RESUMEN
Gamma-aminobutyric acid (GABA, gammaAbu), an unsubstituted gamma-amino acid, is an important inhibitory neurotransmitter in the mammalian brain. The role of GABA in the treatment of epilepsy has triggered a great deal of interest in substituted gamma-amino acids, which may serve as GABA analogs, acting as inhibitors of GABA aminotransferase. Pregabalin (Pgn), a well-known antiepileptic drug, is also a beta-substituted gamma3-amino acid. Pregabalin and gamma4Leu, an isomer of the pregabalin (Pgn) residue, both carrying the same isobutyryl group in the side chain, were introduced in the present study to have a comparison of their respective conformational differences as well as their role in influencing the overall conformation of the peptides, they are inserted in. Two alpha-gamma-alpha-alpha-alpha hybrid pentapeptides were designed that contain Aib-Pgn and Aib-gamma4Leu segments at the N terminus. The study provides a detailed analysis of the conformational properties and non-covalent interactions observed in the crystal structures of two polymorphs of the pentapeptide monohydrate, Boc-Aib-(S)Pgn-Leu-Phe-Val-OMe (C38H63N5O8·H2O) and the isomeric pentapeptide, Boc-Aib-gamma4(R)Leu-Leu-Phe-Val-OMe (C38H63N5O8), obtained from single crystal X-ray diffraction experiments.
Asunto(s)
Aminoácidos/química , Péptidos/química , Pregabalina/química , Ácido gamma-Aminobutírico/química , Cristalografía por Rayos X , Isomerismo , Modelos Moleculares , Oligopéptidos/química , Péptidos/síntesis química , Conformación Proteica , Ácido gamma-Aminobutírico/análogos & derivadosRESUMEN
The solid-state conformations of two αγ hybrid peptides Boc-[Aib-γ(4) (R)Ile]4 -OMe 1 and Boc-[Aib-γ(4) (R)Ile]5 -OMe 2 are described. Peptides 1 and 2 adopt C12 -helical conformations in crystals. The structure of octapeptide 1 is stabilized by six intramolecular 4 â 1 hydrogen bonds, forming 12 atom C12 motifs. The structure of peptide 2 reveals the formation of eight successive C12 hydrogen-bonded turns. Average backbone dihedral angles for αγ C12 helices are peptide 1, Aib; φ (°) = -57.2 ± 0.8, ψ (°) = -44.5 ± 4.7; γ(4) (R)Ile; φ (°) = -127.3 ± 7.3, θ1 (°) = 58.5 ± 12.1, θ2 (°) = 67.6 ± 10.1, ψ (°) = -126.2 ± 16.1; peptide 2, Aib; φ (°) = -58.8 ± 5.1, ψ (°) = -40.3 ± 5.5; ψ(4) (R)Ile; φ (°) = -123.9 ± 2.7, θ1 (°) = 53.3 θ 4.9, θ 2 (°) = 61.2 ± 1.6, ψ (°) = -121.8 ± 5.1. The tendency of γ(4) -substituted residues to adopt gauche-gauche conformations about the C(α) -C(ß) and C(ß) -C(γ) bonds facilitates helical folding. The αγ C12 helix is a backbone expanded analog of α peptide 310 helix. The hydrogen bond parameters for α peptide 310 and α-helices are compared with those for αγ hybrid C12 helix. Copyright © 2016 European Peptide Society and John Wiley & Sons.
Asunto(s)
Proteínas Portadoras/química , Péptidos/química , Secuencia de Aminoácidos , Cristalografía por Rayos X , Proteínas de Unión al ADN , Humanos , Enlace de Hidrógeno , Modelos Moleculares , Péptidos/síntesis química , Estructura Secundaria de ProteínaRESUMEN
The present study describes the synthesis and crystallographic analysis of αγ hybrid peptides, Boc-Gpn-L-Pro-NHMe (1), Boc-Aib-Gpn-L-Pro-NHMe (2), and Boc-L-Pro-Aib-Gpn-L-Pro-NHMe (3). Peptides 1 and 2 adopt expanded 12-membered (C12 ) helical turn over γα segment. Peptide 3 promotes the ribbon structure stabilized by type II ß-turn (C10 ) followed by the expanded C12 helical γα turn. Both right-handed and left-handed helical conformations for Aib residue are observed in peptides 2 and 3, respectively.
