Manuel A. Fernandes

University of the Witwatersrand, Johannesburg, Gauteng, South Africa

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Publications (169)235.5 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The chloride intracellular channel protein, CLIC1, is synthesised as a soluble monomer that can reversibly bind membranes. Soluble CLIC1 is proposed to respond to the low pH found at a membrane surface by partially unfolding and restructuring into a membrane-competent conformation. This transition is proposed to be controlled by strategically located "pH-sensor" residues that become protonated at acidic pH. In this study, we investigate the role of two conserved glutamate residues, Glu85 in the N-domain and Glu228 in the C-domain, as pH-sensors. E85L and E228L CLIC1 variants were created to reduce pH sensitivity by permanently breaking the bonds these residues form. The structure and stability of each variant was compared to the wild type at both pH 7.0 and pH 5.5. Neither substitution significantly altered the structure but both decreased the conformational stability. Furthermore, E85L CLIC1 formed a urea-induced unfolding intermediate state at both pH 7 and pH 5.5 compared to wild-type and E228L CLIC1 which only formed the intermediate at pH 5.5. We conclude that Glu85 and Glu228 are two of the five pH-sensor residues of CLIC1 and contribute to the pH-response in different ways. Glu228 lowers the stability of the native state at pH 5.5, while Glu85 contributes both to the stability of the native state and to the formation of the intermediate state. By putting these interactions into the context of the three previously described CLIC1 pH-sensor residues, we propose a mechanism for the conversion of CLIC1 from the soluble state to the pre-membrane form.
    Molecular and Cellular Biochemistry 09/2014; · 2.33 Impact Factor
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    ABSTRACT: The synthesis of a Co(III) corrole, [10-(2-[[4-(1H-imidazol-1-ylmethyl)benzoyl]amino]phenyl)-5,15-diphenylcorrolato]cobalt(III), DPTC-Co, bearing a tail motif terminating in an imidazole ligand that coordinates Co(III), is described. The corrole therefore places Co(III) in a similar environment to that in aquacobalamin (vitamin B12a, H2OCbl(+)) but with a different equatorial ligand. In coordinating solvents, DPTC-Co is a mixture of five- and six-coordinate species, with a solvent molecule occupying the axial coordination site trans to the proximal imidazole ligand. In an 80:20 MeOH/H2O solution, allowed to age for about 1 h, the predominant species is the six-coordinate aqua species [H2O-DPTC-Co]. It is monomeric at least up to concentrations of 60 μM. The coordinated H2O has a pKa = 9.76(6). Under the same conditions H2OCbl(+) has a pKa = 7.40(2). Equilibrium constants for the substitution of coordinated H2O by exogenous ligands are reported as log K values for neutral N-, P-, and S-donor ligands, and CN(-), NO2(-), N3(-), SCN(-), I(-), and Cys in 80:20 MeOH/H2O solution at low ionic strength. The log K values for [H2O-DPTC-Co] correlate reasonably well with those for H2OCbl(+); therefore, Co(III) displays a similar behavior toward these ligands irrespective of whether the equatorial ligand is a corrole or a corrin. Pyridine is an exception; it is poorly coordinated by H2OCbl(+) because of the sterically hindered coordination site of the corrin. With few exceptions, [H2O-DPTC-Co] has a higher affinity for neutral ligands than H2OCbl(+), but the converse is true for anionic ligands. Density functional theory (DFT) models (BP86/TZVP) show that the Co-ligand bonds tend to be longer in corrin than in corrole complexes, explaining the higher affinity of the latter for neutral ligands. It is argued that the residual charge at the metal center (+2 in corrin, 0 in corrole) increases the affinity of H2OCbl(+) for anionic ligands through an electrostatic attraction. The topological properties of the electron density in the DFT-modeled compounds are used to explore the nature of the bonding between the metal and the ligands.
