Hydration and distortion of peptide helices in crystals. α-Helical structure of a dodecapeptide, Boc-(Ala-Leu-Aib)4-OMe

The dodecapeptide Boc-(Ala-Leu-Aib)(4)-OMe crystallized with two independent helical molecules in a triclinic cell. The two molecules are very similar in conformation, with a 3(10)-helix turn at the N-terminus followed by an alpha-helix, except for an elongated N(7)...O(3) distance in both molecules. All the helices in the crystal pack in a parallel motif. Eleven water sites have been found in the head-to-tail region between the apolar helices that participate in peptide-water hydrogen bonds and a network of water-water hydrogen bonds. The crystal parameters are as follows: 2(C58H104N12O15)+ca. 10H(2)O, space group P1 with a = 12.946(2), b = 17.321(3), c = 20.465(4) Angstrom, alpha = 103.12(2), beta = 105.63(2), gamma = 107.50(2)degrees, Z = 2, R = 10.9% for 5152 data observed > 3 sigma(F), resolution 1.0 Angstrom. In contrast to the shorter sequences [Karle et al. (1988)Proc. Natl. Acad. Sci. USA 85, 299-303] and Boc-(Ala-Leu-Aib)(2)-OMe [Karle et al. (1989) Biopolymers 28, 773-781], no insertion of a water molecule into the helix is observed. However, the elongated N---O distance between Ala(7) NH and Aib(3) CO in both molecules (molecule A, 3.40 Angstrom; molecule B, 3.42 Angstrom) is indicative of an incipient break in the helices. (C) Munksgaard 1994.

Stereochemical Analysis of Higher α,α-Dialkylglycine Containing Peptides. Characterization of Local Helical Conformations at Dipropylglycine Residues and Observation of a Novel Hydrated Multiple β-Turn Structure in Crystals of a Glycine Rich Peptide

The peptide Boc-Gly-Dpg-Gly-Gly-Dpg-Gly-NHMe (1) has been synthesized to examine the conformational preferences of Dpg residues in the context of a poor helix promoting sequence. Single crystals of 1 were obtained in the space group P21/c with a = 13.716(2) Å, b = 12.960(2) Å, c = 22.266(4) Å, and β = 98.05(1)°; R = 6.3% for 3660 data with |Fo| > 4σ. The molecular conformation in crystals revealed that the Gly(1)-Dpg(2) segment adopts φ, ψ values distorted from those expected for an ideal type II‘ β-turn (φGly(1) = +72.0°, ψGly(1) = −166.0°; φDpg(2) = −54.0°, ψDpg(2) = −46.0°) with an inserted water molecule between Boc-CO and Gly(3)NH. The Gly(3)-Gly(4) segment adopts φ, ψ values which lie broadly in the right handed helical region (φGly(3) = −78.0°, ψGly(3) = −9.0°; φGly(4) = −80.0°, ψGly(4) = −18.0°). There is a chiral reversal at Dpg(5) which takes up φ, ψ values in the left handed helical region. The Dpg(5)-Gly(6) segment closely resembles an ideal type I‘ β-turn (φDpg(5) = +56.0°, ψDpg(5) = +32.0°; φGly(6) = +85.0°, ψGly(6) = −3.0°). Molecules of both chiral senses are found in the centrosymmetric crystal. The C-terminus forms a hydrated Schellman motif, with water insertion into the potential 6 → 1 hydrogen bond between Gly(1)CO and Gly(6)NH. NMR studies in CDCl3 suggest substantial retention of the multiple turn conformation observed in crystals. In solution the observed NOEs support local helical conformation at the two Dpg residues.

Characterization of Alkali Induced Formation of Lanthionine, Trisulfides, and Tetrasulfides from Peptide Disulfides using Negative Ion Mass Spectrometry

