QUANTITATIVE EVALUATION OF γ-TURN CONFORMATION IN PROLINE-CONTAINING PEPTIDES USING13 C N.M.R.

The dependence of the ¹³C shift difference of proline carbons C_β and C_γ on the dihedral angle ø has been studied using the model peptide acetyl-d -proline N-methylamide. The shift difference Δ_βγ is shown to be correlated with the percent cis isomer about the acetylproline bond, both factors depending strongly on the degree of intermolecular hydrogen bonding. Both the fraction of trans peptide bond and the fractional γ-turn conformation increase as the sample concentration is decreased in CDCl₃. Δ_βγ values have been used to evaluate the fractional γ-turn probabilities in a number of cyclic and linear peptides including thyrotropin releasing factor and bradykinin. Using this parameter, it is concluded that in bradykinin the γ-turn probability is low in D₂O and not strongly temperature dependent. In contrast, studies of a model peptide for the portion of bradykinin believed to adopt a γ-turn conformation are consistent with an increased γ-turn probability in less polar solvents. Data for X-Pro-Y peptides (Y = imino acid) indicate significantly reduced values of Δ_βγ, and this appears to be a useful basis for assigning the Pro C_β resonances corresponding to this sequence.     

Observation of a mixed antiparallel and parallel β-sheet motif in the crystal structure of Boc-Ala-Ile-Aib-OMe

A diastereomeric mixture of the tripeptide Boc-Ala-Ile-Aib-OMe crystallized in the space group Pl from CH₃OH/H₂O. The unit cell parameters are a= 10.593(2) Å, b= 14.377(3) Å, c= 17.872(4) Å, α= 104.41(2)°, β= 90.55(2)°, γ= 106.91(2)°, V= 2512.4 ų, Z=4. X-Ray crystallographic studies shows the presence of four molecules in the asymmetric unit consisting of two pairs of diastereomeric peptides, Boc-l -Ala-l -Ile-Aib-OMe and Boc-l -Ala-d -Ile-Aib-OMe. The four molecules in the asymmetric unit form a rarely found mixed antiparallel and parallel β-sheet hydrogen bond motif. The Ala and (l ,d )-Ile residues in all the four molecules adopt the extended conformations, while the φ, ψ values of the Aib residues are in the right-handed helical region. In one of the molecules the Ile sidechain adopts the unusual gauche conformation about the C^β-C^γ bond. © Munksgaard 1996.     

Empirical rules predicting conformation of cyclic tetrapeptides from primary structure

A useful set of empirical rules is put forward to predict the conformations of cyclic tetrapeptides and cyclic tetradepsipeptides on the basis of primary structure, briefly presented as follows: 1. A conformation allowing an intramolecular hydrogen bond (IMHB) of γ-turn is preferred, and an ester bond always adopts a trans form. 2. On a right-handed peptide ring, the carbonyl group acylating a D residue is oriented to the upper side of the main ring. 3. The carbonyl group acylating a d proline or an N-methyl-d -amino acid residue is oriented to the lower side of the ring, forming a cis bond. 4. The lddl configurational sequence adopts a cis-trans-cis-trans backbone with C_i symmetry. 5. A glycine residue behaves as a d residue in an l -peptide. Conformations of cyclotetrapeptides containing two glycine residues at diametric positions or containing an N-methyl-dehydroamino acid residue are predicted by use of appendices of rule 5. Almost all conformations of cyclic tetrapeptides are predicted by these rules. Energetical rationalization of the rules and prediction of possible new conformations are described. Conformations of cyclo (-l -Pro-l -Leu-d -Tyr(Me)-l -Ile-)(1) and cyclo (-l -Pro-d -Leu-d -Tyr(Me)-l -Ile)(2) are compared. Results of n.m.r. experiments showed that compound 1 adopts a unique cis-trans-trans-trans backbone with a γ-turn IMHB, and 2 has a cis-trans-cis-trans backbone with C_i symmetry. These observations confirmed the rules described above. Peptides 1 and 2 are the first diastereomeric peptides with trans (ld ) and cis (dd ) secondary amide bonds.     