    Inorganic Chemistry 04/2014; · 4.59 Impact Factor
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    ABSTRACT: In order to investigate possible isostructural solid solutions of disubstituted N-phenylformamides and thioamides, we have studied the re-crystallization of pairs of compounds selected from 2,6-difluoro-N-phenylformamide (I), 2,6-dichloro-N-phenylformamide (II), 2,6-dimethyl-N-phenylformamide (III), 2,6-dichloro-N-phenylthioamide (IV), 2,6-dimethyl-N-phenylthioamide (V), 2,6-diisopropyl-N-phenylformamide (VI) and 2,6-diisopropyl-N-phenylthioamide (VII). For single-component 2,6-disubstituted-N-phenylformamides only the trans form occurs in the pure crystal, while for thioamides the cis form occurs, with only one exception. By forming solid solutions of pairs of these molecules the resulting structures all adopt similar N-H...O/S chains in the crystals. Solid solutions (1), (2) and (3), resulting from the mixing of (I) and (II), (II) and (III), and (IV) and (V), respectively, are all isostructural with each other (space group Pbca). Only co-crystal (1) is isostructural to both starting materials, while (2) is isostructural to only one of the starting pair, (II). Solid solution (3), which adopts the same Pbca structure as (1) and (2), is different to the monoclinic structures of both the reactants. Solid solution (4) is monoclinic, with similar hydrogen-bonded chains, and isostructural to the two components, resulting from the composition from the mixing of (VI) and (VII). Isostructural indices were used to quantify crystal-packing similarities and differences. Occupancy factors of the reactants in each co-crystal differ widely.
    Acta crystallographica Section B, Structural science, crystal engineering and materials. 02/2014; 70(Pt 1):106-114.
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    ABSTRACT: An octadentate cyclen-based europium complex with amidic and hydroxyalkyl pendent moieties exhibits pH dependent ligand denticity associated with anion recognition. Unusually high hydration numbers are determined for ortho-phthalate ternary outer-sphere complexes for which modulation of lanthanide-based luminescence is observed.
    Chemical Communications 01/2014; · 6.38 Impact Factor
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    ABSTRACT: In this work, 2-((2-((2-hydroxyethyl)amino)ethyl)amino)cyclohexanol, HEAC, was prepared in solvent by the ring opening of cyclohexene oxide with 2-(2-amino-ethylamino)ethanol. Four complexes of HEAC, including [Pd(HEAC)Cl2] (1), [Cd2(HEAC)2(μ-Br)2Br2] (2), [Cd(HEAC)(OAc)2] (3) and [Hg(HEAC)Cl2] (4), were prepared and identified by elemental analysis, FT-IR, Raman, 1H NMR spectroscopy and single-crystal X-ray diffraction. Redox properties of HEAC before and after complexation were investigated in DMSO. In the crystal structure of HEAC, the two hydroxyl arms are trans to each other and the cyclohexane ring has a chair conformation with two C-chiral centers. Two new N-chiral centers are produced during the complexation process. In the crystal structure of 1, the palladium atom has a distorted square planar PdN2Cl2 environment. X-ray analysis of 2 reveals a dimer structure containing two bromide bridges. Each cadmium atom in 2 is found to be in a CdN2OBr3 distorted octahedral environment. The Cd2(μ-Br)2 moiety is placed on a plane and forms a parallelogram. The complex has a center of inversion at the center of the parallelogram and Ci symmetry. In the crystal structure of 3, the cadmium atom with a CdN2O5 environment has a distorted capped trigonal prismatic geometry. Complex 4 also has a distorted square-pyramidal geometry (HgN2OCl2). In the networks of HEAC and the complexes 1–4, intermolecular hydrogen bonds form different types of hydrogen bond motifs between adjacent molecules.
