Conformation and hydrogen bonding of N-formylmethionyl peptides

Crystals of N-formyl-L-methionyl-L-phenylalanine (C₁₅H₂₀N₂O₄S). grown from aqueous methanol solution are orthorhombic, space group, P2₁2₁2₁, with cell parameters at 294K of a = 4.900(2), b = 17.947(4), c = 18.726(4)Å, V = 1646.8ų, M.W. = 324.4, Z = 4 and D_m= 1.308 g/cc, and as expected, all nearly identical to that of N-f-D-Met-D-Phe studied by Jeffs, Heald, Chodosh & Eggleston (Int. J. Peptide Protein Res. 24 , 442–446, 1984). The crystal structure was solved and refined using CAD-4 data (1095 reflections ≥ 3σ) to a final R value of 0.042. Molecules related by the a-translation form a parallel β-sheet rather than anti-parallel sheet as stated in the earlier study of Jeffs et al. The formation of the parallel rather than the anti-parallel p-sheet structure, the use of the C-H…O hydrogen bonds to stabilize the b-sheet and the very short O-H…O hydrogen bond between the carboxyl OH and the N-acyl oxygen atom emerge as the main structural features of the chemotactic N-formyl methionyl peptides.     

Heterochiral N-formyl methionyl peptides

Crystal and molecular structures for the heterochiral sequence N-formyl-l -methionine-d -phenylalanine, 1, and its tertiary butyl ester, 2, are reported. The solid-state peptide conformation is compared to that observed in solution by n.m.r. techniques. For N-f-Met-d -Phe, 1, the crystal was orthorhombic, space group P2₁ 2₁2₁ with a cell of dimensions a = 5.061(3), b = 16.575(5) and c = 19.656(6) Å at ambient temperature of 293K; V = 1649(2)ų, Z = 4, D_m= 1.31(2)gcm^?3, D_x= 1.307gcm^?3, μ(Mokx) = 2.047cm^?1. For N-f-Met-d -Phe-OtBu. 2, the crystal was monoclinic, space group P2₁ with a cell of dimensions a = 9.963(2), b = 11.147(2), c = 19.166(3)Å. β= 102.31(1) at 273K; V = 2080(2) ų Z = 4, D_m= 1.22(2)gcm^?3, D_x= 1.215gcm^?3μ(MoKx) = 1.714cm^?1. The structures were solved from diffractometer data and refined to conventional final R = 0.046, R_w= 0.053 for F-Met-d -Phe (1301 observations. I ≥ 3σ(I)) and to R = 0.056, R_w= 0.064 for the t-butylester (2411 observations. I ≥ 3σ(I)). The l-d acid, 1, crystallizes in an extended β-sheet conformation with trans-planar peptide bond; the principal torsion angle values are φ₁=– 141.2(4).Ψ₁= 149.6(4)³, φ₂= 157.4(4)°. The methionine side chain adopts a common coiled conformation with x¹₁= - 58.0(5).x²¹= 175.1(4), x³₁= 76.5(5). The Phe side chain adopts the statistically least favored g orientation in contrast to the most populated rotamer in solution. The crystal structure is composed of parallel β-sheets held together by four weak intermolecular contacts including two C-H O contacts from the alpha carbons to the formyl and peptide carbonyl oxygens. Sheet layers are joined in a head-to-tail fashion through a very short (2.569(4) Å) contact between the carboxyl OH and the formyl oxygen and may be further stabilized by a C-H—O interaction between the formyl proton and the carboxyl OH. Two crystallographically independent molecules are observed in the crystal structure of N-f-l -Met-d -Phe-OtBu, 2. These are distinct conformational isomers differing principally at both the N and C termini. Particularly noteworthy is the synplanar orientation of the ester C = O with respect to the peptide nitrogen in molecule A. which contrasts to the antiplanar orientation in molecule B. Additionally, the formyl group is coiled more towards the C-terminus in molecule B. Principal torsion angles are φ₁(A) = - 120.6(5), Ψ₁(A) = 102.0(6)°, φ₂(A) = 128.1(6), φ₁(B) = - 94.6(5), Ψ₁(B) = 91.9(6)°. 121.7(6)°. The peptide bond is trans-planar in both molecules. Side chain dispositions are essentially identical in both structures. The Met side chain adopts the zig-zag trans-planar conformation while the Phe residue adopts an orientation near + 60° in agreement with rotamer populations observed by solution n.m.r. Typical peptide intermolecular H-bonding is observed in the ester crystal structure; both the peptide and formyl groups participate in the proposed H-bonding scheme.     