Ten-membered cyclotripeptides

The 10-membered cyclotripeptide cyclo(-βAla-Phe-Pro-) (III) has been synthesized by cyclizing under mild conditions the linear precursor βAla-Phe-Pro-Onp·TFA. Crystal and molecular structure of (III) is reported and compared with that of the related models cyclo-(-MeAnt-Phe-Pro-) (I) and cyclo(-Hyb-Phe-Pro-) (II). Crystals of (III) are orthorhombic, C222₁, with a= 8.224(1), b= 14.056(2), c= 28.559(3)A and Z = 8. The backbone of (III) is characterized by a cis-cis-trans conformation. Both the βAla-Phe and Phe-Pro peptide bonds are cis with ω values of – 14.4° and –0.1°, whereas the Pro-βAla junction exhibits trans conformation with high deviation from planarity (ω= 158.6°). The pyrrolidine ring has C₂-C^β-endo-C^γ-exo conformation and the benzylic side chain is extended toward the Phe-CO group. The molecular conformation of (III) shows a striking resemblance to that of the heterodetic model (II) and strongly differs from the all-cis conformation shown by the homodetic analogue (I).     

Backbone modifications in cyclic pep tides Conformational analysis of a cyclic pseudopentapeptide containing a thiomethylene ether amide bond replacement

NMR and X-ray crystallographic studies have shown that cyclic pentapeptides of the general structure cyclo(D-Xxx-Pro-Gly-Pro-Gly) possess β- and γ-turn intramolecular hydrogen bonds. As part of our continuing series surveying the compatibility of various amide bond replacements on peptide structure, we have synthesized cyclo(D-Phe-Proψ [CH₂S]Gly-Pro-Gly). The pseudopeptide was prepared by solid phase methods and cleaved from the resin by a new procedure involving phase transfer catalysis using K₂CO₃ and tetrabutylammonium hydrogen sulfate. Cyclization was carried out with the use of DPPA, HOBt, and DMAP to afford the product in 69% yield. The conformational behavior of the pseudopeptide was analyzed by ¹H and ¹³C (1D and 2D) NMR techniques. The backbone modification replaced the amide bond that is involved in a γ-turn intramolecular hydrogen bond in the all-amide structure. In CDCl₃, the pseudopeptide adopted the same all-trans conformation as its parent, although the remaining β-turn hydrogen bond was weaker according to Δδ/ΔT_NH measurements. In DMSO-d₆, the all-trans conformer and a second conformer were observed in a ratio of 55:45. These conformers, which slowly inter converted on the NMR time scale, could be separately assigned; peaks due to chemical exchange were readily distinguishable by the ROESY technique as reported earlier by others. ¹³C and ROESY experiments suggested the minor conformer contained one cis amide bond at the Gly¹-Pro² position. Thus, both the location and type of amide surrogate are important determinants affecting the compatibility of the replacement with a particular conformational feature.     

Peptides related to the active fragment of “proline rich polypeptide”, an immunoregulatory protein of the ovine colostrums

The preferred solution conformation of the PRP-hexapeptide (Tyr-Val-Pro-Leu-Phe-Pro) and of some of its structural analogues was investigated by NMR- spectroscopy, spectrofluorimetry and computer simulation technic. It was found that the preferred conformation is characterized by cis′-conformation of Pro³ and the γ-turn on the Leu⁴-residue: for Val² and Phe⁵ a β-structure seems to be privileged. In such a conformation Val² and Leu⁴ residues occupy exactly the same positions in space as residues i and i+ 3 in an α-helix. It suggests that the PRP-hexapeptide can interact with receptor protein inducing or stabilizing its helical conformation by “knobs into holes” packing.     

Crystal structure of tert.-butyloxycarbonyl-L-prolyl-D-alanyl-D-alanyl-N-methylamide Dimeric β-sheet formation

The crystal structure of the tripeptide t-Boc-L-Pro-D-Ala-D-Ala-NHCH₃, monohydrate, (C₁₇H₃₀N₄O₅·H₂O, molecular weight = 404.44) has been determined by single crystal X-ray diffraction. The crystals are mono-clinic, space group P2₁, a = 9.2585(4), b = 9.3541(5). c = 12.4529(4) Å, β= 96.449(3)°, Z = 2. The peptide units are in the trans and the tBoc-Pro bond in the cis orientation. The first and third peptide units show significant deviations from planarity (Δω=5.2° and Δω=3.7°, respectively). The backbone torsion angles are: φ¹, = -60°, ψ_1/= 143.3°, ω₁= -174.8°, φ₂= 148.4°, ψ₂= -143.1°, ω₂= -179.7°, φ₃= 151.4°, ψ₃= -151.9°, ω₃= -176.3°. The pyrrolidine ring of the proline residue adopts the C₂— C^γ conformation. The molecular packing gives rise to an antiparallel β-sheet structure formed of dimeric repeating units of the peptide. The surface of the dimeric β-sheet is hydrophobic. Water molecules are found systematically at the edges of the sheets interacting with the urethane oxygen and terminal amino groups. Surface catalysis of an L-Ala to D-Ala epimerization process by water molecules adsorbed on to an incipient β-sheet is suggested as a mechanism whereby crystals of the title peptide were obtained from a solution of tBoc-Pro-D-Ala-Ala-NHCH₃.     