    Polyhedron 01/2014; 67:27–35. · 2.05 Impact Factor
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    ABSTRACT: In order to investigate possible isostructural solid solutions of disubstituted N-phenylformamides and thioamides, we have studied the re-crystallization of pairs of compounds selected from 2,6-difluoro-N-phenylformamide (I), 2,6-dichloro-Nphenylformamide (II), 2,6-dimethyl-N-phenylformamide (III), 2,6-dichloro-N-phenylthioamide (IV), 2,6-dimethyl-Nphenylthioamide (V), 2,6-diisopropyl-N-phenylformamide (VI) and 2,6-diisopropyl-N-phenylthioamide (VII). For single-component 2,6-disubstituted--phenylformamides only the trans form occurs in the pure crystal, while for thioamides the cis form occurs, with only one exception. By forming solid solutions of pairs of these molecules the resulting structures all adopt similar N—H� � �O/S chains in the crystals. Solid solutions (1), (2) and (3), resulting from the mixing of (I) and (II), (II) and (III), and (IV) and (V), respectively, are all isostructural with each other (space group Pbca). Only cocrystal (1) is isostructural to both starting materials, while (2) is isostructural to only one of the starting pair, (II). Solid solution (3), which adopts the same Pbca structure as (1) and (2), is different to the monoclinic structures of both the reactants. Solid solution (4) is monoclinic, with similar hydrogen-bonded chains, and isostructural to the two components, resulting from the composition from the mixing of (VI) and (VII). Isostructural indices were used to quantify crystal-packing similarities and differences. Occupancy factors of the reactants in each co-crystal differ widely.
    Acta Crystallographica Section B 01/2014; B70:106-114.
  • Sanaz Khorasani, Manuel A. Fernandes
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    ABSTRACT: Electron donor-to-acceptor interactions between 9-methylanthracene and bis(N-cyclobutylimino)-1,4-dithiin lead to the formation of chiral charge-transfer (CT) crystals. The structure consists of charge-transfer stacks where these two molecules arrange in a 1:1 alternating arrangement. These undergo a topochemical thermal single-crystal-to-single-crystal (SCSC) [2 + 4] Diels–Alder reaction in the solid state. CT crystals were reacted at 40 °C, their structures were determined by X-ray diffraction at various degrees of conversion, and they were examined using Hirshfeld surfaces and lattice energy calculations to find evidence of reaction cooperativity and feedback mechanisms. The results show that steric effects between product molecules and reactant molecules during the SCSC reaction influence the formation of products along the b axis, resulting in a more ordered structure than initially suggested by the crystal structure analysis. A maximum reaction conversion of around 96% was obtained, which indicates that the reaction is also nonrandom within the charge-transfer stacks. Lattice and intramolecular energy calculations show that the energy of an inherently metastable crystal obtained via the SCSC reaction is slightly higher compared to that of the recrystallized product crystal. Finally, structural analysis using CrystalExplorer shows that the shape, size, and surface curvature of the Hirshfeld surface are not much changed by the reaction, indicating that the reaction cavity remains relatively constant and that the reaction is under topochemical control.
    Crystal Growth & Design 11/2013; 13(12):5499–5505. · 4.69 Impact Factor
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    ABSTRACT: Preliminary results towards the synthesis of a corrole-based vitamin B12 analogue are reported. The synthesis of three simple corroles, 5,10,15-triphenylcorrole (TPCrl), 5,10,15-tri(2-nitrophenyl)corrole and 10-(4-methoxyphenyl)-5,15-diphenylcorrole is described. The synthesis of 10-[2-(benzoylamino)phenyl]-5,15-diphenylcorrole (DPAPCrl) suggests that a large, bulky meso substituent can be incorporated into the corrole with no loss of stability or significant decrease in yield. Both TPCrl and DPAPCrl were crystallized and their crystal structure is reported.