Asunto(s)
Oligopéptidos/química , Secuencia de Aminoácidos , Cristalografía por Rayos X , Enlace de Hidrógeno , Modelos Moleculares , Conformación Proteica en Hélice alfa , Estabilidad ProteicaRESUMEN
N-Protected derivatives of 1-amino-cyclo-hexa-neacetic acid (ß(3,3)-Ac6c), namely Valeroyl-ß(3,3)-Ac6c-OH [2-(1-pentanamidocyclohexyl)acetic acid, C13H23NO3], (I), Fmoc-ß(3,3)-Ac6c-OH [2-(1-{[(9H-fluoren-9-yloxy)carbonyl]amino}cyclohexyl)acetic acid, C23H25NO4], (II), and Pyr-ß(3,3)-Ac6c-OH {2-[1-(pyrazine-2-amido)cyclohexyl]acetic acid, C13H17N3O3}, (III), were synthesized and their conformational properties were determined by X-ray diffraction analysis. The backbone torsion angles (Ï, θ) for ß(3,3)-Ac6c-OH are restricted to gauche conformations in all the derivatives, with a chair conformation of the cyclo-hexane ring. In the crystal structure of (I), the packing of mol-ecules shows both carb-oxy-lic acid R 2 (2)(8) O-Hâ¯O and centrosymmetric R (2) 2(14) N-Hâ¯O hydrogen-bonding inter-actions, giving rise to chains along the c-axis direction. In (II), centrosymmetric carb-oxy-lic acid R 2 (2)(8) O-Hâ¯O dimers are extended through N-Hâ¯O hydrogen bonds and together with inter-ring π-π inter-actions between Fmoc groups [ring centroid distance = 3.786â (2)â Å], generate a layered structure lying parallel to (010). In the case of compound (III), carb-oxy-lic acid O-Hâ¯Npyrazine hydrogen bonds give rise to zigzag ribbon structures extending along the c-axis direction.
RESUMEN
The crystal structures of several designed peptide hairpins have been determined in order to establish features of molecular conformations and modes of aggregation in the crystals. Hairpin formation has been induced using a centrally positioned (D)Pro-Xxx segment (Xxx = (L)Pro, Aib, Ac6c, Ala; Aib = α-aminoisobutyric acid; Ac6c = 1-aminocyclohexane-1-carboxylic acid). Structures of the peptides Boc-Leu-Phe-Val-(D)Pro-(L)Pro-Leu-Phe-Val-OMe (1), Boc-Leu-Tyr-Val-(D)Pro-(L)Pro-Leu-Phe-Val-OMe (2, polymorphic forms labeled as 2a and 2b), Boc-Leu-Val-Val-(D)Pro-(L)Pro-Leu-Val-Val-OMe (3), Boc-Leu-Phe-Val-(D)Pro-Aib-Leu-Phe-Val-OMe (4, polymorphic forms labeled as 4a and 4b), Boc-Leu-Phe-Val-(D)Pro-Ac6c-Leu-Phe-Val-OMe (5) and Boc-Leu-Phe-Val-(D)Pro-Ala-Leu-Phe-Val-OMe (6) are described. All the octapeptides adopt type II' ß-turn nucleated hairpins, stabilized by three or four cross-strand intramolecular hydrogen bonds. The angle of twist between the two antiparallel strands lies in the range of -9.8° to -26.7°. A detailed analysis of packing motifs in peptide hairpin crystals is presented, revealing three broad modes of association: parallel packing, antiparallel packing and orthogonal packing. An attempt to correlate aggregation modes in solution with observed packing motifs in crystals has been made by indexing of crystal faces in the case of three of the peptide hairpins. The observed modes of hairpin aggregation may be of relevance in modeling multiple modes of association, which may provide insights into the structure of insoluble polypeptide aggregates.
