Ring conformation of cyclic octapeptide cyclo (L -Pro-Sar)4 in the crystalline state

A single-crystal X-ray diffraction analysis has been made of the structure of the cyclic octapeptide cyclo(l -Pro-Sar)₄. The material [C₃₂H₄₈O₈N₈ · (21/4) H₂O° (1/2) CH₃OH, M_r = 799.43] crystallizes in the monoclinic space group C2 with cell dimensions a = 14.544 (3), b = 11.902 (2), c = 14.064 (3), and β = 122.26 (2)° (Λ = 1.54178 Å, T = 293 K). The final R value for the 1980 observed reflections is 0.079. The ring conformation has the peptide bond sequences of cis-cis-trans-trans-cis-cis-trans-trans (Pro-Sar-Pro peptide bond linkages are cis-cis -or trans-trans). The pyrrolidine rings in the four proline residues take an envelope form in which the γ-carbon atom deviates from the plane of the remaining four atoms in the ring.     

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.     

Solvent effects on the conformation of cyclo(-D-Trp-D-Asp-Pro-D-val-Leu-) An NMR spectroscopy and molecular modeling study

The conformations of cyclo(-D-Trp-D-Asp-Pro-D-val-Leu-) in dimethyl sulfoxide-d₆ (DMSO-d₆) and water were determined using two-dimensional nuclear magnetic resonance spectroscopy and restrained molecular dynamics. Comparisons were made between conformations of the cyclic pentapeptide in both solvents. The NMR study revealed that, while the backbone remained relatively unchanged in both solvents, the side-chains adopted distinctly different orientations in DMSO-d₆ vs. H₂O. A modeling study, minus NOE constraints, produced a set of low-energy conformers possessing agreement in backbone conformation with the NMR-derived structures; however, lowest-energy conformers did not have this agreement. These results show that different solvents can significantly affect the preferred side-chain conformation of small cyclic peptides in solution. This finding will impact the selection of solvent when determining structures for use as templates in rational drug design.     

Cyclo(l-propyl-l-N-methylphenylalanyl) Conformation in solution and in the crystal

Detailed analysis of the proton and carbon-13 NMR spectra of cyclo(l -prolyl-l -N-methylphenylalanyl) in chloroform and methanol in relation to its nonmethylated analog provided information on the conformation of the title compound in solution as well as on the effect of N-methylation and solvation. The N-ray structure of the title compound in the crystalline state showed the same conformational features as the solution structure. The phenyl group folds over the diketopiperazine ring which resembles a flattened half-chair. Both amide bonds are considerably nonplanar. The pyrrolidine ring of proline shows a strong pucker at the ring junction with the largest χ5 value hitherto observed.     

Crystal structure and conformation of the cyclic tetramer of a repeat tripeptide of elastin,cyclo(l-valyl-l-prolylglycyl)4

X-ray diffraction data were used to determine the crystal structure of cyclo-(l -Val-l -Pro-Gly)₄, the cyclic tetramer of a repeat tripeptide of elastin. The crystals are monoclinic, space group C2, with a = 29.639(3), b = 7.099(1), c = 20.325 (2) Å, and β = 130.4(4)°. The structure was solved by direct methods and refined by least squares to R = 0.082 for 2603 observed reflections. The cyclic dodecapeptide contains two β(II) turns. Hydrophilic and hydrophobic channels that run parallel to the b axis are formed by the stacking of cyclic peptides on twofold axes.     

Conformation and complexation with metal ions of cyclic hexapeptides: cyclo (l-Leu-l-Phe-l-Pro)2 and cyclo (l-Cys(Acm)-l-Phe-l-Pro]2

