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  • 151.
    Säwén, Elin
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Stevensson, Baltzar
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK), Avdelningen för fysikalisk kemi.
    Östervall, Jennie
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi. Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK), Avdelningen för fysikalisk kemi.
    Maliniak, Arnold
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK), Avdelningen för fysikalisk kemi.
    Widmalm, Göran
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Molecular conformations in the pentasaccharide LNF-1 derived from NMR spectroscopy and molecular dynamics simulations2011Ingår i: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 115, nr 21, s. 7109-7121Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The conformational dynamics of the human milk oligosaccharide lacto-N-fucopentaose (LNF-1), α-l-Fucp-(1 → 2)-β-d-Galp-(1 → 3)-β-d-GlcpNAc-(1 → 3)-β-d-Galp-(1 → 4)-d-Glcp, has been analyzed using NMR spectroscopy and molecular dynamics (MD) computer simulations. Employing the Hadamard 13C-excitation technique and the J-HMBC experiment, 1H,13C trans-glycosidic J coupling constants were obtained, and from one- and two-dimensional 1H,1H T-ROESY experiments, proton–proton cross-relaxation rates were determined in isotropic D2O solution. In the lyotropic liquid-crystalline medium consisting of ditetradecylphosphatidylcholine, dihexylphosphatidylcholine, N-cetyl-N,N,N-trimethylammonium bromide, and D2O, 1H, 1H and one-bond 1H, 13C residual dipolar couplings (RDCs), as well as relative sign information on homonuclear RDCs, were determined for the pentasaccharide. Molecular dynamics simulations with explicit water were carried out from which the internal isomerization relaxation time constant, τN, was calculated for transitions at the ψ torsion angle of the β-(1 → 3) linkage to the lactosyl group in LNF-1. Compared to the global reorientation time, τM, of 0.6 ns determined experimentally in D2O solution, the time constant for the isomerization relaxation process, τN(scaled), is about one-third as large. The NMR parameters derived from the isotropic solution show very good agreement with those calculated from the MD simulations. The only notable difference occurs at the reducing end, which should be more flexible than observed by the molecular simulation, a conclusion in complete agreement with previous 13C NMR relaxation data. A hydrogen-bond analysis of the MD simulation revealed that inter-residue hydrogen bonds on the order of 30% were present across the glycosidic linkages to sugar ring oxygens. This finding highlights that intramolecular hydrogen bonds might be important in preserving well-defined structures in otherwise flexible molecules. An analysis including generalized order parameters obtained from nuclear spin relaxation experiments was performed and successfully shown to limit the conformational space accessible to the molecule when the number of experimental data are too scarce for a complete conformational analysis.

  • 152.
    Säwén, Elin
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Östervall, Jennie
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Landersjö, Clas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Edblad, Malin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Weintraub, Andrej
    Karolinska Univ Hosp, Div Clin Microbiol, Dept Lab Med, Karolinska Inst, Huddinge, Sweden .
    Ansaruzzaman, Mohammad
    Int Ctr Diarrhoeal Dis Res, Dhaka 1000, Bangladesh .
    Widmalm, Göran
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Structural studies of the O-antigenic polysaccharide from Plesiomonas shigelloides strain AM365652012Ingår i: Carbohydrate Research, ISSN 0008-6215, E-ISSN 1873-426X, Vol. 348, s. 99-103Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The structure of the repeating unit of the O-antigenic polysaccharide from Plesiomonas shigelloides strain AM36565 has been determined. Component analysis and H-1 and C-13 NMR spectroscopy experiments were employed to elucidate the structure. Inter-residue correlations were determined by H-1,C-13 heteronuclear multiple-bond correlation, H-1-H-1-NOESY, and H-1,C-13-HSQC-H-1,H-1-NOESY experiments. The O-antigen polysaccharide is composed of repeating units with the following structure: -> 3)-alpha-L-Rhap-(1 -> 2)-alpha-L-Rhap-(1 -> 4)[(beta-D-GalpNAc-(1 -> 3)]-alpha-D-GlcpNAc-(1 ->, in which the monosaccharide side-chain substitutes the backbone in half of the repeating units. A matrix-assisted laser desorption/ionization mass spectrometry experiment suggested that the polysaccharide consists of two regions, one with tetrasaccharide repeating units and one with trisaccharide repeating units.

  • 153. Tavagnacco, Letizia
    et al.
    Engström, Olof
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Schnupf, Udo
    Saboungi, Marie-Louise
    Himmel, Michael
    Widmalm, Göran
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Cesaro, Attilio
    Brady, John W.
    Caffeine and Sugars Interact in Aqueous Solutions: A Simulation and NMR Study2012Ingår i: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 116, nr 38, s. 11701-11711Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Molecular dynamics simulations were carried out on several systems of caffeine interacting with simple sugars. These included a single caffeine molecule in a 3 in solution of alpha-D-glucopyranose, at a caffeine concentration of 0.083 m, a single caffeine in a 3 in solution of beta-D-glucopyranose, and a single caffeine molecule in a 1.08 m solution of sucrose (table sugar). Parallel nuclear magnetic resonance titration experiments were carried out on the same solutions under similar conditions. Consistent with previous thermodynamic experiments, the sugars were found to have an affinity for the caffeine molecules in both the simulations and experiments, and the binding in these complexes occurs by face-to-face stacking of the hydrophobic triad of protons of the pyranose rings against the caffeine face, rather than by hydrogen bonding. For the disaccharide, the binding occurs via stacking of the glucose ring against the caffeine, with a lesser affinity for the fructose observed. These findings are consistent with the association being driven by hydrophobic hydration and are similar to the previously observed binding of glucose rings to various other planar molecules, including indole, serotonin, and phenol.