    South African journal of chemistry. Suid-Afrikaanse tydskrif vir chemie 08/2013; 66. · 0.46 Impact Factor
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    ABSTRACT: In this work, we identify and describe a moiety that may be capable of encouraging the formation of polymorphs. Four new N-phenylbenzamide-based compounds have been synthesized yielding four pairs of polymorphs upon recrystallization. The structures of these have been discussed and compared with the previously reported polymorphs of N-[2-(hydroxymethyl)phenyl]benzamide. The results indicate that the conformation of the N-phenylbenzamide group is generally constant but is sometimes altered by the crystal packing. The N-phenylbenzamide group is capable of intermolecular N–H···O hydrogen bonding but requires a change in conformation which is generally resisted by the molecule. As a consequence, weak forces such as C–H···O, C–H···N, C–H···π, and π···π interactions play significant but varying roles in these structures. One possible reason for the varying nature of the π···π interactions may be due to the variation of the electrostatic potential across the N-phenylbenzamide group in which negative and positive regions alternate across the face of the molecule. It is the combination of all these attributes that possibly leads to polymorphism being observed in the structures reported here.
    Crystal Growth & Design 07/2013; 13(8):3463–3474. · 4.69 Impact Factor
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    ABSTRACT: Cob(i)alamin reacts with phenylacetylene to produce two diastereomers in which the organic ligand is coordinated to the upper (β) and lower (α) face of the corrin ring, respectively. The isomers were separated chromatographically and characterised by ESI-MS and, in the case of the β isomer, by (1)H and (13)C NMR. Only the β isomer crystallised and its molecular structure, determined by X-ray diffraction, shows that the organic ligand coordinates Co(iii) through the β carbon of the phenylvinyl ligand. The Co-C bond length is 2.004(8) Å while the Co-N bond length to the trans 5,6-dimethylbenzimidazole (dmbzm) base is 2.217(8) Å, one of the longest Co-Ndmbzm bond lengths known in an organocobalamin. Unlike benzylcobalamin (BzCbl), phenylvinylcobalamin (PhVnCbl) is stable towards homolysis. DFT calculations (BP86/TZVP) on model compounds of BzCbl and PhVnCbl show that the Co-C bond dissociation energy for homolysis to Co(ii) and an organic radical in the former is 8 kcal mol(-1) lower than in the latter. An analysis of the electron density at the Co-C bond critical point using Bader's QTAIM approach shows that the Co-C bond in PhVnCbl is shorter, stronger and somewhat more covalent than that in BzCbl, and has some multiple bond character. Together with calculations that show that the benzyl radical is more stable than the phenylvinyl radical, this rationalises the stability of PhVnCbl compared to BzCbl. The phenylvinyl ligand has a large trans influence. The pKa for deprotonation of dmbzm and its coordination by the metal in β-PhVnCbl is 4.60 ± 0.01, one of the highest values reported to date in cobalamin chemistry. The displacement of dmbzm ligand by CN(-) in β-PhVnCbl occurs with log K = 0.7 ± 0.1; the trans influence order of C-donor ligands is therefore CN(-) < CCH < CHCH2 = PhVn < Me < Et.
    Dalton Transactions 03/2013; · 3.81 Impact Factor
  • Laurence Carlton, Lebohang V Mokoena, Manuel A Fernandes
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    ABSTRACT: Tungsten-183 NMR data are reported for the complexes cis-[W(CO)(4) (PPh(3) )(4-RC(5) H(4) N)] (R = H, Me, Ph, COMe, COPh, OMe, NMe(2) , Cl, NO(2) ). The (183) W chemical shift (obtained by indirect detection using (31) P) is found to correlate with the Hammett σ function for the group R, with (183) W shielding increasing approximately linearly with the donor strength of the pyridine over a range of 93 ppm. The X-ray structures of cis-[W(CO)(4) (PPh(3) )(4-MeOC(5) H(4) N)] and cis-[W(CO)(4) (PPh(3) )(4-PhCOC(5) H(4) N)] are also reported. Copyright © 2013 John Wiley & Sons, Ltd.