Hydrogen bonding in peptide helices Analysis of two independent helices in the crystal structure of a peptide Boc-Val-Ala-Leu-Aib-Val-Ala-Phe-OMe

The crystal structure determination of the heptapeptide Boc-Val-Ala-Leu-Aib-Val-Ala-Phe-OMe reveals two peptide helices in the asymmetric unit. Crystal parameters are: space group P2₁, a =10.356(2) Å, b = 19.488(5) Å, c=23.756(6) Å, β= 102.25(2)°, V=4685.4ų, Z=4 and R = 5.7% for 7615 reflections [I>3σ(I)].Both molecules adopt largely α-helical conformations with variations at the C-terminus. Helix type is determined by analysing both 4 → 1 and 5 → 1 hydrogen-bond interactions and comparison with the results of analysis of protein structures. The presence of two 4 → 1 hydrogen-bond interactions, besides four 5→1 interactions in both the conformations provides an opportunity to characterize bifurcated hydrogen bonds at high resolution. Comparison of the two helical conformations with related peptide structures suggests that distortions at the C-terminus are more facile than at the N-terminus. © Munksgaard 1997.     

Observations on the strength of hydrogen bonding

Both proton transfer and hydrogen bonding play important roles in biological systems. In order to measure hydrogen bond basicity, we are building a new scale that differs significantly from the pK_a scale of proton transfer basicity. The strength of hydrogen bond acceptors (HBAs) is measured from the Gibbs energy change ΔG_HB for the formation of 1:1 hydrogen bonding complexes between hydrogen bond acceptors (bases) and a reference hydrogen bond donor (4-fluorophenol) in tetrachloromethane at 298 K. The pK_HB database (1.364 pK_HB =–ΔG_HB (kcal mol^-1)) comprises ca. 1000 hydrogen bond acceptors. The HBA strength depends on (i) the position of the acceptor atom in the periodic table, (ii) polarizability, field/inductive and resonance effects of substituents around the acceptor atom, and (iii) proximity effects including steric hindrance of the acceptor site, intramolecular hydrogen bonding and lone-pair–lone-pair repulsions. The ranking of oxygen and sp nitrogen bases does not depend very much on the solvent and the reference hydrogen bond donor, but sp² and sp³ nitrogen bases gain strength in solvents of higher reaction field than CCl₄ and lose strength toward CH and weak NH donors. The complete scatter pattern exhibited by the pK_a versus pK_HB plot demonstrates the non-equivalence of the two scales. The HBA strength scale is applied to the prediction of the hydrogen bonding site in polybasic drugs (e.g strychnine and carbimazole), and to the calculation of octanol–water partition coefficients. A possible relationship between HBA strength and antihistaminic activity is studied for the `push–pull' drugs cimetidine, ranitidine and famotidine. This revised version was published online in August 2006 with corrections to the Cover Date.     

Conformation of cis-4-Hydroxy-praziquantel and its crystal and molecular structure

The crystal structure of racemic cis-4-OH-PZQ - the main metabolite of the anthelmintic drug Praziquantel - has been determined by X-ray analysis and refined to R = 0.064. In the unit cell there are two independent molecules, but with a similar conformation. The molecules of the same enantiomer (joined by H-bonds) form in the crystal a column along a-axis direction. Molecular mechanics calculations indicate that the conformation in the solid state does not correspond to the energy minimum and there are two lower energy conformations. Thus, in solutions these two conformers can most probably exist. Their concentration in solutions depends on the solvent polarity and the value of the dipole moment for the respective form of the molecule.     