  • 154.
    Thaning, Johan
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för fysikalisk kemi, oorganisk kemi och strukturkemi.
    Stevensson, Baltzar
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för fysikalisk kemi, oorganisk kemi och strukturkemi.
    Östervall, Jennie
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Naidoo, Kevin J.
    University of Cape Town. , CSIR Campus Rosebank..
    Widmalm, Göran
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Maliniak, Arnold
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för fysikalisk kemi, oorganisk kemi och strukturkemi.
    NMR Studies of Molecular Conformations in α-Cyclodextrin2008Ingår i: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 112, nr 29, s. 8434-8436Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A new approach for analysis of NMR parameters is proposed. The experimental data set includes scalar couplings, NOEs, and residual dipolar couplings. The method, which aims at construction of the conformational distribution function, is applied to α-cyclodextrin in isotropic solution and dissolved in a dilute liquid crystal. An attempt to analyze the experimental data using an average molecular conformation resulted in unacceptable errors. Our approach rests on the maximum entropy method (ME), which gives the flattest possible distribution, consistent with the experimental data. Very good agreement between experimental and calculated NMR parameters was observed. In fact, two conformational states were required in order to obtain a satisfactory agreement between calculated and experimental data. In addition, good agreement with Langevin dynamics computer simulations was obtained.

  • 155. Thorsheim, Karin
    et al.
    Willen, Daniel
    Tykesson, Emil
    Ståhle, Jonas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Praly, Jean-Pierre
    Vidal, Sebastien
    Johnson, Magnus T.
    Widmalm, Göran
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Manner, Sophie
    Ellervik, Ulf
    Naphthyl Thio- and Carba-xylopyranosides for Exploration of the Active Site of-1,4-Galactosyltransferase 7 (4GalT7)2017Ingår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 23, nr 71, s. 18057-18065Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Xyloside analogues with substitution of the endocyclic oxygen atom by sulfur or carbon were investigated as substrates for -1,4-galactosyltransferase7 (4GalT7), a key enzyme in the biosynthesis of glycosaminoglycan chains. The analogues with an endocyclic sulfur atom proved to be excellent substrates for 4GalT7, and were galactosylated approximately fifteen times more efficiently than the corresponding xyloside. The 5a-carba--xylopyranoside in the d-configuration proved to be a good substrate for 4GalT7, whereas the enantiomer in the l-configuration showed no activity. Further investigations by X-ray crystallography, NMR spectroscopy, and molecular modeling provided a rationale for the pronounced activity of the sulfur analogues. Favorable - interactions between the 2-naphthyl moiety and a tyrosine side chain of the enzyme were observed for the thio analogues, which open up for the design of efficient GAG primers and inhibitors.

  • 156. Tomshich, S V
    et al.
    Komandrova, N A
    Widmalm, Göran
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Nedashkovskaya, O I
    Shashkov, A S
    Perepelov, A V
    Structure of acidic O-specific polysaccharide from the marine bacterium Cellulophaga baltica2007Ingår i: Russian Journal of Bioorganic Chemistry, ISSN 1068-1620, Vol. 33, nr 1, s. 83-87Artikel i tidskrift (Refereegranskat)
  • 157. Urbina, Felipe
    et al.
    Nordmark, Eva-Lisa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Yang, Zhennai
    Weintraub, Andrej
    Scheutz, Flemming
    Widmalm, Göran
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Structural elucidation of the O-antigenic polysaccharide from the enteroaggregative Escherichia coli strain 180/C3 and its immunochemical relationship with Escherichia coli O5 and O652005Ingår i: Carbohydrate Research, ISSN 0008-6215, E-ISSN 1873-426X, Vol. 340, nr 4, s. 645-650Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The structure of the O-antigen polysaccharide (PS) from the enteroaggregative Escherichia coli strain 180/C3 has been determined. Sugar and methylation analysis together with 1H and 13C NMR spectroscopy were the main methods used. The PS is composed of tetrasaccharide repeating units with the following structure:→2)-β-d-Quip3NAc-(1→3)-β-d-Ribf-(1→4)-β-d-Galp-(1→3)-α-d-GalpNAc-(1→Analysis of NMR data indicates that the presented sequence of sugar residues also represents the biological repeating unit of the O-chain. The structure is closely related to that of O-antigen polysaccharide from E. coli O5 and partially to that of E. coli O65. The difference between the O-antigen from the 180/C3 strain and that of E. coli O5 is the linkage to the d-Quip3NAc residue, which in the latter strain is 4-O-substituted. The E. coli O65 O-antigen contains as part of its linear pentasaccharide repeating unit a similar structural element, namely →4)-β-d-GalpA-(1→3)-α-d-GlcpNAc-(1→2)-β-d-Quip3NAc-(1→, thereby indicating that a common epitope could be present for the two polysaccharides. Monospecific anti-E. coli O5 rabbit serum did not distinguish between the two positional isomeric structures neither in slide agglutination nor in an indirect enzyme immunoassay. The anti-O65 serum did react with both the 180/C3 and O5 LPS showing a partial cross-reactivity.