Peptide disulfides are unstable under alkaline conditions, resulting in the formation of products containing lanthionine and polysulfied linkages. Electrospray ionization mass spectrometry has been used to characterize major species obtained when cyclic and acyclic peptide disulfides are exposed to alkaline media. Studies on a model cyclic peptide disulfide (Boc - Cys - Pro - Leu - Cys - NHMe) and an acyclic peptide, oxidized glutathione, bis ((gamma)Glu Cys - Gly - COOH), are described. Disulfide cleavage reactions are initiated by the abstraction of (CH)-H-alpha or (CH)-H-beta protons of Cys residues, with Subsequent elimination of H2S or H2S2. The buildup of reactive thiol species which act on intermediates containing dehydroalanine residues, rationalizes the formation of lanthionine and polysulfide products. In the case of the cyclic peptide disulfide, the formation of cyclic products is facilitated by the intramolecular nature of the Michael addition reaction of thiols to the dehydroalanine residue. Mass spectral evidence for the intermediate species is presented by using alkylation of thiol groups as a trapping method. Mass spectral fragmentation in the negative ion mode of the peptides derived from trisulfides and tetrasulfides results in elimination of S-2. (J Am Soc Mass Spectrom 2009, 20, 783-791) (C) 2009 American Society for Mass Spectrometry.

Characterization of Alkali Induced Formation of Lanthionine, Trisulfides, and Tetrasulfides from Peptide Disulfides using Negative Ion Mass Spectrometry

Peptide disulfides are unstable under alkaline conditions, resulting in the formation of products containing lanthionine and polysulfied linkages. Electrospray ionization mass spectrometry has been used to characterize major species obtained when cyclic and acyclic peptide disulfides are exposed to alkaline media. Studies on a model cyclic peptide disulfide (Boc - Cys - Pro - Leu - Cys - NHMe) and an acyclic peptide, oxidized glutathione, bis ((gamma)Glu Cys - Gly - COOH), are described. Disulfide cleavage reactions are initiated by the abstraction of (CH)-H-alpha or (CH)-H-beta protons of Cys residues, with Subsequent elimination of H2S or H2S2. The buildup of reactive thiol species which act on intermediates containing dehydroalanine residues, rationalizes the formation of lanthionine and polysulfide products. In the case of the cyclic peptide disulfide, the formation of cyclic products is facilitated by the intramolecular nature of the Michael addition reaction of thiols to the dehydroalanine residue. Mass spectral evidence for the intermediate species is presented by using alkylation of thiol groups as a trapping method. Mass spectral fragmentation in the negative ion mode of the peptides derived from trisulfides and tetrasulfides results in elimination of S-2. (J Am Soc Mass Spectrom 2009, 20, 783-791) (C) 2009 American Society for Mass Spectrometry.

Crystal structure of dimeric FabZ of Plasmodium falciparum reveals conformational switching to active hexamers by peptide flips

The crystal structure of beta-hydroxyacyl acyl carrier protein dehydratase of Plasmodium falciparum (PfFabZ) has been determined at a resolution of 2.4 angstrom. PfFabZ has been found to exist as a homodimer (d-PfFabZ) in the crystals of the present study in contrast to the reported hexameric form (h-PfFabZ) which is a trimer of dimers crystallized in a different condition. The catalytic sites of this enzyme are located in deep narrow tunnel-shaped pockets formed at the dimer interface. A histidine residue from one subunit of the dimer and a glutamate residue from the other subunit lining the tunnel form the catalytic dyad in the reported crystal structures. While the position of glutamate remains unaltered in the crystal structure of d-PffabZ compared to that in b-PfFabZ, the histidine residue takes up an entirely different conformation and moves away from the tunnel leading to a His-Phe cis-trans peptide flip at the histidine residue. In addition, a loop in the vicinity has been observed to undergo a similar flip at a Tyr-Pro peptide bond. These alterations not only prevent the formation of a hexamer but also distort the active site geometry resulting in a dimeric form of FabZ that is incapable of substrate binding. The dimeric state and an altered catalytic site architecture make d-PfFabZ distinctly different from the FabZ structures described so far. Dynamic light scattering and size exclusion chromatographic studies clearly indicate a pH-related switching of the dimers to active hexamers. (c) 2006 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserv.

Synthetic application of the diels-alder adduct of β-trans-ocimene and maleic anhydride-II. An approach towards the synthesis of valerenic acid

By a series of reactions the Diels-Alder adduct IV of maleic anhydride and β-trans-Ocimene gave 1-hydroxy-1,4-dimethyl-7-hydroxymethyloctahydroindane (XII). Its further synthetic elaboration furnished 1,4-dimethyl-7-(2-ethoxycarbonyl-1-propenyl)-Δ1-octahydroindane of the valerenic acid skeleton.