Synthesis and X‐ray crystal structure study of the hydroxyurea and hydantoin derivatives of l‐valine

Abstract: The novel hydroxyurea 5 derivative of L ‐valine was prepared by aminolysis of N‐(1‐benzotriazolecarbonyl)‐L ‐valine cyclohexanemethylamide 4 with hydroxylamine. The corresponding hydantoin derivative 6 was synthesized by base catalyzed cyclization of the amide 4 . The exact stereostructure of hydantoin derivative 6 has been determined by X‐ray crystal structure analysis. The chiral atom of the hydantoin ring in 6 has S configuration what is in agreement with its configuration in the starting L ‐valine. The molecules of 6 are joined into infinite chains by N–H?O intermolecular hydrogen bond. The infinite chains are additionally linked by two C–H?O hydrogen bonds, thus forming two‐dimensional network. The hydantoin derivative of L ‐valine 6 and its L ‐leucine analogue LH have similar packing arrangements, so they are homostructural.     

The delineation of hydrogen-bonding patterns in supramolecular self-assembly of several core oxalo retro-peptides and crystal structure of MeO-Ser-Leu-COCO-Leu-Ser-OMe

Pseudo-C₅-type intramolecular hydrogen bonding, arising from the C₂ disposition of the core NH-CO-CO-NH unit in oxalo retro-peptides, is formed in addition to extended hydrogen bonding with neighbors forming sheets in MeO-Aib-COCO-Aib-OMe ( 1 ), helices in MeO-Leu-COCO-Leu-OMe ( 2 ) and ribbons in MeO-Ser-Leu-COCO-Leu-Ser-OMe ( 3 ). In 3 the OH in the Ser side-chains form hydrogen bonds with the backbone carbonyl of Leu groups from neighboring molecules. Crystal parameters for 3 are: C₂₂H₃₈N₄O₁₀, monoclinic, space group P2₁, a = 7.374(1), b = 18.218(4), c = 10.661(3) Å, β= 95.72(2) ?, R = 0.063 for 1738 observed reflections with ‖Fo‖> 3σ(F).     

Stabilization of amphipathic α-helical and β-helical conformations in synthetic peptides in the presence and absence of ionic interactions

The role of ionic interactions in stabilizing amphipathic α-helices was studied in the synthetic peptide Ac-NLEELKKKLEELKG-NH₂ (NLEKG14), potentially stabilized by attraction between complementary ions in successive turns of the helix, and in the peptide Ac-NLEELEEELEELEG-NH₂ (NLEG14), in which no side-chain ionic attractions are possible. At a pH below the pK_a of glutamate, NLEG14 had a higher helix content than NLEKG14. At pH 3 to pH 10, the helicity of NLEKG14 did not change, whereas NLEG14 was converted to random coil at pH 7. The role of ionic interactions in stabilizing the conformation of β-structures was studied in the synthetic peptides Ac-KLKLKLELELELG-NH₂ (KLEG13) and Ac-ELELELELELELG-NH₂ (ELG13). At a pH below the pK_a of glutamate, ELG13 had a higher β-content than KLEG13, as judged by their dichroic spectra, but at higher pH, ELG13 was converted to random coil, whereas KLEG13 retained a predominantly β-conformation. At pH 7, high NaCl concentration produced a significant increase in the α-helix content of NLEKG14, converted NLEG14 from random coil to α-helix and converted ELG13 from random coil to β-conformation. Overall, the results demonstrate that ionic attraction between side-chains plays a lesser role than hydrogen bonding and hydrophobic effects in stabilizing the α- and β-conformations exhibited by these amphipathic peptides.     