  • 158. Vasur, Jonas
    et al.
    Kawai, Rie
    Jonsson, K. Hanna M.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Widmalm, Göran
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Engström, Åke
    Frank, Martin
    Andersson, Evalena
    Hansson, Henrik
    Forsberg, Zarah
    Igarashi, Kiyohiko
    Samejima, Masahiro
    Sandgren, Mats
    Ståhlberg, Jerry
    Synthesis of cyclic β-glucan using Laminarinase 16A glycosynthase mutant from the basidiomycete Phanerochaete chrysosporium2010Ingår i: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 132, nr 5, s. 1724-1730Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Glycosynthases are precise molecular instruments for making specifically linked oligosaccharides. X-ray crystallography screening of ligands bound to the 1,3(4)-β-d-glucanase nucleophile mutant E115S of Phanerochaete chrysosporium Laminarinase 16A (Lam16A) showed that laminariheptaose (L7) bound in an arch with the reducing and nonreducing ends occupying either side of the catalytic cleft of the enzyme. The X-ray structure of Lam16A E115S in complex with α-laminariheptaosyl fluoride (αL7F) revealed how αL7F could make a nucleophilic attack upon itself. Indeed, when Lam16A E115S was allowed to react with αL7F the major product was a cyclic β-1,3-heptaglucan, as shown by mass spectrometry. NMR confirmed uniquely β-1,3-linkages and no reducing end. Molecular dynamics simulations indicate that the cyclic laminariheptaose molecule is not completely planar and that torsion angles at the glycosidic linkages fluctuate between two energy minima. This is the first report of a glycosynthase that joins the reducing and nonreducing ends of a single oligosaccharide and the first reported synthesis of cyclic β-glucan.

  • 159. Vilchez, Samuel
    et al.
    Lundborg, Magnus
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Urbina, Felipe
    Weintraub, Andrej
    Widmalm, Göran
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Structural studies of the O-antigenic polysaccharides from the enteroaggregative Escherichia coli strain 94/D4 and the international type strain Escherichia coli O822009Ingår i: Carbohydrate Research, ISSN 0008-6215, E-ISSN 1873-426X, Vol. 344, nr 18, s. 2528-2532Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The structure of the O-antigen polysaccharides (PS) from the enteroaggregative Escherichia coli strain 94/D4 and the international type strain E. coli O82 have been determined. Component analysis and 1H, 13C, and 31P NMR spectroscopy experiments were employed to elucidate the structure. Inter-residue correlations were determined by 1H, 13C-heteronuclear multiple-bond correlation, and 1H, 1H-NOESY experiments. d-GroA as a substituent is linked via its O-2 in a phosphodiester-linkage to O-6 of the α-d-Glcp residue. The PS is composed of tetrasaccharide repeating units with the following structure:

    →4)-α-d-Glcp6-(P-2-d-GroA)-(1→4)-β-d-Galp-(1→4)-β-d-Glcp-(1→3)-β-d-GlcpNAc-(1→

    Cross-peaks of low intensity from an α-d-Glcp residue were present in the NMR spectra and spectral analysis indicates that they originate from the terminal residue of the polysaccharide. Consequently, the biological repeating unit has a 3-substituted N-acetyl-d-glucosamine residue at its reducing end. Enzyme immunoassay using specific anti-E. coli O82 rabbit sera showed identical reactivity to the LPS of the two strains, in agreement with the structural analysis of their O-antigen polysaccharides.

