Structure and conformation of peptides containing the sulphonamide junction. III. Synthesis, crystal and molecular structure of a taurine containing peptidic oxa-cyclol

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 alpha. The crystal structure and molecular conformation of 5 has been determined. Crystals are orthorhombic, s.g. P2(1)2(1)2(1), with a = 6.607, b = 12.297, c = 16.622 A. 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 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. P2(1)2(1)2(1), with a = 5.454, b = 13.486, c = 24.025 A. The structure has been solved by direct methods and refined to R = 0.039 for 1974 reflections with I greater than 1.5 sigma (I). The 10-measured 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 [delta omega[ values are ca. 12 degrees. The sulfonamide SO2NH junction adopts a cisoidal conformation with a C alpha 1-S1-N2-C alpha 2 torsion angle of 70.8 degrees. 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 (chi 1 = -68.6 degrees). The crystal packing is characterized by a weak intermolecular hydrogen bond between NH group and the MeTau O1' oxygen.     

Peptides containing the sulfonamide junction. 2. Structure and conformation of Z-Tau-Pro-D-Phe-NHiPr

The taurine (Tau) containing N-protected pseudotripeptide isopropylamide Z-Tau-Pro-D-Phe-NHiPr (1) has been specifically designed and synthesized as suitable model to test the ability of the sulfonamido group to participate as H-bond acceptor to a type II beta-turn and to get information on the preferred rotameric conformation around the S-N bond and the hybridization state of the nitrogen atom. The present structural investigation reveals that, although the sulfonamide junction is invariably folded in a gauche mode, the beta-turn structure, stabilized by the 4 --> 1 hydrogen bond, is not found in the crystal and the sulfonamido oxygen atoms are not involved in any intra- or intermolecular hydrogen-bond interaction. More than one conformer populates the CDCl(3) solution with only a minor contribution by the expected beta-turn. The Pro nitrogen is significantly pyramidalized and the nitrogen lone pair points in opposite direction to that of the Pro C(alpha)H bond thus adopting R chirality, in an arrangement practically identical to that found in the previously studied homochiral analogue Z-Tau-Pro-Phe-NHiPr.     

Structure and conformation of linear peptides. I. Structure of L-tyrosyl-L-tyrosine

L-tyrosyl-L-tyrosine crystallizes as a dihydrate in the orthorhombic system, space group C222(1), with a = 12.105(2), b = 12.789(2), c = 24.492(3) A, 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 psi 1 = 149.4 degrees, phi 2 = -161.2 degrees, psi 2 = 158.3 degrees. The values of the side-chain torsion angles (chi 1, chi 2) are (-58.8 degrees, -63.1 degrees) for the first tyrosine and (-171.7 degrees, -116.5 degrees) for the second. The planes of the aromatic rings are nearly parallel (dihedral angle of 6.1 degrees), and their centers are separated by 10.9 A. The carboxyl plane forms a dihedral angle of 23.8 degrees with the plane of the peptide bond.     

Structure and conformation of linear peptides. III. Structure of glycyl-glycyl-L-valine

The tripeptide, glycyl-glycyl-L-valine, crystallizes as a dihydrate in the monoclinic space group P2(1), with a = 5.786(1), b = 7.954(2), c = 14.420(3)A, beta = 93.85(2) degrees, 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. XIII. Structure of L-phenylalanyl-glycyl-glycine

The crystal structure of a tripeptide, L-phenylalanyl-glycyl-glycine (C13H17N3O4), molecular weight = 279.3, has been determined. The crystals are orthorhombic, space group P2(1)2(1)2(1), 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 sin theta/lambda less than or equal to 0.55 A-1 and I greater than 1 sigma. 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 ([delta w[ = 5.1 degrees). The peptide backbone is folded, with the torsion angles of: psi 1 = 116.2(5) degrees, omega 1 = 178.8(4), phi 2 = -89.7(5). psi 2 = -28.9(6), omega 2 = -174.9(4), phi 3 = 134.9(5), psi 31 = 7.8(6), psi 32 = -172.6(4). The terminal glycine adopts a "D-residue" conformation. For the sidechain of phenylalanine, chi 1 = 175.5(4), chi 2 = -127.0(6).     