Variability in the backbone conformation of cyclic pentapeptides

All the peptide bonds in cyclic(Gly-LPro-DPhe-Gly-LAla) are in the trans conformation; however, the peptide bond C₅'-N₁ is twisted by 19° from planarity (ω₅= - 161°). A Type II β-turn encompasses the LPro-DPhe residues. Carbonyl oxygens O₂, O₄ and O₅ are directed to the same side of the average plane through the backbone ring and they form hydrogen bonds with N₃, N₅ and N₁, respectively, in adjacent molecules in a stacked column where the adjacent molecules are related by one translational unit. The conformation of the backbone is different from that established in other molecules with the DLDDL chirality sequence. The P2₁ cell contains two molecules of C₂₁H₂₆N₅O₅ with a = 4.836(2) A, b = 18.346(8) A, c = 12.464(5) A and β= 100.05(4)°. The R factor for 1382 data with ¶F₀¶ > 1 ¶ is 7.0%.     

Importance of the C‐terminal phenylalanine of gastrin for binding to the human CCK2 receptor

Abstract: The importance of the C‐terminal Phe of gastrin and structural requirements at position 17 for binding to the human CCK₂ receptor were assessed using analogs of [Leu¹⁵]G(11?17). The following peptides were synthesized, Ac[Leu¹⁵]G(11?17), Ac[Leu¹⁵]G(11?16)NH₂, [Leu¹⁵]G(11?17), [Leu¹⁵,Ala¹⁷]G(11?17), [Leu¹⁵,Abu¹⁷]G(11?17), [Leu¹⁵,Val¹⁷]G(11?17), [Leu¹⁵,Leu¹⁷]G(11?17), [Leu¹⁵,Cha¹⁷]G(11?17), [Leu¹⁵,Trp¹⁷]G(11?17), [Leu¹⁵,Tic¹⁷]G(11?17), [Leu¹⁵, d ‐Phe¹⁷]G(11?17) and [Leu¹⁵,p‐X‐Phe¹⁷]G(11?17), where X = F, Cl, Br, I, OH, CH₃, NH₂ and NO_2. Competition binding experiments with [³H]CCK‐8 were performed using human CCK₂ receptors stably expressed in CHO cells. Phe¹⁷ was shown to be important for binding. A hydrophobic side‐chain larger than Leu is required at position 17 but aromaticity does not appear to be essential. Constraint of the aromatic side‐chain either in the g(+) or g(–) conformation, as in the case of Tic, results in a significant decrease in affinity. In addition, the peptide conformation induced by incorporation of d ‐Phe decreases binding. The size and electron withdrawing/donating properties of the para substituent are not important for interaction with the receptor. The current study shows that the use of des‐Phe analogs of gastrin is not a viable strategy for development of antagonists for the human CCK₂ receptor.     

Comparative conformational analysis and in vitro pharmacological evaluation of three cyclic hexapeptide NK-2 antagonists

The conformational analysis of three cyclic hexapeptides is presented. Cyclo-(-Gln⁶-Trp⁷-Phe⁸-Gly⁹-Leu¹⁰-d -Met¹¹-) (1) and cyclo-(-Gln⁶-Trp⁷-Phe⁸-Gly⁹-Leu¹⁰-Met¹¹-) (2) are NK-2 antagonists in the hamster trachea assay, whereas cyclo-(-Gln⁶-Trp⁷-Phe⁸-(R)-Gly⁹-[ANC-2]Leu¹⁰-Met¹¹-) (3), where Gly⁹[ANC-2]Leu¹⁰ represents (2S)-2-((3R)-3-amino-2-oxo-1-pyrrolidinyl)-4-methylpentanoyl, is inactive as agonist and antagonist in this assay. In DMSO, the NMR results cannot be interpreted as being consistent with a single conformation. However, the combined interpretation of results from NMR spectroscopy, restrained molecular dynamics simulations with application of proton–proton distance information from ROESY spectra, and pharmacological results leads to a reduced number of conformational domains for each peptide, which can be compared with each other and may be classified as responsible for their biological activity. Trying to match the conformational domains approximately with regular β- and γ-turns, we find a γⁿ-turn at the position of the methionine occuring in all peptides. For the active peptides 1 and 2 we arrive at an inverse γⁱ-turn at Phe⁸, and βI′- or βII-turns with Gly⁹ and Leu¹⁰ at the corner positions, these β-turns having a similar topology with respect to the linking peptide unit. Other conformational domains common to only 1 and 2 support their classification as responsible for the biological activity.     