Crystal and molecular structure of Boc-Phe-Val-OMe; comparison of the peptide conformation with its dehydro analogue

The crystal structure of the peptide Boc-Phe-Val-OMe determined by X-ray diffraction methods is reported in this paper. The crystals grown from aqueous methanol are orthorhombic, space group P 2₁2₁ 2₁, a= 11.843(2), b= 21.493(4), c= 26.676(4) A and V= 6790 ų. Data were collected on a CAD4 diffractometer using MoK_α radiation (λ= 0.7107 Å) up to Bragg angle θ=26°. The structure was solved by direct methods and refined by a least-squares procedure to an R value of 6.8% for 3288 observed reflections. There are three crystal-lographically independent peptide molecules in the asymmetric unit. All the three molecules exhibit extended conformation. The sidechain of the Val² residue shows two different conformations. The conformation of the peptide Boc-Phe-Val-OMe is compared with the conformation of Ac-ΔPhe-Val-OH. It is observed that while Boc-Phe-Val-OMe exhibits an extended conformation, Ac-ΔPhe-Val-OH shows a folded conformation. The results of this comparison highlight the conformation constraining property of the ΔPhe residue. Interestingly, even though Boc-Phe-Val-OMe and Ac-ΔPhe-Val-OH are conformation ally different, they exhibit similar packing patterns in the solid state. © Munksgaard 1995.     

Self-assembling bis-dendritic peptides: design,synthesis and characterization of oxalyl-linked bis-glutamyl peptides [Glun(CO2Me)n+1-CO-]2; n = 1,3,7

Three generations of glutamic acid dendrons [Glu_n(CO₂Me)_n+1; n = 1,3,7] have been joined together head-to-head by an oxalyl unit to form highly sterically congested bis-Glu-dendritic peptides with gelling properties. The single crystal X-ray structure of the first generation bis-dendritic peptide showed an extended hydrogen-bonded chiral tape with modest nonlinear optical activity.     

Conformation and structure of acidic dipeptides

The crystal structures of the dipeptides L-alanyl-L-aspartic acid, C₇H₁₂N₂O₅, and α-L-glutamyl-L-aspartic acid, C₉H₁₄N₂O₇, have been determined from three-dimensional X-ray diffractometer data. Alanylaspartic acid crystallizes in the orthorhombic space group P2₁2₁2₁ with four formula units in a cell of dimensions a = 13.389(5), b = 14.467(3), c = 4.782(1)Å. Glutamylaspartic acid also crystallizes in space group P2₁2₁2₁ with four formula units in a cell of dimensions a = 13.709(5), b = 16.126(7), c = 4.939(5)Å. Both structures were solved by direct methods and refined by full-matrix least squares methods; the final value of the weighted R-factors (on F) were 0.040 based on 790 independent intesities with I-2s?(I) for Ala-Asp and 0.033 based on 1105 intensities with I-2s?(I) for Glu-Asp. Each dipeptide occurs as a zwitterion with the amino terminus protonated and the main chain carboxyl group deprotonated. The conformation of the peptide linkage is trans in both molecules, the ω torsion angle being -175.9° in Ala-Asp and 174.3° in Glu-Asp. There is considerable intermolecular, but not intramolecular, hydrogen bonding in the crystals. The conformations and structures of Ala-Asp and Glu-Asp are compared to those of other structurally characterized acidic dipeptides.     

EPSA: A Novel Supercritical Fluid Chromatography Technique Enabling the Design of Permeable Cyclic Peptides

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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.     

抗癌药达沙替尼的热稳定性与晶型研究

本文对药物达沙替尼的热稳定性和晶型进行分析与研究。通过差示扫描量热仪(DSC)和热重分析仪(TGA)分析达沙替尼的热稳定性;通过X射线粉末衍射仪(XRD)及其原位高温附件(in situ high temperature)测定达沙替尼试样的多晶型结构及相转变。结果表明,达沙替尼存在两种晶型(分子中分别含1个结晶水和1.5个结晶水),在加热过程中两种晶型都会发生结构变化,失去结晶水后,最终变为相同的晶体结构,其熔点分别为285.68℃和285.50℃。     

Desolvation Energy: A Major Determinant of Absorption,But Not Clearance,of Peptides in Rats

The oral delivery of peptidic drugs is problematic because of their degradation in the gastrointestinal tract and low absorption through the intestinal mucosa. Earlier in vitro studies with two series of digestion-resistant, radiolabeled peptides that varied in physical properties (molecular weight, lipophilicity, and hydrogen bonding sites) had suggested that intestinal transport of these peptides was most influenced by the number of hydrogen bonding sites, the major determinant of desolvation energy. To determine whether this correlation could be confirmed in vivo, intestinal absorption was determined by comparing the biliary and urinary recovery of these radiolabeled peptides in rats given intravenous or intraduodenal doses. Absorption was inversely correlated to the number of calculated hydrogen bonding sites for the model peptides, similar to what had been found in vitro. Clearance by liver and kidneys appeared to be unaffected by desolvation energy but was well correlated with lipophilicity.     