Structure and conformation of linear peptides. VIII. Structure of t-Boc-glycyl-L-phenylalanine

The crystal structure of t-Boc-glycyl-L-phenylalanine (C14H22N2O5, molecular weight = 298) has been determined. Crystals are monoclinic, space group P2(1), with a = 7.599(1) A, b = 9.576(2), c = 12.841(2), beta = 97.21(1) degrees, Z = 2, Dm = 1.149, Dc = 1.168 g X cm-3. Trial structure was obtained by direct methods and refined to a final R-index of 0.064 for 1465 reflections with I greater than 1 sigma. 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 degrees with the peptide unit. The backbone torsion angles are omega 0 = -176.9 degrees, phi 1 = -88.0 degrees, psi 1 = -14.5 degrees, omega 1 = 176.4 degrees, phi 2 = -164.7 degrees and psi 2 = 170.3 degrees. The phenylalanine side chain conformation is represented by the torsion angles chi 1 = 52.0 degrees, chi 2 = 85.8 degrees.     

Structure and conformation of linear peptides. V. Structure of L-prolyl-glycyl-glycine

The tripeptide, L-prolyl-glycyl-glycine, crystallizes in the trigonal space group P3(2), with a = b = 8.682(2) A, 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 greater than 1.0 sigma). The molecule exists as a zwitterion in the crystal. The peptide units are trans and show significant deviations from planarity (omega 1 = 169.7 degrees, omega 2 = -170.1 degrees). The peptide backbone adopts a left-handed helical conformation similar to that of polyglycine II and polyproline II.     

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 P2(1)2(1)2(1), 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 theta)/lambda less than or equal to 0.6 A-1) with I greater than 2 sigma (I). The molecule exists as a zwitterion, with terminal NH3+ and COO- groups. The peptide units are trans and nearly perpendicular to the plane of the carboxyl group. The backbone torsion angles are: psi 1 = 132.7 degrees, omega 1 = 174.2 degrees, phi 2 = 88.2 degrees, psi 2 = 8.6 degrees, omega 2 = -179.8 degrees, phi 3 = -85.2 degrees, psi 31 = -178.1 degrees, psi 32 = 5.0 degrees. For the sidechain of tryptophan, chi 1 = -171.6 degrees, chi 2 = 101.0 degrees.     

Type II' beta-bend conformation of tert.-butyloxycarbonyl-L-amino-succinyl-L-alanyl-glycine methyl ester in the solid state

Boc-L-Asu-L-Ala-Gly-OMe crystallizes in the monoclinic space group P2(1) with cell dimensions a = 14.315 (3) A, b = 9.280 (2) A, c = 14.358(3) A, beta = 103.63(1) A, V= 1853.4 (9) A3, with two molecules in the asymmetric unit. The conformation of the two molecules is characterized by a type II' beta-bend, similar to that predicted earlier by potential energy calculations, stabilized by an intramolecular hydrogen bond. I.r. and 1H-n.m.r. data show that the folded conformation is also stable in chloroform solution.     

X-Pro peptides: Solution and solid-state conformation of benzyloxycarbonyl-(Aib-Pro)2methyl ester,a type I β-turn

The synthesis of the tetrapeptide benzyloxycarbonyl(α-aminoisobutyryl-L -prolyl)₂-methyl ester (Z-(Aib-Pro)₂-OMe) and an analysis of its conformation in solution and the solid state are reported. Stepwise synthesis using dicyclohexylcarbodiimide leads to racemization at Pro(2). Evidence for the presence of diastereomeric tetrapeptides is obtained from 270-MHz¹H-nmr and 67.89-MHz ¹³C-nmr. The all-L tetrapeptide is obtained by fractional crystallization from ethyl acetate. The NH of Aib(3) is shown to be involved in an intramo-lecular hydrogen bond by variable-temperature ¹H-nmr and the solvent dependence of NH chemical shifts. The results are consistent with a β-turn conformation with Aib(1) and Pro(2) at the corners stabilized by a 4 → 1 hydrogen bond. The molecule crystallizes in the space group P2₁2₁2₁, with a = 8.839, b = 14.938, and c = 22.015 Å. The structure has been refined to an R value of 0.051. The peptide backbone is all-trans, and a 4 → 1 hydrogen bond, between the CO group of the urethane moiety and Aib(3) NH, is observed. Aib(1) and Pro(2) occupy the corner positions of a type I β-turn with ? = ?55.4°, Ψ = ?31.3° for Aib(1) and ? = ?71.6°, Ψ = ?38° for Pro(2). The tertiary amide unit linking Pro(2) and Aib(3) is significantly distorted from planarity (Δω = 14.3°).     

