103 research outputs found
Parallel packing of α-helices in crystals of the zervamicin IIA analog Boc-Trp-Ile-Ala-Aib-Ile-Val-Aib-Leu-Aib-Pro-OMe.2H<SUB>2</SUB>0
Get PDFAn apolar synthetic analog of the first 10 residues at the NH2-terminal end of zervamicin HA crystallizes in the triclinic space group P1 with cell dimensions a = 10.206 ± 0.002 A, b = 12.244 ± 0.002 A, c = 15.049 ± 0.002 A, α = 93.94 ± 0.01°, β = 95.10 ± 0.01°, γ = 104.56 ± 0.01°, Z = 1, C60H97N1103.2H2O. Despite the relatively few a-aminoisobutyric acid residues, the peptide maintains a helical form. The first intrahelical hydrogen bond is of the 310 type between N(3) and 0(0), followed by five α-helix-type hydrogen bonds. Solution 1H NMR studies in chloroform also favor a helical conformation, with seven solvent-shielded NH groups. Continuous columns are formed by head-to-tail hydrogen bonds between the helical molecules along the helix axis. The absence of polar side chains precludes any lateral hydrogen bonds. Since the peptide crystallizes with one molecule in a trilinic space group, aggregation of the helical columns must necessarily be parallel rather than antiparallel. The packdng of the columns is rather inefficient, as indicated by very few good van der Waals' contacts and the occurrence of voids between the molecules
Apolar peptide models for conformational heterogeneity, hydration, and packing of polypeptide helices: crystal structure of hepta- and octapeptides containing α-aminoisobutyric acid
Get PDFThe crystal structures of two helical peptides Boc-Val-Ala-Leu-Aib-Val-Ala-Leu-OMe (VALU-7) and Boc-Val-Ala-Leu-Aib-Val-Ala-Leu-Aib-OMe (VALU-8) have been determined to a resolution of 1.0 and 0.9 Å, respectively. Both the seven and eight residue peptides crystallize with two conformers per asymmetric unit. The VALU-8 conformers are completely helical and differ only at the C-terminus by a sign reversal of the φ ψ angles of the last residue. One of the VALUE-7 conformers occurs as a normal -helix, whereas in the other, the N(7) = O(3) α-type hydrogen bond is ruptured by the entry of a water molecule (W) into the helix, which in turn makes hydrogen bonds N(7)W = 2.97 Å and O(3) = 2.77 Å. The other side of the water molecule is surrounded by a hydrophobic pocket. These two conformers give a static representation of a step in a possible helix unwinding or folding process. In the value-8 crystal the helices aggregate in a parallel mode, whereas the aggregation is antiparallel in the VALUE-7 crystal. The crystal parameters are VALUE-7 crystal. The crystal parameters are VALUE-7, P21, a = 10.203 (3) Å, b = 19.744 (6) Å, c = 22.561 (6) Å, α = 96.76°, Z = 4, C38, H69N7O10·0.5 H2O, R = 6.65% for 3674 reflections observed gt; 3σ(F): and VALU-8, P21, a; = 10.596 (4) Å, b = 27.57 (6) Å, c = 17.745 (5) Å, β = 95.76 (3)°, Z = 4, C42H76N76O11·0.25 CH3OH, R = 6.63% for 4701 reflections observed gt; 3σ(F)
Designed β-hairpin peptides with defined tight turn stereochemistry
Get PDFThe conformational analysis of two synthetic octapeptides, Boc-Leu-Val-Val-D-Pro-L-Ala-Leu-Val-Val-OMe (1) and Boc-Leu-Val-Val-D-Pro-D-Ala-Leu-Val-Val-OMe (2) has been carried out in order to investigate the effect of β-turn stereochemistry on designed β-hairpin structures. Five hundred megahertz 1H NMR studies establish that both peptides 1 and 2 adopt predominantly β-hairpin conformations in methanol solution. Specific nuclear Overhauser effects provide evidence for a type II′ β-turn conformation for the D-Pro-L-Ala segment in 1, while the NMR data suggest that the type I D-Pro-D-Ala β-turn conformation predominates in peptide 2. Evidence for a minor conformation in peptide 2, in slow exchange on the NMR time scale, is also presented. Interstrand registry is demonstrated in both peptides 1 and 2. The crystal structure of 1 reveals two independent molecules in the crystallographic asymmetric unit, both of which adopt β-hairpin conformations nucleated by D-Pro-L-Ala type II′ β-turns and are stabilized by three cross-strand hydrogen bonds. CD spectra for peptides 1 and 2 show marked differences, presumably as a consequence of the superposition of spectral bands arising from both β-turn and β-strand conformations
Helix packing of leucine-rich peptides: A parallel leucine ladder in the structure of Boc-Aib-Leu-Aib-Aib-Leu-Leu-Leu-Aib-Leu-Aib-OMe