Cyclic hexapeptides, cyclo (l -Leu-l -Phe-l -Pro)₂ and cyclo[l -Cys(Acm)-l -Phe-l -Pro]₂, in which Acm represents an acetoamide-methyl group, were synthesized, and the conformation and complexation with metal ions were investigated. Cooperation of the carbonyl groups of the Cys(Acm) side chains with those of the cyclic skeleton in complexation was especially examined. Cyclo(l -Leu-l -Phe-l -Pro)₂, which possesses no functional groups on side chains, was taken as the reference compound. ¹³C- and two-dimensional n.m.r. measurements revealed that cyclo(l -Leu-l -Phe-l -Pro)₂ and cyclo[l -Cys(Acm)-l -Phe-l -Pro]₂ took a C₂-symmetric conformation contaIntng cisl -Phe-l -Pro bonds in chloroform and acetonitrile. Both cyclic hexapeptides were found to complex selectively with Ba²⁺ and Ca²⁺ in acetonitrile. On complexation the conformation of either cyclic hexapeptide changed into a similar one. However, the binding constant of cyclo[l -Cys(Acm)-l -Phe-l -Pro]₂ was higher than that of cyclo(l -Leu-l -Phe-l -Pro)₂. The n.m.r. measurements showed that the amide carbonyl groups of Cys(Acm) side chains as well as those of cyclic skeleton in cyclo[l -Cys(Acm)-l -Phe-l -Pro], cooperatively bound the cations.     

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.     

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.     

Crystal and molecular structure of cyclo(L-prolyl-glycyl)3

The crystal structure of cyclo(L-Pro-Gly)₃ was solved using X-ray crystallographic techniques. The backbone of the peptide is asymmetric and is made up of five trans peptide units and one cis peptide. There is a hydrogen bonded water bridge that links the carbonyl oxygens, O1 and O4. The molecules exist as dimers in the crystal lattice. The two molecules of the dimer are related by crystallographic twofold symmetry and are linked by two N-H O hydrogen bonds. The crystals are trigonal, space group P3₂12 with a = 11.379(3), c = 32.93(1) and z = 6. The structure was solved by multisolution methods and refined by least squares technique to an R of 0.083.     

Multiple conformational equilibria of cyclic octapeptide,cyclo (L-Pro-Sar)4 in solution

Cyclo (l -Pro-Sar)₄ is asynthetic cyclic octapeptide composed of only N -substituted amino acids. The conformation of this peptide in different solvents was examined by ¹H-and ¹³C-n.m.r. spectroscopy, ¹H-n.m.r. data of this cyclic peptide demonstrated that multiple conformational equilibria take place in solution and they vary with solvent polarity. Three conformers are interconverting with each other in the nonpolar chloroform (CDCl₃); one C₄-symmetric conformer (49%) and two C₂-symmetric conformers (37% and 14%). While three C₂-symmetric (59%, 19%, and 18%) and one asymmetric conformer (4%) are detected to coexist in acetonitrile (CD₃CN), one largely populated C₂-symmetric one (97%) is favored in the polar dimethyl sulfoxide (Me₂SO-d ₆). N.m.r. measurement employing various strategy predicted the occurrence of trans-cis-cis-cis-trans-cis-cis-cis (two Sar-Pro bonds: trans) (tccctccc) peptide bond sequence in a predominant C₂-symmetric conformer of Me₂SO-d ₆ solution. In the same way, tccctccc and ctttcttt (two Sar-Pro bonds: cis) peptide unit arrangement was proposed for the first and the secondly populated conformer in CD₃CN, respectively. In CDCl₃ a conformer having tctctctc (four Sar-Pro bonds: trans) C₄-symmetric peptide bond sequence was deduced.     

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.     

NMR and X-ray crystallographic studies on cyclic tetrapeptide,cyclo (D-Phe-Pro-Sar-Gly)

The conformation of the synthetic cyclic tetrapeptide cyclo (D-Phe-Pro-Sar-Gly) has been determined in solution using the nuclear magnetic resonance technique and in the crystal state by X-ray crystallography. Results showed that the peptide exhibited two different conformations in solution, conformer 1 having cis-trans-cis-trans peptide bonds and conformer 2 having trans-cis-trans-cis peptide bonds. No intramolecular hydrogen bonds were observed in the structures. The X-ray diffraction studies showed the crystals to be orthorhombic with space group P2₁2₁2₁ with unit-cell dimensions, a = 5.790, b= 10.344, c = 31.446 Å, Z=4, R= 0.104 for 2301 observed reflections. The crystal structure showed only one type of conformer having cis-trans-cis-trans peptide bonds similar to the conformer 1 in solution. © Munksgaard 1996.     

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.     