X-Pro peptides: Synthesis and solution conformation of benzyloxycarbonyl-(Aib-Pro)4methyl ester. Evidence for a novel helical structure

The synthesis of the octapeptide, benzyloxycarbonyl-(α-aminoisobutyryl-L-prolyl)₄-methyl ester [Z-(Aib-Pro)₄-OMe] and an analysis of its solution conformation is reported. The octapeptide is shown to possess three strong intramolecular hydrogen bonds on the basis of studies of the solvent and temperature dependence of NH chemical shifts and rates of hydrogen–deuterium exchange. ¹³C studies are consistent with a structure involving only trans Aib-Pro bonds, while ir experiments support a hydrogen-bonded conformation. The Aib 3, 5, and 7 NH groups are shown to participate in hydrogen bonding. A 3₁₀ helical conformation compatible with the spectroscopic data is suggested. The proposed conformation consists of three type III β-turns with Aib and Pro at the corners and stabilized by 4 → 1 intramolecular hydrogen bonds.     

Crystal-state conformation of Calpha,alpha-dialkylated peptides containing chiral beta-homo-residues.

Secondary structure formation and stability are essential features in the knowledge of complex folding topology of biomolecules. To better understand the relationships between preferred conformations and functional properties of beta-homo-amino acids, the synthesis and conformational characterization by X-ray diffraction analysis of peptides containing conformationally constrained Calpha,alpha-dialkylated amino acid residues, such as alpha-aminoisobutyric acid or 1-aminocyclohexane-1-carboxylic acid and a single beta-homoamino acid, differently displaced along the peptide sequence have been carried out. The peptides investigated are: Boc-betaHLeu-(Ac6c)2-OMe, Boc-Ac6c-betaHLeu-(Ac6c)2-OMe and Boc-betaHVal-(Aib)5-OtBu, together with the C-protected beta-homo-residue HCl.H-betaHVal-OMe. The results indicate that the insertion of a betaH-residue at position 1 or 2 of peptides containing strong helix-inducing, bulky Calpha,alpha-disubstituted amino acid residues does not induce any specific conformational preferences. In the crystal state, most of the NH groups of beta-homo residues of tri- and tetrapeptides are not involved in intramolecular hydrogen bonds, thus failing to achieve helical structures similar to those of peptides exclusively constituted of Calpha,alpha-disubstituted amino acid residues. However, by repeating the structural motifs observed in the molecules investigated, a beta-pleated sheet secondary structure, and a new helical structure, named (14/15)-helix, were generated, corresponding to calculated minimum-energy conformations. Our findings, as well as literature data, strongly indicate that conformations of betaH-residues, with the micro torsion angle equal to -60 degrees, are very unlikely.     

Alpha,beta-dehydrophenylalanine containing cecropin-melittin hybrid peptides: conformation and activity.

Synthesis and conformational studies of a cecropin-melittin hybrid pentadecapeptide CA(1-7)MEL(2-9), and its three alpha, beta-dehydrophenylalanine (DeltaPhe) containing analogs in water-TFE mixtures are described. DeltaPhe is placed at strategic positions in order to preserve the amphipathicity of the molecule. The wild type CAMEL0 and its three analogs, containing one, two and three DeltaPhe residues namely CAMELDeltaPhe1, CAMELDeltaPhe2 and CAMELDeltaPhe3 respectively were synthesized in solid phase and their conformation determined by CD and NMR. CAMELDeltaPhe2 and CAMELDeltaPhe3 peptides exhibit the presence of 3(10)-helix and beta-turns in the former and only turns in the latter. CAMELDeltaPhe1 peptide was found to have a largely extended conformation. Antibacterial and hemolytic activities of the peptides were also evaluated. CAMELDeltaPhe2 peptide is maximally potent against both Staphylococcus aureus ATCC 259230 and Escherichia coli ATCC 11303. CAMELDeltaPhe1 with a single DeltaPhe at the center shows minimal hemolysis.     