Asunto(s)
Péptidos/química , Cristalización , Cristalografía por Rayos X , Modelos Moleculares , Péptidos/síntesis química , Estructura Secundaria de ProteínaRESUMEN
2-{1-[(Pyrazin-2-ylformamido)methyl]cyclohexyl}acetic acid (Pyr-Gpn-OH), C14H19N3O3, is an N-protected derivative of gabapentin (Gpn). The compound crystallizes in the triclinic space group P1 and the molecular conformation is stabilized by intramolecular five- (C5) and seven-membered (C7) hydrogen-bonded rings. The packing of the molecules reveals intermolecular O-H···O and C-H···N hydrogen bonds, together with π-π interactions.
Asunto(s)
Aminas/química , Ácidos Ciclohexanocarboxílicos/química , Ciclohexanos/química , Pirazinas/química , Ácido gamma-Aminobutírico/química , Cristalografía por Rayos X , Gabapentina , Enlace de Hidrógeno , Conformación Molecular , Estructura MolecularRESUMEN
The title compound, C12H23NO2·0.5H2O, crystallized with two 2-(1-amino-4-tert-butylcyclohexyl)acetic acid mol-ecules, which are present as zwitterions, and one water mol-ecule in the asymmetric unit. The mol-ecular structure of each zwitterion is stabilized by an intra-molecular six-membered (C 6 ) N-Hâ¯O hydrogen bond. In the crystal, the two independent zwitterions are linked head-to-head by N-Hâ¯O hydrogen bonds. Further O-Hâ¯O and N-Hâ¯O hydrogen bonds link the zwitterions and the water molecules, forming sandwich-like layers, with a hydrophilic filling and a hydrophobic exterior, lying parallel to the ab plane.
RESUMEN
An 18-residue sequence Boc-Aib-Val-Ala-Leu-Aib-Val-Ala-Leu-Gly-Pro-Val-Ala-Leu-Aib-Val-Ala-Leu-Aib-OMe (UK18) was designed to examine the effect of introducing a Gly-Pro segment into the middle of a potentially helical peptide. The crystal structures of two polymorphic forms yielded a view of the conformation of three independent molecules. Form 1 (space group P2(1)2(1)2(1,) a = 14.620Å; b = 26.506Å, c = 28.858Å, Z = 4) has one molecule in the asymmetric unit, with one cocrystallized water molecule. Form 2 (space group P2(1)2(1)2(1,) a = 9.696Å; b = 19.641Å, c = 114.31Å, Z = 8) has two molecules in the asymmetric unit with four cocrystallized water molecules. In Form 1, residues 1 to 18 adopt Ï,ψ values that lie in the right-handed helical (α(R) ) region of the Ramachandran map. Two residues, Leu (8) (Ï = -92.0°, ψ = -7.5°) and Leu (17) (Ï = -94.7°, ψ = -1.7°) adopt conformations that deviate significantly from helical values. In Form 2, molecule A, residues 2 to 16 lie in the α(R) region of Ï,ψ space, with Leu (8) (Ï = -94.9°, ψ = -2.9°) deviating significantly from helical values. Aib (1) and Aib (18) adopt left-handed (α(L)) helical conformation. Significant distortion is observed at Leu (17) (Ï = -121.3°, ψ = -31.3°). Molecule B, Form 2, adopts a right-handed helix over residues 1 to 17. In all three molecules, a distinct bend in the helix is observed, with the bend angle values varying from 40.8° to 58.9°.