  • 160. von der Lieth, Claus-Wilhelm
    et al.
    Ardà Freire, Ana
    Blank, Dennis
    Campbell, Matthew P.
    Ceroni, Alessio
    Damerell, David R.
    Dell, Anne
    Dwek, Raymond A.
    Ernst, Beat
    Fogh, Rasmus
    Frank, Martin
    Geyer, Hildegard
    Geyer, Rudolf
    Harrison, Mathew J.
    Henrick, Kim
    Herget, Stefan
    Hull, William E.
    Ionides, John
    Joshi, Hiren J.
    Kamerling, Johannis P.
    Leeflang, Bas R.
    Lütteke, Thomas
    Lundborg, Magnus
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Maass, Kai
    Merry, Anthony
    Ranzinger, René
    Rosen, Jimmy
    Royle, Louise
    Rudd, Pauline M.
    Schloissnig, Siegfried
    Stenutz, Roland
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Vranken, Wim F.
    Widmalm, Göran
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Haslam, Stuart M.
    EUROCarbDB: an open-access platform for glycoinformatics2011Ingår i: Glycobiology, ISSN 0959-6658, E-ISSN 1460-2423, Vol. 21, nr 4, s. 493-502Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The EUROCarbDB project is a design study for a technical framework, which provides sophisticated, freely accessible, open-source informatics tools and databases to support glycobiology and glycomic research. EUROCarbDB is a relational database containing glycan structures, their biological context and, when available, primary and interpreted analytical data from high-performance liquid chromatography, mass spectrometry and nuclear magnetic resonance experiments. Database content can be accessed via a web-based user interface. The database is complemented by a suite of glycoinformatics tools, specifically designed to assist the elucidation and submission of glycan structure and experimental data when used in conjunction with contemporary carbohydrate research workflows. All software tools and source code are licensed under the terms of the Lesser General Public License, and publicly contributed structures and data are freely accessible. The public test version of the web interface to the EUROCarbDB can be found at http://www.ebi.ac.uk/eurocarb.

  • 161.
    Widmalm, Göran
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    A perspective on the primary and three-dimensional structures of carbohydrates2013Ingår i: Carbohydrate Research, ISSN 0008-6215, E-ISSN 1873-426X, Vol. 378, s. 123-132Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Carbohydrates, in more biologically oriented areas referred to as glycans, constitute one of the four groups of biomolecules. The glycans, often present as glycoproteins or glycolipids, form highly complex structures. In mammals ten monosaccharides are utilized in building glycoconjugates in the form of oligo-(up to about a dozen monomers) and polysaccharides. Subsequent modifications and additions create a large number of different compounds. In bacteria, more than a hundred monosaccharides have been reported to be constituents of lipopolysaccharides, capsular polysaccharides, and exopolysaccharides. Thus, the number of polysaccharide structures possible to create is huge. NMR spectroscopy plays an essential part in elucidating the primary structure, that is, monosaccharide identity and ring size, anomeric configuration, linkage position, and sequence, of the sugar residues. The structural studies may also employ computational approaches for NMR chemical shift predictions (CASPER program). Once the components and sequence of sugar residues have been unraveled, the three-dimensional arrangement of the sugar residues relative to each other (conformation), their flexibility (transitions between and populations of conformational states), together with the dynamics (timescales) should be addressed. To shed light on these aspects we have utilized a combination of experimental liquid state NMR techniques together with molecular dynamics simulations. For the latter a molecular mechanics force field such as our CHARMM-based PARM22/SU01 has been used. The experimental NMR parameters acquired are typically H-1, H-1 cross-relaxation rates (related to NOEs), (3)JCH and (3)JCC trans-glycosidic coupling constants and H-1, C-13-and H-1, H-1-residual dipolar couplings. At a glycosidic linkage two torsion angles phi and psi are defined and for 6-substituted residues also the omega torsion angle is required. Major conformers can be identified for which highly populated states are present. Thus, in many cases a well-defined albeit not rigid structure can be identified. However, on longer timescales, oligosaccharides must be considered as highly flexible molecules since also anti-conformations have been shown to exist with H-C-O-C torsion angles of similar to 180 degrees, compared to syn-conformations in which the protons at the carbon atoms forming the glycosidic linkage are in close proximity. The accessible conformational space governs possible interactions with proteins and both minor changes and significant alterations occur for the oligosaccharides in these interaction processes. Transferred NOE NMR experiments give information on the conformation of the glycan ligand when bound to the proteins whereas saturation transfer difference NMR experiments report on the carbohydrate part in contact with the protein. It is anticipated that the subtle differences in conformational preferences for glycan structures facilitate a means to regulate biochemical processes in different environments. Further developments in the analysis of glycan structure and in particular its role in interactions with other molecules, will lead to clarifications of the importance of structure in biochemical regulation processes essential to health and disease.

  • 162.
    Widmalm, Göran
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Computational and experimental analysis of oligosaccharide conformation and dynamics2011Ingår i: Abstracts of Papers, 241st ACS National Meeting & Exposition, Anaheim, CA, United States, March 27-31, 2011, American Chemical Society (ACS), 2011Konferensbidrag (Refereegranskat)
    Abstract [en]

    Carbohydrate structures in the form of glycoconjugates are found in Nature, e.g., as N- and O-linked glycoproteins, glycolipids, short-chain lipopolysaccharides also referred to as lipooligosaccharides and saponins.  The carbohydrate constituent may be studied as part of the glycoconjugate or as oligosaccharides. A number of experimental biophysical techniques are available in order to investigate their conformation and dynamics, in particular, NMR spectroscopy, both in solution and in the solid state, X-ray diffraction on crystals, neutron diffraction with isotopic substitution carried out in the solution state, optical rotation, ultrasonic relaxation and more recently Raman optical activity. Computational approaches including molecular mechanics,1 molecular dynamics simulations,2 ab initio and DFT methods3 may subsequently be employed to study and interpret conformational equilibria based on experimental data. The use of carbon-13 site-specifically synthesized oligosaccharides for obtaining, in particular, conformationally dependent trans-glycosidic homo- and heteronuclear coupling constants and interpretation of conformational equilibria from these based on recently developed Karplus-type relationships for spin-spin coupling constants over three bonds4 will be presented for different oligosaccharides in quest for a description of the population distribution of the torsion angles at the glycosidic linkage.