Structure and conformation of peptides involving prolyl residue. IV. L-Prolyl-L-leucine monohydrate

The dipeptide, L-prolyl-L-leucine monohydrate (C11H20N2O3.H2O, molecular weight, 246.3) crystallizes in the monoclinic space group P2(1), with cell constants: a = 6.492(2)A, b = 5.417(8)A, c = 20.491(5)A, beta = 96.59(2) degrees, Z = 2, Do = 1.15 g/cm3, and Dc = 1.142 g/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 greater than 2 sigma (I)) measured on an Enraf Nonius CAD-4 diffractometer (CuK alpha, lambda = 1.5418 A, 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: chi 1 = -59.3(13) degrees, chi 21 = -63.1(16) degrees and chi 22 = 174.8(15) degrees 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.     

Structure and conformation on linear peptides. VI. Structure of D,L-alanyl-L,D-norvaline

The dipeptide, (DL)-alanyl-(DL)-norvaline, crystallizes in the monoclinic space group P2(1)/c, with a = 12.559(2)A, b = 5.265(1), c = 16.003(3), beta = 103.53(2) degrees, Z = 4. The structure was solved by direct methods and refined to an R-value of 0.054 for 871 reflections with I greater than 2 sigma. The molecule exists as a zwitterion in the crystal. The peptide unit is trans and shows significant deviations from planarity (delta omega = 12.4 degrees). 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.     

Peptides containing the sulfonamide junction: Synthesis,structure, and conformation of Z-Tau-Pro-Phe-NHiPr

The taurine (Tau) containing tripeptide derivative Z-Tau-Pro-Phe-NHiPr (1) has been synthesized as suitable sulfonamido-pseudopeptide model to investigate formation and conformational properties of folded secondary structures stabilized by intramolecular H bonds directly involving the sulfonamide junction. In the crystal the pseudopeptide 1 adopts a type I β-turn with the Pro and Phe residues located at the (i + 1) and (i + 2) corner positions, respectively. The turn is stabilized by a 4 → 1 H bond engaging one of the SO₂ oxygen atoms and the isopropylamide NH. In CDCl₃ solution the β-turn folding is accompanied by a γ-turn centered at the Pro and involving a 3 → 1 H bond between the SO₂ and the Phe NH. A comparison of the structural and conformational properties found in 1 with those of the already known sulfonamido-pseudopeptides, with particular reference to the models containing the Tau-Pro junction, is also reported. © 1997 John Wiley & Sons, Inc. Biopoly 41: 555–567, 1997.     

Structure and conformation of a novel inhibitor of angiotensin I converting enzyme--a tripeptide containing phosphonic acid

A novel phosphotripeptide, (IR)-1-(N-(N-acetyl-L-isoleucyl)-L-tyrosyl)amino-2-(4-hydroxyphenyl)ethy l- phosphonic acid, is a potent inhibitor of angiotensin I converting enzyme (ACE). ACE inhibitory activity in vitro of the peptide is comparable to that of captopril. Its diethylester (C29H42N3O8P, molecular weight, 591.6) crystallizes in the monoclinic space group C2, with cell constants: a = 25.666(9), b = 9.590(8), c = 13.557(2)A, beta = 91.65(2) degrees, Z = 4, Dc = 1.17 g/cm3. The structure was solved by MULTAN 11/82 and refined by full matrix least-squares methods to a final R-factor of 0.063 for 2123 unique reflections (F greater than 3 sigma(F] measured on an Enraf-Nonius CAD-4 diffractometer (CuK alpha, lambda = 1.541 8 A, T = 295 K). The absolute configuration of the alpha-carbon where the phosphonic acid is attached was determined unequivocally by referring to the L-isoleucyl moiety whose absolute configuration is known. The conformation of the molecule is relatively rigid owing to the intramolecular requisites and the resultant relative disposition of hetero atoms, which are necessary to its biological activities, are confined to the corresponding disposition in captopril.