Get PDFThe packing of peptide helices in crystals of the leucine-rich decapeptide Boc-Aib-Leu-Aib-Aib-Leu-Leu-Leu-Aib-Leu-Aib-OMe provides an example of ladder-like leucylleucyl interactions between neighboring molecules. The peptide molecule forms a helix with five 5→1 hydrogen bonds and two 4→1 hydrogen bonds near the C terminus. Three head-to-tail NH c O = C hydrogen bonds between helices form continuous columns of helices in the crystal. The helicial columns associate in an antiparallel fashion, except for the association of Leu Leu side chains, which occurs along the diagonal of the cell where the peptide helices are parallel. The peptide, with formula C56H102N10O13, crystallizes in space group P212121 with Z = 4 and cell parameters a = 16.774(3) Å, b = 20.032(3) Å and c = 20.117(3) Å; overall agreement factor R = 10.7% for 2014 data with |Fobs| <3σ(F); resolution 1.0 Å
Conformation of a 16-residue zervamicin IIA analog peptide containing three different structural features: 3<SUB>10</SUB>-helix, α-helix, and β-bend ribbon
Get PDFBoc-Trp-Ile-Ala-Aib-Ile-Val-Aib-Leu-Aib- Pro-Ala-Aib-Pro-Aib-Pro-Phe-OMe (where Boc is t-butoxycarbonyl and Aib is a-aminoisobutyric acid), a synthetic apolar analog of the membrane-active fungal peptide antibiotic zervamycin IIA, crystallizes in space group P1 with Z = 1 and cell parameters a = 9.086 ± 0.002 A:, b = 10.410 ± 0.002 A, c = 28.188 ± 0.004 A, α = 86.13 ± 0.01°, β = 87.90 ± 0.01°, and γ = 89.27 ± 0.01°; overall agreement factor R = 7.3% for 7180 data (Fo > 3σ) and 0.91-A resolution. The peptide backbone makes a continuous spiral that begins as a 310-helix at the N-terminus, changes to an α-helix for two turns, and ends in a spiral of three β-bends in a ribbon. Each of the β-bends contains a proline residue at one of the corners. The torsion angles φi range from -51° to -91° (average value -64°), and the torsion angles ψi range from -1° to -46° (average value -31°). There are 10 intramolecular NH-..OC hydrogen bonds in the helix and two direct head-to-tail hydrogen bonds between successive molecules. Two H20 and two CH3OH solvent molecules fill additional space with appropriate hydrogen bonding in the head-to-tail region, and two additional H20 molecules form hydrogen bonds with carbonyl oxygens near the curve in the helix at Pro-10. Since there is only one peptide molecule per cell in space group P1, the molecules repeat only by translation, and consequently the helices pack parallel to each other
Aggregation studies in crystals of apolar helical peptides: Boc-Aib-Val-Ala-Leu-Aib-Val-Ala-Leu-Aib-OMe
Get PDFIn the crystal, the backbone of Boc-(Aib-Val-Ala-Leu)2-Aib-OMc adopts a helical form with four α-type hydrogen bonds in the middle, flanked by 310-type hydrogen bonds at either end. The helical molecules stack in columns with head-to-tail hydrogen bonds, either directly between NH and CO, or bridged by solvent molecules. The packing of the helices is parallel, even in space group P21. Cell parameters are a = 9.837(2) Å. b = 15.565(3) Å. c = 20.087(5) Å, β= 96.42(2)°. dcalc= 1.091 g/cm3 for C46H83,N9O12· 1.5H2O·0.67CH3OH. There appears to be some hydration of the backbone in this apolar helix
Peptide hairpins with strand segments containing α- and β-amino acid residues: Cross-strand aromatic interactions of facing Phe residues
Get PDFThe incporation of β-amino acid residues into the strand segments of designed β-hairpin leads to the formation of polar sheets, since in the case of β-peptide strands, all adjacent carbonyl groups point in one direction and the amide groups orient in the opposite direction. The conformational analysis of two designed peptide hairpins composed of α/β-hybrid segments are described: Boc-βLeu-βPhe-Val-D-Pro-Gly-βLeu-βPhe-Val-OMe (1) and Boc-βLeu-Phe-βVal-D-Pro-Gly-βLeu-Phe-βVal-OMe (2). A 500-MHz 1H-NMR (nuclear magnetic resonance) analysis in methanol supports a significant population of hairpin conformations in both peptides. Diagnostic nuclear Overhauser effects (NOEs) are observed in both cases. X-ray diffraction studies on single crystals of peptide 1 reveal a β-hairpin conformation in both the molecules, which constitute the crystallographic asymmetric unit. Three cross-strand hydrogen bonds and a nucleating type II′ β-turn at the D-Pro-Gly segment are observed in the two independent molecules. In peptide 1, the Phe residues at positions 2 and 7 occur at the nonhydrogen-bonding position, with the benzyl side chains pointing on opposite faces of the β-sheet. The observed aromatic