Crystal structure and conformation of glycyl-glycyl-sarcosine

Crystals of the tripeptide, glycyl-glycyl-sarcosine (C₇H₁₃N₃O₄) from aqueous methanol are orthorhombic, space group Pbcn with cell parameters at 294 K of a = 8.279(1), b = 9.229(4), c = 24.447(5) Å, V = 1868.0 ų, M.W. = 203.2, and Z = 8. The crystal structure was solved and refined using CAD-4 data (1171 reflections ≥ 3σ) to a final R-value of 0.053. The first peptide linkage is trans and planar whereas the second peptide link between Gly and sarcosine is cis and appreciably non-planar (w = 7.4°). The peptide backbone has an extended conformation at the N-terminal part but adopts a polyglycine-II type of conformation at the C-terminal part. The backbone torsion angles are: Ψ₁, =? 173.9, w₁=? 177.8, (φ, Ψ₂) = (-178.8, -170.8), w₂= 7.4, (φ₃, Ψ₃) = (-81.6, 165.6°).     

Simulations of conformers of tuftsin and a cyclic tuftsin analog

The conformational properties of the configurational isomers of tuftsin, a linear tetrapeptide with the sequence Thr-Lys-Pro-Arg, were investigated with six 1 ns molecular dynamics simulations in explicit water and in a 1.0 M NaCl solution. The average conformation of the cis isomer is a type VI β-turn. Our results indicate that water-peptide hydrogen bonding, in addition to intramolecular hydrogen bonds, stabilizes the cis conformer. The trans isomer is neither a β- nor a γ-turn. Results are compared with parallel studies on a cyclic analog of tuftsin, cyclo(Thr-Lys-Pro-Arg-Gly). The addition of salt does not influence the backbone conformation of the peptide. Differences between the structures are confined to the side-chain orientations of the Lys and Arg residues. © Munksgaard 1995.     

Synthesis and crystal structures of Boc-L-Asn-L-Pro-OBzl·CH3OH and dehydration side product,Boc-β-cyano-L-alanine-L-Pro-OBzl

Boc-L-Asn-L-Pro-OBzl:C₂₁H₂₉O₆N₃·CH³OH, M_r= 419.48 + CH₃OH, monoclinic, P2₁, a= 10.049(1), b= 10.399(2), c= 11.702(1)Åβ= 92.50(1)°, V = 1221.7(3)ų, d_x= 1.14g cm^-3, Z = 2, CuKα (λ= 1.54178 Å), F(000) = 484 (with solvent), 23°, unique reflections (I > 3σ(I)) = 1745, R = 0.043, R_w= 0.062, S = 1.66. Boc-β-cyano-L-alanine-L-Pro-OBzl: C₂₁H₂₇O₅N₃, M_r= 401.46, orthorhombic, P2₁2₁2₁, a= 15.741(3), b= 21.060(3), c= 6.496(3)ÅV= 2153(1)ų, d_x= 1.24g·cm^-3, Z = 4, CuKα (λ= 1.54178 Å), F(000) = 856, 23°, unique reflections (I > 3σ(I)) = 1573, R = 0.055, R_w= 0.078, S = 1.86. The tert.-butyloxycarbonyl (Boc) protected dipeptide benzyl ester (OBzl), BOC-L-Asn-L-Pro-OBzl, prepared from a mixed anhydride reaction using isobutylchloroformate, BOC-L-asparagine, and HCI·L-proline-OBzl, crystallized with one methanol per asymmetric unit in an extended conformation with the Asn-Pro peptide bond trans. Intermolecular hydrogen bonding occurs between the methanol and the Asn side chain and between the peptide backbone and the Asn side chain. A minor impurity due to the dehydration of the Asn side chain to a β-CNaia crystallized with a similar extended conformation and a single intermolecular hydrogen bond.     