Synthesis and conformational study of a cyclic hexapeptide analogue of somatostatin: cyclo(Phe-D-Trp-Lys-Thr-o-AMPA)

The active sequence Phe⁷-D-Trp⁸-Lys⁹-Thr¹⁰ of somatostatin has been cyclized through o-(aminomethyl)phenylacetic acid, a spacer molecule, designed to mimic a Gly-Gly dipeptide containing a cis-constrained peptide bond. The resulting analogue shows no GH-inhibition. A 2D n.m.r. study reveals conformations different from the proposed bio-active one and still sensitive to the medium (solvent).     

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 peptides involving prolyl residue

The dipeptide, L-prolyl-L-leucine monohydrate (C₁₁ H₂₀ N₂ O₃· H₂O, molecular weight, 246.3) crystallizes in the monoclinic space group P2_1/, with cell constants: a = 6.492(2)Å b = 5.417(8)Å c = 20.491(5)Å, β= 96.59(2)°, Z = 2, Do = 1.15g/cm³, and Dc = 1.142g/cm³. The structure was solved by SHELX-86 and refined by full matrix least squares methods to a final R-factor of 0.081 for 660 unique reflections (I > 2σ (I)) measured on an Enraf Nonius CAD-4 diffractometer (CuK_x, λ= 1.5418 4AR, T = 293 K). The peptide linkage exists in the trans conformation. The pyrrolidine ring exists in the envelope conformation. The values of the sidechain torsion angles are: ψ₁= -59.3(13)°, ψ₂₁= -63.1(16)° and ψ₂₂= 174.8(15)° for leucine (C-terminal). The crystal structure is stabilised by a three-dimensional network of N—H… O, O—H… O, and C—H…O hydrogen bonds.     

Conformational stability of antamanide and analogs Crystal structure of perhydrosymmetric antamanide,cyclic (-Val-Pro-Pro-Cha-Cha-Val-Pro-Pro-Cha-cha-)

The synthetic perhydrogenated symmetric analog of the cyclic decapeptide antamanide is biologically inactive, although the conformation of the molecule and the crystal packing are very similar to that of the active symmetric analog of antamanide. In fact, the same conformation for the molecule has now been found in six polymorphs of uncomplexed antamanide and its analogs. The differences between the active and inactive antamanide analogs are displayed dramatically in the conformations of their metal ion (Na⁺ or Li⁺) complexes, thus suggesting strongly that for physiological activity antamanide is not in the conformation assumed by the uncomplexed molecule, but rather in the conformation assumed by the complexed state of natural antamanide. The present structure crystallizes in space group P2₁2₁2₁ with a = 20.515(14) Å, b = 21.316(16) Å, c = 17.128(16) Å and four peptide molecules in the unit cell. There are three cocrystallized water molecules at full occupancy intrinsic to the peptide, and several more water molecules or other solvent molecules at partial occupancy. The formula of the peptide is C₆₆ H₁₀₆ N₁₀O₁₀· 4-H₂O·2X.     

Structure and solution conformation of the cytostatic cyclic tetrapeptide WF-3161, cyclo[L-leucyl-L-pipecolyl-L-(2-amino-8-oxo-9, 10-epoxydecanoyl)-D-phenylalanyl]

The sequence and configuration of amino acids in the cytostatic cyclic tetrapeptide WF-3161 are established as cyclo(L-Leu-L-Pip-L-Aoe-D-Phe) where Pip = pipecolic acid and Aoe = 2-amino-8-oxo-9,10-epoxydecanoic acid. In chloroform, WF-3161 adopts a conformation with a possible gamma-turn between Leu NH and Aoe C = O and a cis amide bond between Leu and Pip. The torsion angles for this conformation are L-Aoe, phi, -95 degrees, psi, +85 degrees, omega, -155 degrees; D-Phe, phi, +120 degrees, psi, -80 degrees, omega, -175 degrees; L-Leu, phi, -145 degrees, psi, +35 degrees, omega, -10 degrees; L-Pip, phi, +20 degrees, psi, -135 degrees, omega, -170 degrees. The cis,trans,trans,trans amide bond sequence is related to the dimethyl sulfoxide conformation of chlamydocin, another cytostatic cyclic tetrapeptide.