    Magnetic Resonance in Chemistry 02/2013; · 1.53 Impact Factor
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    ABSTRACT: The title indole derivative, C(17)H(15)NO(3)S, crystallizes with two independent mol-ecules in the asymmetric unit. The benzene ring of the tosyl group is almost perpedicular to the indole ring in both mol-ecules, with inter-planar angles of 82.60 (5)° and 81.82 (6)°. The two mol-ecules are, as a consequence, able to form an almost centrosymmetric non-bonded dimer, in which the molecules are linked by pairs of C-H⋯π inter-actions. The crystal structure displays a three-dimensional network of C-H⋯O inter-actions. A π-π inter-action occurs between inversion-related indole rings with a centroid-centroid distance of 3.6774 (16) Å and an inter-planar angle of 1.53 (15)°. This inter-action leads to a stacking of mol-ecules along the a axis.
    Acta Crystallographica Section E Structure Reports Online 02/2013; 69(Pt 2):o219. · 0.35 Impact Factor
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    ABSTRACT: The HIV protease plays a major role in the life cycle of the virus and has long been a target in antiviral therapy. Resistance of HIV protease to protease inhibitors (PIs) is problematic for the effective treatment of HIV infection. The South African HIV-1 subtype C protease (C-SA PR), which contains eight polymorphisms relative to the consensus HIV-1 subtype B protease, was expressed in Escherichia coli, purified, and crystallized. The crystal structure of the C-SA PR was resolved at 2.7 Å, which is the first crystal structure of a HIV-1 subtype C protease that predominates in Africa. Structural analyses of the C-SA PR in comparison to HIV-1 subtype B proteases indicated that polymorphisms at position 36 of the homodimeric HIV-1 protease may impact on the stability of the hinge region of the protease, and hence the dynamics of the flap region. Molecular dynamics simulations showed that the flap region of the C-SA PR displays a wider range of movements over time as compared to the subtype B proteases. Reduced stability in the hinge region resulting from the absent E35-R57 salt bridge in the C-SA PR, most likely contributes to the increased flexibility of the flaps which may be associated with reduced susceptibility to PIs. An animated interactive 3D complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:JBSD:36.
    Journal of biomolecular structure & dynamics 11/2012; · 4.99 Impact Factor
  • Sanaz Khorasani, Manuel A. Fernandes, Christopher B. Perry
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    ABSTRACT: Conformational flexibility in molecules plays a key role in many chemical and biological processes. It is a common belief that the larger the cycloalkane the more flexible it will be, and the more conformations it will adopt. While theoretical studies have shown that cyclododecane has many possible conformations, they have also consistently shown that one conformation is slightly more stable. In this work, we examine the effect of substitution and crystal packing on the conformation of singly substituted cyclododecane rings. This has been done by exploiting polymorphism in an attempt to induce new conformations in a specific molecule, as well as by examining structures reported in the Cambridge Structural Database (CSD). To this end, three polymorphs of N,N′-biscyclododecyl pyromellitic diimide (PMDI-12) have been identified and their structures elucidated. To rationalize the differences between the various polymorphs, molecule···molecule interaction energies have been calculated using atom–atom potential methods. Though the conformation of the PMDI-12 molecules as a whole may differ, examination of the conformation of the 12-membered ring indicates that it is conformationally identical in all three polymorphs. Examination of 20 other organic and organometallic structures containing this group in the CSD, indicates that they have the same conformation (only one possible exception in the 34 rings examined in this work), which suggests that the 12-membered ring adopts a single conformation ([3333] with D2 symmetry) in the solid-state that is relatively unaffected by crystal packing.
