct methods and refined to R = 0.039 for 1974 reflections with I > 1.50 σ(I). The 10-membered cyclopeptide adopts a backbone conformation in the crystals characterized by Phe-DPro and DPro-MeTau peptide bonds in trans and cis conformation, respectively. Both the peptide bonds deviate significantly from planarity and the corresponding |δω| values are ca. 12°. The sulfonamide SO₂NH junction adopts a cisoidal conformation with a C^α₁- S₁-N₂- C₂^α torsion angle of 70.8°. ¹³C n.m.r. data show that the trans geometry at the Phe-DPro junction found in the crystals is retained in DMSO solution. The 10-membered ring of 3 is characterized by a pseudo mirror-plane passing through the Phe nitrogen and the DPrO carbonylic carbon. The DPrO ring adopts a half-chair conformation. The Phe side chain conformation corresponds to the statistically most favored g^? rotamer (χ¹= - 68.6°). The crystal packing is characterized by a weak intermolecular hydrogen bond between the NH group and the MeTau O₁’ oxygen.     

Crystal and molecular structure of L-lysyl-L-valine hydrochloride – a new lysine conformation

Thin plates of L-lysyl-L-valine hydrochloride (C₁₁H₂₄N₃O₃Cl) were obtained using the vapour diffusion technique and analysed by X-ray diffraction. The unit cell is orthorhombic, space group P2₁2₁2₁, a = 5.465(6)Å, b = 19.657(4) Å, c = 13.522(2) Å, V = 1452.6(2.1) ų and Z = 4. The structure was solved by direct methods and refined to an agreement factor of 6.7% for 939 reflections with I > 3 σ(I). The lysine side chain conformation (g^- g^- tt) has never been found in peptide crystal structures, although it has been reported to occur in proteins. A network of hydrogen bonds between peptide molecules spreads along the a and c directions while no direct bonds are observed to occur between peptides along the b axis direction. This asymmetric pattern of interactions correlates with the crystal morphology.     

Crystal structure and conformation of two N-tosyl-protected dipeptides containing amino acids with polar side-chains

X-Ray diffraction studies and energy-minimization calculations were carried out on two dipeptides, N-tosyl-l -Ser-Gly-OMe monohydrate (C₁₃H₁₈N₂O₆S·H₂O, compound A) and N-tosyl-l -Thr-Gly-OMe (C₁₄H₂₀N₂O₆, compound B). Compound A crystallized in the monoclinic system, space group P2₁ with unit cell parameters a= 4.915(1), b= 15.625(4), c= 11.003(1) Å, β= 91.28(1)°, V= 844.8 ų. M_r= 348.4, d= 1.37(2) g cm^?3, Z = 2, λ(Cu Kα) = 1.5418 Å, μ= 1.99 mm^?1, T=293 K. R= 0.032 for 1451 unique reflections with I > 2σ(I). Compound B crystallized in the orthorhombic system, space group P2₁2₁2₁, with unit cell parameters a= 5.050(2), b= 16.483(3), c= 20.769(5) Å, V= 1729.3 ų, Z = 4. M_r= 344.4, d= 1.32(2) g cm^?3, μ(Cu Kα)= 1.90 mm^?1. R= 0.040 for 1060 unique reflections with I > 2σ(I). The major difference in the backbone conformation of the two compounds is in their glycine residues, with the glycine residue in compound A adopting an extended conformation with φ= - 132.6(3)° and ψ= 175.3(3)° and that in compound B having a folded conformation with φ=?56.3(6)° and ψ=?42.6(7)°. In compound A the oxygen atom of the Ser side-chain and the carbonyl oxygen atom of glycine are bridged by the water of crystallization through O—H ··· O hydrogen bonds, resulting in the relatively rare trans conformation [χ=? 175.7(2)°] for this side-chain. The Thr side-chain in compound B is in the sterically preferred (tg^?) conformation [χ^1,1=? 179.4(4)° and χ^1,2=?62.3(5)°]. The conformations were found to be in general agreement with those obtained by an energy-minimization procedure. The energy-minimized structure of N-tosyl-l -Ser-Gly-Ome (anhydrous) showed a strong hydrophobic interaction between the methyl substituents of the tosyl group and the methyl ester (C—C = 4.08 Å).     

Crystal structure and molecular conformation of achatin-I (H-Gly-d-Phe-Ala-Asp-OH), an endogenous neuropeptide containing a d-amino acid residue

In order to investigate the active conformation of achatin-I (H-Gly-d -Phe-Ala-Asp-OH), an endogenous neuropeptide from the Achatina fulica ganglia, its crystal structure and molecular conformation were analysed by the X-ray diffraction method. Crystals from methanol/dioxane are monoclinic, space group P2₁ with a=5.083(1), b= 9.125(1), c= 20.939(3) Å, β=94.73(1)° The structure was solved by direct methods and refined to R = 0.051 for 1714 independent reflections with Fo > σ(Fo). The molecule exists as a zwitterion with the Gly N-terminal end protonated and Asp β-carboxyl deprotonated; the C-terminal of Asp is in a neutral state. The molecule takes a kind of β turn structure with the d -Phe-Ala residues at the corner of the bend. This turn conformation is primarily formed by the strong intramolecular hydrogen bonds of NH(Gly)—O^δ1 (Asp) and NH(Asp)- O^δ1(Asp) pairs, thus forming a 15-membered ring structure. Judging from the published data concerning the structure-activity relationship, this turn conformation may reflect an important feature related to the neuroexcitatory activity of achatin-I.