  • 163.
    Widmalm, Göran
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    General NMR Spectroscopy of Carbohydrates and Conformational Analysis in Solution2007Ingår i: Molecular Interactions Biochemistry of Glycans, Elsevier Ltd , 2007, s. 101-132Kapitel i bok, del av antologi (Refereegranskat)
  • 164. Wu, Emilia L.
    et al.
    Engström, Olof
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Jo, Sunhwan
    Stuhlsatz, Danielle
    Yeom, Min Sun
    Klauda, Jeffery B.
    Widmalm, Göran
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Im, Wonpil
    Molecular Dynamics and NMR Spectroscopy Studies of E. coli Lipopolysaccharide Structure and Dynamics2013Ingår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 105, nr 6, s. 1444-1455Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Lipopolysaccharide (LPS), a component of Gram-negative bacterial outer membranes, comprises three regions: lipid A, core oligosaccharide, and O-antigen polysaccharide. Using the CHARMM36 lipid and carbohydrate force fields, we have constructed a model of an Escherichia coil R1 (core) 06 (antigen) LPS molecule. Several all-atom bilayers are built and simulated with lipid A only (LIPA) and varying lengths of 0 (LPS0), 5 (LPS5), and 10 (LPS10) O6 antigen repeating units; a single unit of 06 antigen contains five sugar residues. From H-1,H-1-NOESY experiments, cross-relaxation rates are obtained from an O-antigen polysaccharide sample. Although some experimental deviations are due to spin-diffusion, the remaining effective proton-proton distances show generally very good agreement between NMR experiments and molecular dynamics simulations. The simulation results show that increasing the LPS molecular length has an impact on LPS structure and dynamics and also on LPS bilayer properties. Terminal residues in a LPS bilayer are more flexible and extended along the membrane normal. As the core and O-antigen are added, per-lipid area increases and lipid bilayer order decreases. In addition, results from mixed LPS0/5 and LPS0/10 bilayer simulation's show that the LPS O-antigen conformations at a higher concentration of LPS5 and LPS10 are more orthogonal to the membrane and less flexible. The O-antigen concentration of mixed LPS bilayers does not have a significant effect on per-lipid area and hydrophobic thickness. Analysis of ion and water penetration shows that water molecules can penetrate inside the inner core region, and hydration is critical to maintain the integrity of the bilayer structure.

  • 165. Wu, Emilia L.
    et al.
    Fleming, Patrick J.
    Yeom, Min Sun
    Widmalm, Göran
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Klauda, Jeffery B.
    Fleming, Karen G.
    Im, Wonpil
    E. coil Outer Membrane and Interactions with OmpLA2014Ingår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 106, nr 11, s. 2493-2502Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The outer membrane of Gram-negative bacteria is a unique asymmetric lipid bilayer composed of phospholipids (PLs) in the inner leaflet and lipopolysaccharides (LPSs) in the outer leaflet. Its function as a selective barrier is crucial for the survival of bacteria in many distinct environments, and it also renders Gram-negative bacteria more resistant to antibiotics than their Gram-positive counterparts. Here, we report the structural properties of a model of the Escherichia coli outer membrane and its interaction with outer membrane phospholipase A (OmpLA) utilizing molecular dynamics simulations. Our results reveal that given the lipid composition used here, the hydrophobic thickness of the outer membrane is similar to 3 angstrom thinner than the corresponding PL bilayer, mainly because of the thinner LPS leaflet. Further thinning in the vicinity of OmpLA is observed due to hydrophobic matching. The particular shape of the OmpLA barrel induces various interactions between LPS and PL leaflets, resulting in asymmetric thinning around the protein. The interaction between OmpLA extracellular loops and LPS (headgroups and core oligosaccharides) stabilizes the loop conformation with reduced dynamics, which leads to secondary structure variation and loop displacement compared to that in a DLPC bilayer. In addition, we demonstrate that the LPS/PL ratios in asymmetric bilayers can be reliably estimated by the per-lipid surface area of each lipid type, and there is no statistical difference in the overall membrane structure for the outer membranes with one more or less LPS in the outer leaflet, although individual lipid properties vary slightly.