Asunto(s)
Secuencia de Aminoácidos , Conformación Proteica , Enlace de Hidrógeno , Oligopéptidos/química , Péptidos/química , Estructura Secundaria de Proteína , AguaRESUMEN
The effect of incorporation of a centrally positioned Ac(6)c-Xxx segment where Xxx = (L)Val/(D)Val into a host oligopeptide composed of l-amino acid residues has been investigated. Studies of four designed octapeptides Boc-Leu-Phe-Val-Ac(6)c-Xxx-Leu-Phe-Val-OMe (Xxx = (D)Val 1, (L)Val 2) Boc-Leu-Val-Val-Ac(6)c-Xxx-Leu-Val-Val-OMe (Xxx = (D)Val 3, (L)Val 4) are reported. Diagnostic nuclear Overhouse effects characteristic of hairpin conformations are observed for Xxx = (D)Val peptides (1 and 3) while continuous helical conformation characterized by sequential N(i)H â N(i+1)H NOEs are favored for Xxx = (L)Val peptides (2 and 4) in methanol solutions. Temperature co-efficient of NH chemical shifts are in agreement with distinctly different conformational preferences upon changing the configuration of the residue at position 5. Crystal structures of peptides 2 and 4 (Xxx = (L)Val) establish helical conformations in the solid state, in agreement with the structures deduced from NMR data. The results support the design principle that centrally positioned type I ß-turns may be used to nucleate helices in short peptides, while type I'ß-turns can facilitate folding into ß-hairpins.
Asunto(s)
Dipéptidos/química , Péptidos/química , Cristalografía por Rayos X , Enlace de Hidrógeno , Modelos Moleculares , Estructura Secundaria de ProteínaRESUMEN
[This corrects the article DOI: 10.1039/C3RA42884B.].
RESUMEN
Peptide nanotubes with filled and empty pores and close-packed structures are formed in closely related pentapeptides. Enantiomorphic sequences, Boc-(D)Pro-Aib-Xxx-Aib-Val-OMe (Xxx = Leu, 1; Val, 2; Ala, 3; Phe, 4) and Boc-Pro-Aib-(D)Xxx-Aib-(D)Val-OMe ((D)Xxx = (D)Leu, 5; (D)Val, 6; (D)Ala, 7; (D)Phe, 8), yield molecular structures with a very similar backbone conformation but varied packing patterns in crystals. Peptides 1, 2, 5, and 6 show tubular structures with the molecules self-assembling along the crystallographic six-fold axis (c-axis) and revealing a honeycomb arrangement laterally (ab plane). Two forms of entrapped water wires have been characterized in 2: 2a with d(O...O) = 2.6 A and 2b with d(O...O) = 3.5 A. The latter is observed in 6 (6a) also. A polymorphic form of 6 (6b), grown from a solution of methanol-water, was observed to crystallize in a monoclinic system as a close-packed structure. Single-file water wire arrangements encapsulated inside hydrophobic channels formed by peptide nanotubes could be established by modeling the published structures in the cases of a cyclic peptide and a dipeptide. In all the entrapped water wires, each water molecule is involved in a hydrogen bond with a previous and succeeding water molecule. The O-H group of the water not involved in any hydrogen bond does not seem to be involved in an energetically significant interaction with the nanotube interior, a general feature of the one-dimensional water wires encapsulated in hydrophobic environments. Water wires in hydrophobic channels are contrasted with the single-file arrangements in amphipathic channels formed by aquaporins.
Asunto(s)
Nanotubos/química , Péptidos/química , Agua/química , Cristalografía por Rayos X , Interacciones Hidrofóbicas e Hidrofílicas , Modelos Moleculares , Conformación MolecularRESUMEN
The alpha-aminoisobutyric acid-D-proline (Aib-(D)Pro) dipeptide is an obligatory Type I' beta-turn forming segment that nucleates hairpin formation.
Asunto(s)
Dipéptidos/química , Secuencia de Aminoácidos , Enlace de Hidrógeno , Modelos Moleculares , Estructura Secundaria de ProteínaRESUMEN
The crystallographic observation of a hydrophobic, empty channel (diameter approximately 5.2 A) in the peptide Boc-(D)Pro-Aib-Leu-Aib-Val-OMe, prompted the investigation of the analog Boc-(D)Pro-Aib-Val-Aib-Val-OMe in which the side chain at position 3 was shortened, resulting in the structure of a channel (diameter approximately 7.5 A) containing a one-dimensional wire of water molecules. Crystallization in the space group P6(5) facilitates formation of a pore lined entirely by hydrocarbon side chains. Two forms of the entrapped water wires, with O...O separations of 3.5 and 2.6 A, are discussed. A lone hydrogen bond between the adjacent pairs of water molecules in the wire, with no strong interactions between the second water hydrogen and the hydrophobic walls of the channel, is a feature of the one-dimensional array. The structure provides the first crystallographic characterization of a water wire in a hydrophobic channel with implications in water and proton transport in membranes and carbon nanotubes.