Potent pseudopeptide bombesin-like agonists and antagonists

Bombesin-like pseudopeptides have been synthesized, and certain physicochemical properties and biological activities have been examined. Bombesin and the related peptide litorin were modified at positions 13–14 and 8–9, respectively, with ψ[CH₂S] and ψ[CH₂N(CH₃)]. [Phe¹³ψ[CH₂S]Leu¹⁴]bombesin and [Phe⁸ψ[CH₂S]-Leu⁹]litorin bound to the murine pancreatic bombesin gastrin releasing peptide receptor with similar dissociation constants (K_d= 3.9 and 3.4 nM. respectively). Increased potency was achieved by oxidation of the thiomethylene ether to two diastereomeric sulfoxides (isomer I, K_d= 1.6 nM and isomer II, K_d= 0.89nM. Further oxidation to the sulfone decreased potency ([Phe⁸ψ[CH₂SO₂]Leu⁹]litoin, K_d= 9.9nM). All five analogs were receptor antagonists as determined by phosphatidylinositol turnover in murine pancreas. In contrast to these peptide backbone substitutions, a ψCH₂N(CH₃)] at the 8–9 amide bond position resulted in an agonist. The analogs were compared with those of litorin (K_d= 0.1 nM) and [Leu⁹]litorin (K_d= 0.17 nM) by CD and fluorescence spectroscopy. The CD spectra demonstrated ordered conformation for all the peptides in TFE. Different conformations corresponding to agonist and antagonist peptides were suggested by CD. Based on the pH-dependence of the fluorescence spectra of the peptides in a zwitterionic detergent, two titratable groups were identified (pK_a= 6.3 and 8.5). The lower pK_a is found in the agonist analogs but not in the ψ[CH₂S]-containing antagonist.     

Cystine peptides Antiparallel β-sheet conformation of the cyclic biscystine pep tide [Boc-Cys-Ala-Cys-NHCH3]2

The crystal structure analysis of the cyclic biscystine peptide [Boc-Cys¹-Ala²-Cys³-NHCH₃]₂ with two disulfide bridges confirms the antiparallel β-sheet conformation for the molecule as proposed for the conformation in solution. The molecule has exact twofold rotation symmetry. The 22-membered ring contains two transannular NH ? OC hydrogen bonds and two additional NH ? OC bonds are formed at both ends of the molecule between the terminal (CH₃)₃COCO and NHCH₃ groups. The antiparallel peptide strands are distorted from a regularly pleated sheet, caused mainly by the L-Ala residue in which φ=– 155° and ψ= 162°. In the disulfide bridge C^α (1)-C^β (1)-S(1)-(3′)-C^β(3′)-C^α(3′), S—S = 2.030 Å, angles C^β SS = 107° and 105°, and the torsional angles are –49, –104, +99, –81, –61°, respectively. The biscystine peptide crystallizes in space group C2 with a = 14.555(2) Å, b = 10.854(2) Å, c = 16.512(2)Å, and β= 101.34(1) with one-half formula unit of C₃₀H₅₂N₈O₁₀S₄· 2(CH₃)₂SO per asymmetric unit. Least-squares refinement of 1375 reflections observed with |F| > 3σ(F) yielded an R factor of 7.2%.     

Conformational investigation of α,β-dehydropeptides VII*. Conformation of Ac-Pro-ΔAla-NHCH3 and Ac-Pro-(E)-ΔAbu-NHCH3: comparison with (Z)-substituted α,β-dehydropeptides†

The crystal structure and solution conformation of Ac-Pro-ΔAla-NHCH₃ and the solution conformation of Ac-Pro-(E)-ΔAbu-NHCH₃ were investigated by X-ray diffraction method and NMR, FTIR and CD spectroscopies. Ac-Pro-ΔAla-NHCH, adopts an extended-coil conformation in the crystalline state, with all-trans peptide bonds and the ΔAla residue being in a C₅ form, φ₁=– 71.4(4), ψ₁=– 16.8(4), φ₂=– 178.4(3) and ψ₂= 172.4(3)°. In inert solvents the peptide also assumes the C₅ conformation, but a γ-turn on the Pro residue cannot be ruled out. In these solvents Ac-Pro-(E)- ΔAbu-NHCH₃ accommodates a βII-turn, but a minor conformer with a nearly planar disposition of the CO—NH and C=C bonds (φ₂～0°) is also present. Previous spectroscopic studies of the (Z)-substituted dehydropeptides Ac-Pro-(Z)- ΔAbu-NHCH, and Ac-Pro-ΔVal-NHCH₃ reveal that both peptides prefer a βII-turn in solution. Comparison of conformations in the family of four Ac-Pro-ΔXaa-NHCH₃ peptides let us formulate the following order of their tendency to adopt a β-turn in solution: (Z)- ΔAbu > (E)- δAbu > ΔVal; ΔAla does not. None of the folded structures formed by the four compounds is stable in strongly solvating media. © Munksgaard 1996.     