  • 166. Yang, Mingjun
    et al.
    Angles d'Ortoli, Thibault
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Säwén, Elin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Jana, Madhurima
    Widmalm, Göran
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    MacKerell, Jr., Alexander D.
    Delineating the conformational flexibility of trisaccharides from NMR spectroscopy experiments and computer simulations2016Ingår i: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 18, nr 28, s. 18776-18794Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The conformation of saccharides in solution is challenging to characterize in the context of a single well-defined three-dimensional structure. Instead, they are better represented by an ensemble of conformations associated with their structural diversity and flexibility. In this study, we delineate the conformational heterogeneity of five trisaccharides via a combination of experimental and computational techniques. Experimental NMR measurements target conformationally sensitive parameters, including J couplings and effective distances around the glycosidic linkages, while the computational simulations apply the well-calibrated additive CHARMM carbohydrate force field in combination with efficient enhanced sampling molecular dynamics simulation methods. Analysis of conformational heterogeneity is performed based on sampling of discreet states as defined by dihedral angles, on root-mean-square differences of Cartesian coordinates and on the extent of volume sampled. Conformational clustering, based on the glycosidic linkage dihedral angles, shows that accounting for the full range of sampled conformations is required to reproduce the experimental data, emphasizing the utility of the molecular simulations in obtaining an atomic detailed description of the conformational properties of the saccharides. Results show the presence of differential conformational preferences as a function of primary sequence and glycosidic linkage types. Significant differences in conformational ensembles associated with the anomeric configuration of a single glycosidic linkage reinforce the impact of such changes on the conformational properties of carbohydrates. The present structural insights of the studied trisaccharides represent a foundation for understanding the range of conformations adopted in larger oligosaccharides and how these molecules encode their conformational heterogeneity into the monosaccharide sequence.

  • 167.
    Zaccheus, Mona
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Pendrill, Robert
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Jackson, Trudy A.
    Wang, An
    Auzanneau, France-Isabelle
    Widmalm, Göran
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Conformational Dynamics of a Central Trisaccharide Fragment of the LeaLex Tumor Associated Antigen Studied by NMR Spectroscopy and Molecular Dynamics Simulations2012Ingår i: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, nr 25, s. 4705-4715Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Certain carbohydrate structures are recognized as cancer antigens, and identification of these and relevant epitopes are essential in fighting the disease. The trisaccharide beta-D-GlcpNAc-(1?3)-beta-D-Galp-(1?4)-beta-D-GlcpNAc-OMe represents a model for the central region of the LeaLex hexasaccharide and it has herein been investigated by 1D 1H,1H-NOESY experiments to obtain effective interresidue protonproton distances as well as by 2D J-HMBC experiments to determine transglycosidic 3JCH coupling constants. Molecular dynamics (MD) simulations using explicit water as solvent and three different carbohydrate force fields, namely, GLYCAM06, PARM22/SU01, and CHARMM2011, were employed for the interpretation of experimental data. Overall, the force field based MD simulations are able to reproduce the experimental data and the ? torsion angle at the beta-(1?3)-linkage is concluded to be flexible. In addition, different minor states were present for the three force fields with either anti-? or non-exo-anomeric conformations. Transitions between the exo-anomeric and the non-exo-anomeric conformations for the f torsion angle at the beta-(1?4)-linkage in one of the MD simulations were analyzed in detail. It was found that hydrogen-bonding water molecules, interresidue hydrogen bonds and the transitions between antiperiplanar and synperiplanar conformations for the tH torsion angle of an N-acetyl group were all essential in the description of the glycosidic transition process. In particular, the transition of tH may be a general way of regulating other transitions into less populated but biologically important conformational regions.

  • 168.
    Zaccheus, Mona V.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Ali, Tara
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Cloeckaert, Axel
    Zygmunt, Michel S.
    Weintraub, Andrej
    Iriarte, Maite
    Moriyon, Ignacio
    Widmalm, Göran
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    The Epitopic and Structural Characterization of Brucella suis Biovar 2 O-Polysaccharide Demonstrates the Existence of a New M-Negative C-Negative Smooth Brucella Serovar2013Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 1, s. e53941-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The brucellae are Gram-negative bacteria that cause an important zoonosis. Studies with the main Brucella species have shown that the O-antigens of the Brucella smooth lipopolysaccharide are alpha-(1 -> 2) and alpha-(1 -> 3)-linked N-formyl-perosamine polysaccharides that carry M, A and C (A = M, A>M and A<M) epitopes relevant in serodiagnosis and typing. We report that, in contrast to the B. suis biovar 1 O-antigen used as a reference or to all described Brucella O-antigens, B. suis biovar 2 O-antigen failed to bind monoclonal antibodies of C (A = M), C (M>A) and M specificities. However, the biovar 2 O-antigen bound monoclonal antibodies to the Brucella A epitope, and to the C/Y epitope shared by brucellae and Yersinia enterocolitica O:9, a bacterium that carries an N-formyl-perosamine O-antigen in exclusively alpha-(1 -> 2)-linkages. By C-13 NMR spectroscopy, B. suis biovar 1 but not B. suis biovar 2 or Y.enterocolitica O:9 polysaccharide showed the signal characteristic of alpha-(1 -> 3)-linked N-formyl-perosamine, indicating that biovar 2 may altogether lack this linkage. Taken together, the NMR spectroscopy and monoclonal antibody analyses strongly suggest a role for alpha-(1 -> 3)-linked N-formyl-perosamine in the C (A = M) and C (M>A) epitopes. Moreover, they indicate that B. suis biovar 2 O-antigen lacks some lipopolysaccharide epitopes previously thought to be present in all smooth brucellae, thus representing a new brucella serovar that is M-negative, C-negative. Serologically and structurally this new serovar is more similar to Y. enterocolitica O:9 than to other brucellae.