A designed (3-hairpin peptide in crystals

Beta-hairpin structures have been crystallographically characterized only in very short acyclic peptides, in contrast to helices. The structure of the designed beta-hairpin, t-butoxycarbonyl-Leu-Val-Val-D-Pro-Gly-Leu-Val-Val-OMe in crystals is described. The two independent molecules of the octapeptide fold into almost ideal beta-hairpin conformations with the central D-Pro-Gly segment adopting a Type II' beta-turn conformation. The definitive characterization of a beta-hairpin has implications for de novo peptide and protein design, particularly for the development of three- and four-stranded beta-sheets.

Synthetic investigations on testerone and its analogues—I *1: The total synthesis of 8-isotestosterone and its anthracene analogue

The total synthesis of 8-isotestosterone (II) and the corresponding anthracene analogue (III) following the benzohydrindane route is reported. Catalytic hydrogenation of trans-1β-acetoxy-8-methyl-4,5-(3′-methyl-4′-hydroxybenzo)-hydrindane (V) followed by oxidation has furnished two isomeric tricyclic keto acetates, viz. 1β,2α-(3′-acetoxycyclopentano)-2,5-dimethyl-6-keto-1α,2,3,4,4aα,-5α,6,7,8,8aα-decahydronaphthalene (VII) and 1β,2α-(3′-acetoxycyclopentano)-2,5-dimethyl-6-keto-1α,2,3,4,4aβ,5,6,7,8,8aβ-decahydronaphthalene (IX) which are cis-non-steroid and cis-steroid configurations of the same cyclopentano-cis-decalins. A difference in the direction of enolization of the keto acetate (VII) in alkylation reaction and enol acetylation towards the methine and the methylene carbon atoms respectively has been observed.

Synthetic investigations in the sesamin group - Part I. Synthesis of samin, a degradation product of sesamolin

Ethylα-bromovinylacetate (VII) was condensed with the sodio derivative of ethyl piperonoylacetate (VIII) to give diethylα-vinyl-α′-piperonoylsuccinate (IX). The latter on reduction with lithium aluminium hydride furnished the triol (X), which underwent smooth cyclisation with 1% ethanolic hydrogen chloride to 2-(3′, -methylenedioxyphenyl)-hydroxymethyl-4-vinyltetrahydrofuran (XIa). The structure of XIa was established by Oppenauer oxidation to an aldehyde. Ozonolysis of XIa afforded samin (I).

Potential functions for hydrogen bond interactions - III. Empirical Potential Function for the Peptide N-H...O=C Hydrogen Bond

A careful comparison of the distribution in the (R, θ)-plane of all NH ... O hydrogen bonds with that for bonds between neutral NH and neutral C=O groups indicated that the latter has a larger mean R and a wider range of θ and that the distribution was also broader than for the average case. Therefore, the potential function developed earlier for an average NH ... O hydrogen bond was modified to suit the peptide case. A three-parameter expression of the form {Mathematical expression}, with △ = R - Rmin, was found to be satisfactory. By comparing the theoretically expected distribution in R and θ with observed data (although limited), the best values were found to be p1 = 25, p3 = - 2 and q1 = 1 × 10-3, with Rmin = 2·95 Å and Vmin = - 4·5 kcal/mole. The procedure for obtaining a smooth transition from Vhb to the non-bonded potential Vnb for large R and θ is described, along with a flow chart useful for programming the formulae. Calculated values of ΔH, the enthalpy of formation of the hydrogen bond, using this function are in reasonable agreement with observation. When the atoms involved in the hydrogen bond occur in a five-membered ring as in the sequence[Figure not available: see fulltext.] a different formula for the potential function is needed, which is of the form Vhb = Vmin +p1△2 +q1x2 where x = θ - 50° for θ ≥ 50°, with p1 = 15, q1 = 0·002, Rmin = 2· Å and Vmin = - 2·5 kcal/mole. © 1971 Indian Academy of Sciences.

Synthetic investigation on the building of ring A of steroids

Methyl 7-keto-1,2,3,4,4a,5,6,7-octahydronaphthoate (Va) has been prepared by the reduction of 7-methoxy-1,2,3,4-tetrahydronaphthoic acid (III) with lithium and ammonia followed by hydrolysis of the enol ether, esterification and migration of the double bond. Alkylation of Va has led to the substitution at the expected 8-position. Methyl 4-keto-7-methoxy-1,2,3,4-tetrahydronaphthoate (X), an intermediate in the preparation of III, has been converted into methyl 3-methyl-3-cyano-4-keto-7-methoxy-1,2,3,4-tetrahydronaphthoate (XIII).