Asunto(s)
Interacciones Hidrofóbicas e Hidrofílicas , Péptidos/química , Agua/química , Cristalografía por Rayos X , Enlace de Hidrógeno , Modelos Moleculares , Estructura Terciaria de ProteínaRESUMEN
The alpha-aminoisobutyric (Aib) residue has generally been considered to be a strongly helicogenic residue as evidenced by its ability to promote helical folding in synthetic and natural sequences. Crystal structures of several peptide natural products, peptaibols, have revealed predominantly helical conformations, despite the presence of multiple helix-breaking Pro or Hyp residues. Survey of synthetic Aib-containing peptides shows a preponderance of 3(10)-, alpha-, and mixed 3(10)/alpha-helical structures. This review highlights the examples of Aib residues observed in nonhelical conformations, which fall 'primarily' into the polyproline II (P(II)) and fully extended regions of conformational space. The achiral Aib residue can adopt both left (alpha(L))- and right (alpha(R))-handed helical conformations. In sequences containing chiral amino acids, helix termination can occur by means of chiral reversal at an Aib residue, resulting in formation of a Schellman motif. Examples of Aib residues in unusual conformations are illustrated by surveying a database of Aib-containing crystal structures.
Asunto(s)
Ácidos Aminoisobutíricos/química , Peptaiboles/química , Conformación Proteica , Modelos Moleculares , Conformación Molecular , Péptidos/química , Péptidos Cíclicos/químicaRESUMEN
The crystal structure of the 13 residue peptide Boc-Leu-Aib-Val-Ala-Leu-Aib-Val-DAla-DLeu-Aib-Leu-Aib-Val-OMe reveals a continuous helical conformation providing an unambiguous characterization of contiguous D-residues in a right handed peptide helix.
Asunto(s)
Oligopéptidos/síntesis química , Cristalografía por Rayos X , Enlace de Hidrógeno , Estructura Molecular , Oligopéptidos/química , Estructura Secundaria de Proteína , EstereoisomerismoRESUMEN
The hybrid ßγ dipeptide, methyl 2-[1-({2-[(tert-butoxycarbonyl)amino]benzamido}methyl)cyclohexyl]acetate (Boc-Ant-Gpn-OMe), C22H32N2O5, adopts a folded conformation stabilized by intramolecular six- (C6) and seven-membered (C7) hydrogen-bonded rings, together with weak C-H...O and C-H...π interactions, resulting in a ribbon-like structure.
Asunto(s)
Aminoácidos/química , Benzamidas/química , Ciclohexanos/química , Dipéptidos/química , Cristalografía por Rayos X , Enlace de Hidrógeno , Conformación Molecular , Estructura MolecularRESUMEN
The crystal structure of N-[(1-{2-oxo-2-[2-(pyrazin-2-ylcarbonyl)hydrazin-1-yl]ethyl}cyclohexyl)methyl]pyrazine-2-carboxamide monohydrate (Pyr-Gpn-NN-NH-Pyr·H2O), C19H23N7O3·H2O, reveals an unusual trans-gauche (tg(-)) conformation for the gabapentin (Gpn) residue around the C(γ)-C(ß) (θ1) and C(ß)-C(α) (θ2) bonds. The molecular conformation is stabilized by intramolecular N-H...N hydrogen bonds and weak C-H...O interactions. The packing of the molecules in the crystal lattice shows a network of strong N-H...O and O-H...O hydrogen bonds together with weak C-H...O and π-π inteactions.