  • 169.
    Zaccheus, Mona V.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Broeker, Nina K.
    Lundborg, Magnus
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Uetrecht, Charlotte
    Barbirz, Stefanie
    Widmalm, Göran
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Structural studies of the O‐antigen polysaccharide from Escherichia coli TD2158 having O18 serogroup specificity and aspects of its interaction with the tailspike endoglycosidase of the infecting bacteriophage HK6202012Ingår i: Carbohydrate Research, ISSN 0008-6215, E-ISSN 1873-426X, Vol. 357, s. 118-125Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We have analyzed the O-antigen polysaccharide of the previously uncharacterized Escherichia coli strain TD2158 which is a host of bacteriophage HK620. This bacteriophage recognizes and cleaves the polysaccharide with its tailspike protein (TSP). The polysaccharide preparation as well as oligosaccharides obtained from HK620TSP endoglycosidase digests were analyzed with NMR spectroscopy. Additionally, sugar analysis was performed on the O-antigen polysaccharide and MALDI-TOF MS was used in oligosaccharide analysis. The present study revealed a heterogeneous polysaccharide with a hexasaccharide repeating unit of the following structure: α-D-Glcp-(1→6|) →2)-α-L-Rhap-91→6)-α-D-Glcp-(1→4)-α-D-Ga|lp-(1→3)-α-D-GlcpNAc-(1→ β-D-Glcp/β-D-GlcpNAc-(1→3) A repeating unit with a D-GlcNAc substitution of D-Gal has been described earlier as characteristic for serogroup O18A1. Accordingly, we termed repeating units with D-Glc substitution at D-Gal as O18A2. NMR analyses of the polysaccharide confirmed that O18A1- and O18A2-type repeats were present in a 1:1 ratio. However, HK620TSP preferentially bound the D-GlcNAc-substituted O18A1-type repeating units in its high affinity binding pocket with a dissociation constant of 140 μM and disfavored the O18A2-type having a β-D-Glcp-(1→3)-linked group. As a result, in hexasaccharide preparations, O18A1 and O18A2 repeats were present in a 9:1 ratio stressing the clear preference of O18A1-type repeats to be cleaved by HK620TSP.

  • 170. Zerbetto, Mirco
    et al.
    d'Ortoli, Thibault Angles
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Polimeno, Antonino
    Widmalm, Göran
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Differential Dynamics at Glycosidic Linkages of an Oligosaccharide as Revealed by C-13 NMR Spin Relaxation and Stochastic Modeling2018Ingår i: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 122, nr 8, s. 2287-2294Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Among biomolecules, carbohydrates are unique in that not only can linkages be formed through different positions, but the structures may also be branched. The trisaccharide beta-D-Glcp-(1 -> 3)[beta-D-Glcp-(1 -> 2)]-alpha-D-Manp-OMe represents a model of a branched vicinally disubstituted structure. A C-13 site -specific isotopologue, with labeling in each of the two terminal glucosyl residues, enabled the acquisition of high-quality C-13 NMR relaxation parameters, T-1 and T-2, and heteronuclear NOE, with standard deviations of <= 0.5%. For interpretation of the experimental NMR data, a diffusive chain model was used, in which the dynamics of the glycosidic linkages is coupled to the global reorientation motion of the trisaccharide. Brownian dynamics simulations relying on the potential of mean force at the glycosidic linkages were employed to evaluate spectral densities of the spin probes. Calculated NMR relaxation parameters showed a very good agreement with experimental data, deviating <3%. The resulting dynamics are described by correlation times of 196 and 174 ps for the beta-(1 -> 2)- and beta-(1 -> 3)-linked glucosyl residues, respectively, i.e., different and linkage dependent. Notably, the devised computational protocol was performed without any fitting of parameters.

  • 171. Zerbetto, Mirco
    et al.
    Kotsyubynskyy, Dmytro
    Kowalewski, Jozef
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK).
    Widmalm, Goran
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Polimeno, Antonino
    Stochastic Modeling of Flexible Biomolecules Applied to NMR Relaxation: I. Internal Dynamics of Cyclodextrins; y-Cyclodextrin as a Case Study2012Ingår i: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 116, nr 44, s. 13159-13171Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In this work, we address the description of the dynamics of cyclodextrins in relation with nuclear magnetic resonance (NMR) relaxation data collected for hydroxymethyl groups. We define an integrated computational approach based on the definition and parametrization of a stochastic equation able to describe the relevant degrees of freedom affecting the NMR observables. The computational protocol merges molecular dynamics simulations and hydrodynamics approaches for the evaluation of most of the molecular parameters entering the stochastic description of the system. We apply the method to the interpretation of the C-13 NMR relaxation of the -CH2OH group of cyclodextrins. We use gamma-cyclodextrin as a case study. Results are in agreement with quantitative and qualitative analyses performed in the past with simpler models and molecular dynamics simulations. The element of novelty in our approach is in the treatment of the coupling of the relevant internal (glucopyranose ring twisting/tilting and hydroxymethyl group jumps) and global (molecular tumbling) degrees of freedom.