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.     

Solution conformations of the peptide backbone for DPDPE and its β-MePhe4-substituted analogs

The solution structures of DPDPE, a conformationally restricted pentapeptide with the sequence H-Tyr¹-d -Pen²-Gly³-Phe⁴-d -Pen⁵-OH, and its four β-MePhe⁴-substituted analogs were examined by a combined approach including the NMR measurements in DMSO and water as well as independent energy calculations. It was concluded that several low energy conformers of DPDPE backbone satisfy the NMR data obtained in this study as well as in previous studies by other authors. These possible solution conformers of DPDPE in both DMSO and water share virtually the same type of cyclic backbone structure, with the Gly³ residue in a conformation close to a γ-turn, and the Phe⁴ residue in a conformation close to α-helical torsion angles. They differ in the space arrangements of the flexible Tyr¹ moiety. The solution structures of the β-MePhe⁴-substituted analogs of DPDPE are interesting. For analogs with an S-configuration at the C^α atom in the Phe⁴ residue, the cyclic backbone conformations resemble those of DPDPE itself, whereas for analogs with an R-configuration at the C^α atom, the backbone conformation is somewhat different. This observation is in line with the high biological potencies and selectivities displayed by the former compounds but not by the latter ones. It was noted also that as far as the peptide backbone conformers are concerned, some of the possible DPDPE conformers in water are similar to the previously suggested model for the δ-receptor-bound conformation of DPDPE, becoming virtually identical to this conformation by rotating the side chains of the Tyr¹ and the Phe⁴ residues.     

Peptides containing the sulfonamide transition-state isostere: synthesis and structure of N-acetyl-tauryl-l-proline methylamide

The structure of the sulfonamide isostere-containing peptide N-acetyl-tauryl-proline methylamide 4 was compared to information on the structure of the peptide N-acetyl-β-alanyl-proline methylamide 6. NMR measurements of the β-alanine containing peptide 6 showed the presence of two conformations due to cis/trans isomerism of the β-Ala-Pro amide bond, whereas the sulfonamide-containing peptide 4 appeared in only one conformation. The crystal structure of N-acetyl-tauryl-proline methylamide 4 gave additional evidence for the absence of cis/trans isomerism. The crystals are orthorhombic, space group P2₁2₁2₁, Z= 4, F(000) = 592, a= 7.5919(3), b= 10.3822(2), c= 17.1908(7) Å, V= 1354.99(8) ų, D_x= 1.359 g cm^?3. The oxygen atoms connected to the sulfur take positions similar to both the cis and trans positions of the carbonyl oxygen of an amide. Consequently the tauryl part is placed perpendicular to the proline α-C-C(O) bond, giving it an extended conformation in contrast to the cis/trans isomers of N-acetyl-β-alanyl-proline methylamide 6. © Munksgaard 1995.     

Conformation and crystal structure of L-prolyl-L-glutamic acid dihydrate

The crystal structure of the dipeptide L-prolyl-L-glutamic acid dihydrate, L-Pro-L-Glu · 2H₂O, C₁₀H₂₀O₇N₂, has been determined from three-dimensional X-ray diffractometer data. The dipeptide crystallizes in the space group P2₁ of the monoclinic system with two formula units in a cell of dimensions a= 5.629(2), b= 11.832(5), c= 10.485(4)Å, and β= 103.06(3)°. The structure was solved by direct methods and refined by least squares techniques to a final value of the conventional R-factor (on F) of 0.039 based on 1798 independent intensities with I ≥ 3s?(I). The dipeptide occurs as a zwitterion in the crystal with the pyrrolidine nitrogen atom protonated and the main chain carboxyl group deprotonated. The conformation of the peptide linkage is trans, the ω torsional angle being 173.7°. The pyrrolidine ring adopts the C_s-C^β endo conformation and the conformation of the glutamyl side chain is fully extended. There is considerable intermolecular hydrogen bonding in the crystals.