    Crystal Growth & Design 11/2012; 12(12):5908–5916. · 4.69 Impact Factor
  • Andreas Lemmerer, Manuel A. Fernandes
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    ABSTRACT: The supramolecular reagent isonicotinamide (isonico) was used to co-crystallize with three liquid carboxylic acids, cyclopropanecarboxylic acid (C3A), cyclobutanecarboxylic acid (C4A) and cyclopentanecarboxylic acid (C5A), and a solid carboxylic acid, cyclohexanecarboxylic acid (C6A). A total of six co-crystal structures resulted, which are an illustration of the co-crystal space observed in the ever-expanding research on co-crystallization of multiple molecular components. Co-crystal 1, (C3A)·(isonico), has a crystal structure with one of the highest reported Z′ values. 12 acid and 12 isonico molecules combine in the asymmetric unit to give a Z′ = 12, all forming 1-D ribbons. Co-crystals 2a and 2b, both having a formula of (C4A)2·(isonico), having, respectively, a Z′ of 1 and 2, illustrate both stoichiometric variation as well as polymorphism, resulting in different packing architectures. Co-crystals (C5A)·(isonico) 3 and (C6A)·(isonico) 4 have isostructural structures at low temperature, and both show phase transitions above room temperature. For (C6A)·(isonico), we determined the structure of both the low temperature phase, 4a, as well as a high temperature phase, 4b, by single crystal X-ray diffraction, and monitored the transition of 3 by variable temperature powder X-ray diffraction. In all of the compounds reported here, synthesized from two components that are not necessarily solids at ambient conditions and which we have called co-crystals, the primary hydrogen bonded interaction is the carboxylic acidpyridine hydrogen bond.
    New Journal of Chemistry 10/2012; 36(11):2242-2252. · 2.97 Impact Factor
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    ABSTRACT: The title macrocyclic amino alcohol compound, C14H30N4O, is investigated as a solid-state synthon for the design of a self-assembled tubular structure. It crystallizes in a helical column constructed by stereospecific O—H- - - -N and N—H- - - -N interactions. The hydrogen-bonding interactions, dependent upon macrocyclic ring helicity and molecular conformation, link R,R and S,S enantiomers in a head-to-tail fashion, forming a continuous hydrophilic inner core.
    Acta Crystallographica Section C. 10/2012; C(68):o383-o386.
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    ABSTRACT: The title macrocyclic amino alcohol compound, C14H30N4O, is investigated as a solid-state synthon for the design of a self-assembled tubular structure. It crystallizes in a helical column constructed by stereospecific O—H...N and N—H...N interactions. The hydrogen-bonding interactions, dependent upon macrocyclic ring helicity and molecular conformation, link R,R and S,S enantiomers in a head-to-tail fashion, forming a continuous hydrophilic inner core.
    Acta Crystallographica Section C Crystal Structure Communications 10/2012; 68(10). · 0.78 Impact Factor
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    ABSTRACT: An alternative procedure is described for producing diffraction-quality crystals of the sodium salt of the water-soluble porphyrin diaqua-5,10,15,20-tetra-p-phenylsulfonyporphinatocobalt(III), Na[Co(TPPS)(H2O)2]·4H2O by vapour diffusion of ethyl acetate into an aqueous solution of the porphyrin overlaid with a layer of acetone. The structure contains a large amount of disordered solvent in channels but application of an appropriate algorithm (SQUEEZE – an algorithm incorporated into PLATON that applies a Fourier transform of the observed density in the solvent areas and incorporates its contribution to the structure factors) permits a structure solution.
    Inorganica Chimica Acta. 09/2012; 392:108.