Structural variations in the crystal structures of two homologous DL-Leu and Δ-Leu containing peptides+

The similar conformations and interaction modes of Ac-DL-Leu-Nme₂ and Ac-Δ-Leu-NMe₂ molecules in the solid state allow the comparison of their geometrical parameters. The most evident variations are essentially restricted to the α,β-unsaturated side-chain which adopts the Z-disposition. The dimensions of the peptide backbone are much less sensitive to α,β-unsaturation, with a small shortening by 0.04 Å and 0.02 Å of the N-C^α and C^α-C′ bonds, respectively, and an increase by 6° of the N-C^α- C′ bond angle. The ethylenic and amide groups in the Δ-Leu derivative are far from coplanarity, and a significant electronic conjugation of the π-orbital is likely to be rejected.     

Conformation and structure of linear peptides with regularly alternating l- and d-residues: structure of the blocked hexapeptide tert-butyloxycarbonyl-(d-alloisoleucyl-l-isoleucyl)3 methyl ester monohydrate

Peptides with a regular sequence of enantiomeric residues (l and d ) along the chain have received considerable attention because of their accessibility to unique conformations and because they are model compounds for the naturally occurring peptide gramicidin A, which shows monovalent cation selective transmembrane transport. The solid-state structure of the linear hexapeptide t-Boc-(d -aIle-l -Ile)₃-OMe has been determined by X-ray diffraction techniques and refined to a final R factor of 0.068. The molecule shows a bent U-shaped conformation stabilized by three intramolecular H-bonds of the N—H?O=C type: a type II β-bend (4 → 1 bend or C₁₀ ring structure) with l -Ile² and d -aIle³ at positions 2 and 3 of the bend, an α-turn (5 → 1 bend or C₁₃ ring structure) and a 1 → 5 bend or C₁₇ ring structure. The first two 10-membered and 13-membered bends are enclosed in the latter 17-membered hydrogen-bonded ring structure. This structural motif is common to hepta- and octa-peptide cyclic molecules, showing that ring closure is not required to achieve a particular topology in the molecular design of specific bended conformations. © Munksgaard 1995.     

Curcumin amorphous solid dispersions: the influence of intra and intermolecular bonding on physical stability

Abstract

We have investigated the physical stability of amorphous curcumin dispersions and the role of curcumin–polymer intermolecular interactions in delaying crystallization. Curcumin is an interesting model compound as it forms both intra and intermolecular hydrogen bonds in the crystal. A structurally diverse set of amorphous dispersion polymers was investigated; poly(vinylpyrrolidone), Eudragit E100, carboxymethyl cellulose acetate butyrate, hydroxypropyl methyl cellulose (HPMC) and HPMC-acetate succinate. Mid-infrared spectroscopy was used to determine and quantify the extent of curcumin–polymer interactions. Physical stability under different environmental conditions was monitored by powder X-ray diffraction. Curcumin chemical stability was monitored by UV-Vis spectroscopy. Isolation of stable amorphous curcumin was difficult in the absence of polymers. Polymers proved to be effective curcumin crystallization inhibitors enabling the production of amorphous solid dispersions; however, the polymers showed very different abilities to inhibit crystallization during long-term storage. Curcumin intramolecular hydrogen bonding reduced the extent of its hydrogen bonding with polymers; hence most polymers were not highly effective crystallization inhibitors. Overall, polymers proved to be crystallization inhibitors, but inhibition was limited due to the intramolecular hydrogen bonding in curcumin, which leads to a decrease in the ability of the polymers to interact at a molecular level.