  • 172. Zerbetto, Mirco
    et al.
    Polimeno, Antonino
    Kotsyubynskyy, Dmytro
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för fysikalisk kemi, oorganisk kemi och strukturkemi.
    Ghalebani, Leila
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för fysikalisk kemi, oorganisk kemi och strukturkemi.
    Kowalewski, Jozef
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för fysikalisk kemi, oorganisk kemi och strukturkemi, Avdelningen för fysikalisk kemi.
    Meirovitch, Eva
    Olsson, Ulrika
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Widmalm, Göran
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    An integrated approach to NMR spin relaxation in flexible biomolecules: Application to β-D-glucopyranosyl-(1→6)-α-D-mannopyranosyl-OMe2009Ingår i: Journal of Chemical Physics, ISSN 0021-9606, E-ISSN 1089-7690, Vol. 131, nr 23, s. p234501-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The description of the reorientational dynamics of flexible molecules is a challenging task, in particular when the rates of internal and global motions are comparable. The commonly used simple mode-decoupling models are based on the assumption of statistical independence between these motions. This assumption is not valid when the time scale separation between their rates is small, a situation that was found to arise in oligosaccharides in the context of certain internal motions. To make possible the interpretation of NMR spin relaxation data from such molecules, we developed a comprehensive approach generally applicable to flexible rotators with one internal degree of freedom. This approach integrates a stochastic description of coupled global tumbling and internal torsional motion, quantum chemical calculations of the local potential and the local geometry at the site of the restricted torsion, and hydrodynamics-based calculations of the diffusive properties. The method is applied to the disaccharide -D-Glcp-(16)--D-[6-13C]-Manp-OMe dissolved in a DMSO-d6/D2O cryosolvent. The experimental NMR relaxation parameters, associated with the 13CH2 probe residing at the glycosidic linkage, include 13C T1 and T2 and 13C-{1H} nuclear Overhauser enhancement (NOE) as well as longitudinal and transverse dipole-dipole cross-correlated relaxation rates, acquired in the temperature range of 253–293 K. These data are predicted successfully by the new theory with only the H–C–H angle allowed to vary. Previous attempts to fit these data using mode-decoupling models failed.

  • 173. Öksnes Dalheim, Marianne
    et al.
    Björk Arnfinnsdottir, Nina
    Widmalm, Göran
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Christensen, Björn E.
    The size and shape of three water-soluble, non-ionic polysaccharides produced by lactic acid bacteria: A comparative study2016Ingår i: Carbohydrate Polymers, ISSN 0144-8617, E-ISSN 1879-1344, Vol. 142, s. 91-97Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Three water-soluble, non-ionic extracellular polysaccharides (EPS) obtained from lactic acid bacteria (S. thermophilus THS, L. helveticus K16 and S. thermophilus ST1) were subjected to a comparative study by means of multidetector size-exclusion chromatography, providing distributions and averages of molar masses, radii of gyration and intrinsic viscosities. All polysaccharides displayed random coil character. Further analysis of the data reveals differences in chain stiffness and extension that could be well correlated to structural features. The calculated persistence lengths ranged from 5 to 10 nm and fall within the range typical for many single-stranded bacterial or plant polysaccharides. The ST1 polysaccharide had the highest molar mass but the lowest persistence length, which is attributed to the presence of the flexible (1→6)-linkage in the main chain.

  • 174.
    Šoltésová, Mária
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK). Charles University in Prague.
    Kowalewski, Jozef
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK).
    Widmalm, Göran
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Dynamics of exocyclic groups in the Escherichia coli O91 O-antigen polysaccharide in solution studied by carbon-13 NMR relaxation2013Ingår i: Journal of Biomolecular NMR, ISSN 0925-2738, E-ISSN 1573-5001, Vol. 57, nr 1, s. 37-45Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Carbon-13 relaxation data are reported for exocyclic groups of hexopyranosyl sugar residues in the repeating unit within the Escherichia coli O91 O-antigen polysaccharide in a dilute D2O solution. The measurements of T 1, T 2 and heteronuclear nuclear Overhauser enhancements were carried out at 310 K at two magnetic fields (16.4 T, 21.1 T). The data were analyzed using the standard and extended Lipari–Szabo models, as well as a conformational jump model. The extended version of the Lipari–Szabo and the two-site jump models were most successful for the hydroxymethyl groups of Gal and GlcNAc sugar residues. Different dynamics was found for the hydroxymethyl groups associated with different configurations (d-gluco, d-galacto) of the sugar residues, the latter being faster than the former.

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