centroid-to-centroid distances are 8.92 Å (molecule A) and 8.94 Å (molecule B). In peptide 2, the aromatic rings must occupy facing positions in antiparallel strands, in the NMR-derived structure. Peptide 1 yields a normal hairpin-like CD spectrum in methanol with a minimum at 224 nm. The CD spectrum of peptide 2 reveals a negative band at 234 nm and a positive band at 221 nm, suggestive of an exciton split doublet. Modeling of the facing Phe side chains at the hydrogen-bonding position of a canonical β-hairpin suggests that interring separation is 4.78 Å for the gauche+gauche- (g+g-) rotamer. A previously reported peptide β-hairpin composed of only α-amino acids, Boc-Leu-Phe-Val-D-Pro-Gly-Leu-Phe-Val-OMe also exhibited an anomalous far-UV (ultraviolet) CD (circular dichroism) spectrum, which was interpreted in terms of interactions between facing aromatic chromophores, Phe 2 and Phe
Two novel hexadepsipeptides with several modified amino acid residues isolated from the fungus isaria
Get PDFTwo new cyclohexadepsipeptides have been isolated from the fungus Isaria. Fungal growth in solid media yielded hyphal strands from which peptide fractions were readily isolable by organic-solvent extraction. Two novel cyclodepsipeptides, isaridin A and isaridin B, have been isolated by reverse-phase HPLC, and characterized by ESI-MS and 1H-NMR. Single crystals of both peptides have been obtained, and their 3D structures were elucidated by X-ray diffraction. The isaridins contain several unusual amino acid residues. The sequences are cyclo(β-Gly-HyLeu-Pro-Phe-NMeVal-NMePhe) and cyclo(β-Gly-HyLeu-β-MePro-Phe-NMeVal-NMePhe), where NMeVal is N-methylvaline, NMePhe N-methylphenylalanine, and HyLeu hydroxyleucine (=2-hydroxy-4-methylpentanoic acid). The two peptides differ from one another at residue 3, isaridin A having an (S)-proline at this position, while β-methyl-(S)-proline (=(2S,3S)-2,3,4,5-tetrahydro-3-methyl-1H-pyrrole-2-carboxylic acid) is found in isaridin B. The solid-state conformations of both cyclic depsipeptides are characterized by the presence of two cis peptide bonds at HyLeu(2)-Pro(3)/HyLeu(2)-β-MePro(3) and NMeVal(5)-NMePhe(6), respectively. In isaridin A, a strong intramolecular H-bond is observed between Phe(4)CO...HNβ-Gly(1), and a similar, but weaker, interaction is observed between β-Gly(1)COHNPhe(4). In contrast, in isaridin B, only a single intramolecular H-bond is observed between β-Gly(1)CO...HNPhe(4)
Crystal Structure of (−)-Mefloquine Hydrochloride Reveals Consistency of Configuration with Biological Activity
No full textThe absolute configuration of (−)-mefloquine has been established as 11R,12S by X-ray crystallography of the hydrochloride salt, thus allowing comparison of the configuration of mefloquine's optical isomers to those of quinine and quinidine. (−)-Mefloquine has the same stereochemistry as quinine, and (+)-mefloquine has the same stereochemistry as quinidine. Since (+)-mefloquine is more potent than (−)-mefloquine in vitro against the D6 and W2 strains of Plasmodium falciparum and quinidine is more potent than quinine, a common stereochemical component for antimalarial activity is implicated. The crystal of (−)-mefloquine hydrochloride contained four different conformations which mainly differ in a small rotation of the piperidine ring. These conformations are essentially the same as the crystalline conformations of racemic mefloquine methylsulfonate monohydrate, mefloquine hydrochloride, and mefloquine free base. The crystallographic parameters for (−)-mefloquine hydrochloride hydrate were as follows: C(17)H(17)F (6)N(2)O(+)Cl(−) · 0.25 H(2)O; M(r), 419.3; symmetry of unit cell, orthorhombic; space group, P2(1)2(1)2(1); parameters of unit cell, a = 12.6890 ± 0.0006 Å (1 Å = 0.1 nm), b = 18.9720 ± 0.0009 Å, c = 32.189 ± 0.017 Å; volume of unit cell, 7,749 ± 4 Å(3); number of molecules per unit cell, 16; calculated density, 1.44 g cm(−3); source of radiation, Cu Kα (λ = 1.54178 Å); μ (absorption coefficient), 2.373 mm(−1); room temperature was used; final R(1) (residual index), 0.0874 for 3,692 reflections with intensities greater than 2σ. All of the hydroxyl and amine hydrogen atoms participate in intermolecular hydrogen bonds with chloride ions. The orientation of the amine and hydroxyl groups in (+)-mefloquine may define the optimal geometry for hydrogen bonding with cellular constituents
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