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    ABSTRACT: The reaction between [V(IV)OSO(4)] and the tetradentate N(2)O(2)-donor Schiff base ligand, N,N-bis(o-hydroxybenzaldehyde)phenylenediamine (sal-HBPD), obtained by the condensation of salicylaldehyde and o-phenylenediamine in a molar ratio of 2 : 1 respectively, resulted in the formation of [V(IV)O(sal-HBPD)]. The molecular structure of [V(IV)O(sal-HBPD)] was determined by single crystal X-ray diffraction, and confirmed the distorted square pyramidal geometry of the complex with the N(2)O(2) binding mode of the tetradentate ligand. The formation of the polymer-supported p[V(IV)O(sal-AHBPD)] proceeded via the nitrosation of sal-HBPD, followed by the reduction with hydrogen to form an amine group that was then linked to Merrifield beads followed by the reaction with [V(IV)OSO(4)]. XPS and EPR were used to confirm the presence of oxovanadium(iv) within the beads. The BET surface area and porosity of the heterogeneous catalyst p[V(IV)O(sal-AHBPD)] were found to be 6.9 m(2) g(-1) and 180.8 Å respectively. Microanalysis, TG, UV-Vis and FT-IR were used for further characterization of both [V(IV)O(sal-HBPD)] and p[V(IV)O(sal-AHBPD)]. Oxidation of dibenzothiophene (DBT) and 4,6-dimethyldibenzothiophene (4,6-DMDBT) was investigated using [V(IV)O(sal-HBPD)] and p[V(IV)O(sal-AHBPD)] as catalysts. Progress for oxidation of these model compounds was monitored with a gas chromatograph fitted with a flame ionization detector. The oxidation products were characterized using gas chromatography-mass spectrometry, microanalysis and NMR. Dibenzothiophene sulfone (DBTO(2)) and 4,6-dimethyldibenzothiophene sulfone (4,6-DMDBTO(2)) were found to be the main products of oxidation. Oxovanadium(iv) Schiff base microspherical beads, p[V(IV)O(sal-AHBPD)], were able to catalyse the oxidation of sulfur in dibenzothiophene (DBT) and 4,6-dimethyldibenzothiophene (4,6-DMDBT) to a tune of 88.0% and 71.8% respectively after 3 h at 40 °C. These oxidation results show promise for potential application of this catalyst in the oxidative desulfurization of crude oils.
    Dalton Transactions 09/2012; · 3.81 Impact Factor
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    ABSTRACT: The ion channel protein CLIC1 exists in both a soluble conformation in the cytoplasm and a membrane-bound conformation. The conformational stability of soluble CLIC1 demonstrates pH sensitivity which may be attributable to very specific residues that function as pH sensors. These sensors could be histidine or glutamate residues with pK(a) values that fall within the physiological pH range. The role of Glu81, a member of a topologically conserved buried salt bridge in CLIC1, as a pH sensor was investigated here. The mutants E81M, R29M, and E81M/R29M were designed to break the salt bridge between Glu81 and Arg29 and examine the effect of each member on the stability of the protein. Spectroscopic studies and the solved crystal structures indicated that the global structure of CLIC1 was not affected by the mutations. Urea-induced equilibrium unfolding unexpectedly showed E81M to stabilize CLIC1 at pH 7. This was due to stabilizing hydrophobic interactions with Met81 and a water-mediated compensatory H-bond between Met81 and Arg29. R29M and E81M/R29M destabilized CLIC1 at pH 7, and the unfolding transition changed from two-state to three-state, mimicking the wild type at pH 5.5. This observation points out the significance of the salt bridge in stabilizing the native state. The total unfolding free energy change of E81M CLIC1 does not change with pH, implying that Glu81 forms one of a network of pH-sensor residues in CLIC1 responsible for destabilization of the native state. This allows detachment of the N-domain from the C-domain at low pH.
    Biochemistry 09/2012; 51(40):7854-62. · 3.38 Impact Factor

Publication Stats

180 Citations
235.50 Total Impact Points

Institutions

  • 2001–2014
    • University of the Witwatersrand
      • • School of Chemistry
      • • School of Molecular and Cell Biology (MCB)
      Johannesburg, Gauteng, South Africa
  • 2012
    • University of KwaZulu-Natal
      • Department of Chemistry
      Port Natal, KwaZulu-Natal, South Africa
  • 2009
    • University of North Carolina at Wilmington
      • Department of Chemistry and Biochemistry
      Wilmington, NC, United States