Asunto(s)
Aminas/química , Ácidos Ciclohexanocarboxílicos/química , Hidrazinas/química , Pirazinas/química , Ácido gamma-Aminobutírico/química , Cristalografía por Rayos X , Gabapentina , Enlace de Hidrógeno , Conformación Molecular , Estructura Molecular , EstereoisomerismoRESUMEN
Enzymatic synthesis of oligosaccharides with absolute stereo-selectivity and regio-selectivity provides an economical alternative to classical chemical methods. Here we demonstrate, for the first time, that whole cells of P. etchellsii are highly efficient biocatalysts and can be used for oligosaccharide synthesis using p-nitrophenyl-ß-D-glucopyranoside, o-nitrophenyl-ß-D-glucopyranoside and p-nitrophenyl-ß-D-xylopyranoside as both donors and acceptors. Auto-condensation of p-nitrophenyl-ß-D-glucopyranoside and o-nitrophenyl-ß-D-glucopyranoside resulted in formation of ß-(1â6) linked disaccharide as major products in 4 and 12% yield respectively. By contrast, auto condensation of p-nitrophenyl-ß-D-xylopyranoside exclusively lead to formation of ß-(1â4) linked disaccharide in 24% yield.
Asunto(s)
Glicósido Hidrolasas , Oligosacáridos/biosíntesis , Pichia/enzimología , Glucósidos/química , Glicósido Hidrolasas/química , Glicósido Hidrolasas/metabolismo , Glicósidos/química , Humanos , Pichia/genéticaRESUMEN
In the first such example, NaBH4 in combination with cyanuric chloride (TCT) has been used to obtain 6-hydroxy-4-benzyl ether derivatives from 4,6-benzylidene acetals of carbohydrates. The nature of hydride donor determines the regioselectivity of acetal opening. High regioselectivity, scope for using a broad range of substrates, functional group tolerance, mild reaction conditions, easy handling process, inexpensive reagents and wide application mark the benefits of the newly developed reagent system.
Asunto(s)
Acetales/química , Alcoholes/síntesis química , Borohidruros/química , Carbohidratos/química , Triazinas/química , Alcoholes/química , Estructura Molecular , Oxidación-ReducciónRESUMEN
Crystal structures of eight peptide ß-hairpins in the sequence Boc-Leu-Phe-Val-Xxx-Yyy-Leu-Phe-Val-OMe revealed that the Phe(2) and Phe(7) aromatic rings are in close spacial proximity, with the centroid-centroid distance (R(cen)) of 4.4-5.4 Å between the two phenyl rings. Proton NMR spectra in chloroform and methanol solution reveal a significant upfield shift of the Phe(7) C(δ,δ') H(2) protons (6.65-7.04 ppm). Specific assignments of the aromatic protons have been carried out in the peptide Boc-Leu-Phe-Val-(D)Pro-(L)Pro-Leu-Phe-Val-OMe (6). The anticipated ring current shifts have been estimated from the aromatic ring geometrics observed in crystals for all eight peptides. Only one of the C(δ,δ') H proton lies in the shielding zone with rapid ring flipping, resulting in averaging between the two extreme chemical shifts. An approximate estimate of the population of conformations, which resemble crystal state orientation, may be obtained. Key nuclear Overhauser effects (NOEs) between facing Phe side chains provide support for close similarity between the solid state and solution conformation. Temperature dependence of aromatic ring proton chemical shift and line widths for peptide 6 (Boc-Leu-Phe-Val-(D)Pro-(L)Pro-Leu-Phe-Val-OMe) and the control peptide Boc-Leu-Val-Val-(D)Pro-Gly-Leu-Phe-Val-OMe establish an enhanced barrier to ring flipping when the two Phe rings are in proximity. Modeling studies suggest that small, conformational adjustment about C(α)-C(ß) (χ(1) ) and C(ß)-C(γ) (χ(2) ) bonds of both the Phe residues may be required in order to permit unhindered, uncorrelated flipping of both the Phe rings. The maintenance of the specific aromatic ring orientation in organic solvents provides evidence for significant stabilizing interaction.