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  • 1. Hatcher, Elizabeth
    et al.
    Säwén, Elin
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Widmalm, Göran
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    MacKerell, Jr., Alexander D.
    Conformational properties of methyl β-maltoside and methyl α- and β-cellobioside disaccharides2011In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 115, no 3, p. 597-608Article in journal (Refereed)
    Abstract [en]

    An investigation of the conformational properties of methyl β-maltoside, methyl α-cellobioside, and methyl β-cellobioside disaccharides using NMR spectroscopy and molecular dynamics (MD) techniques, is presented. Emphasis is placed on validation of a recently presented force field for hexopyranose disaccharides followed by elucidation of the conformational properties of two different types of glycosidic linkages, α-(1 → 4) and β-(1 → 4). Both gas-phase and aqueous-phase simulations are performed to gain insight into the effect of solvent on the conformational properties. A number of transglycosidic J-coupling constants and proton−proton distances are calculated from the simulations and are used to identify the percent sampling of the three glycosidic conformations (syn, anti-, and anti-ψ) and, in turn, describe the flexibility around the glycosidic linkage. The results show the force field to be in overall good agreement with experiment, although some very small limitations are evident. Subsequently, a thorough hydrogen bonding analysis is performed to obtain insights into the conformational properties of the disaccharides. In methyl β-maltoside, competition between HO2′−O3 intramolecular hydrogen bonding and intermolecular hydrogen bonding of those groups with solvent leads to increased sampling of syn, anti-, and anti-ψ conformations and better agreement with NMR J-coupling constants. In methyl α- and β-cellobioside, O5′−HO6 and HO2′−O3 hydrogen bonding interactions are in competition with intermolecular hydrogen bonding involving the solvent molecules. This competition leads to retention of the O5′−HO3 hydrogen bond and increased sampling of the syn region of the /ψ map. Moreover, glycosidic torsions are correlated to the intramolecular hydrogen bonding occurring in the molecules. The present results verify that in the β-(1 → 4)-linkage intramolecular hydrogen bonding in the aqueous phase is due to the decreased ability of water to successfully compete for the O5′ and HO3 hydrogen bonding moieties, in contrast to that occurring between the O5′ and HO6 atoms in this α-(1 → 4)-linkage.

  • 2.
    Jonsson, Hanna
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Säwén, Elin
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Widmalm, Göran
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Studies on the conformational flexibility of α-L-Rhap-(1→2)-α-L-Rhap-OMe using molecular simulation and 13C-site-specific labeling: a model for a commonly occurring disaccharide in bacterial polysaccharidesManuscript (preprint) (Other academic)
    Abstract [en]

    Bacterial polysaccharides are comprised of a variety of monosaccharides, L-rhamnose (6-deoxy-Lmannose) being one of them. This sugar is often part of α-(1→2)- and/or α-(1→3)-linkages and wehave therefore studied the disaccharide α-L-Rhap-(1→2)-α-L-Rhap-OMe to obtain information onconformational preferences at this glycosidic linkage. The target disaccharide was synthesized with 13C site-specific labeling at C1' and at C2', i.e., in the terminal group. 2D 1H,13C-HSQC-HECADE and 1H,13C-J-HMBC NMR experiments, 1D 13C and 1H NMR spectra together with total line-shape analysis were used to extract conformationally dependent hetero- and homonuclear spin-spincoupling constants. This resulted in the determination of 2JC2',H1' , 3JC1',C1 , 3JC1',C3 , 3JC2',C2 , 2JC1',C2 ,1JC1',C2' , and 1JC1',H1' . These data together with previously determined JC,H and 1H,1H NOEs result in fourteen conformationally dependent NMR parameters that are available for analysis of glycosidiclinkage flexibility and conformational preferences. A molecular dynamics simulation of the disaccharide with explicit water molecules as solvent showed a major conformational state at ΦH =40° and ψH = –35°, consistent with experimental NMR data.

  • 3. Novoa-Carballal, Ramón
    et al.
    Säwén, Elin
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Fernandez-Megia, Eduardo
    Correa, Juan
    Riguera, Ricardo
    Widmalm, Göran
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    The dynamics of GATG glycodendrimers by NMR diffusion and quantitative 13C relaxation2010In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 12, no 25, p. 6587-6589Article in journal (Refereed)
    Abstract [en]

    The dynamics of GATG glycodendrimers have been investigated by NMR translational diffusion and quantitative 13C relaxation studies (Lipari-Szabo model-free), allowing the determination of the correlation times describing the dendrimer segmental orientational mobility.

  • 4.
    Olsson, Ulrika
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Säwén, Elin
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Stenutz, Roland
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Widmalm, Göran
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Conformational flexibility and dynamics of two (1→6)-linked disaccharides related to an oligosaccharide epitope expressed on malignant tumour cells2009In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 15, no 35, p. 8886-8894Article in journal (Refereed)
    Abstract [en]

    The conformational flexibility and dynamics of two (1→6)-linked disaccharides that are related to the action of the glycosyl transferase GnT-V have been investigated. NMR NOE and T-ROE spectroscopy experiments, conformation-dependent coupling constants and molecular dynamics (MD) simulations were used in the analyses. To facilitate these studies, the compounds were synthesised as α-d-[6-13C]-Manp-OMe derivatives, which reduced the 1H NMR spectral overlap and facilitated the determination of two- and three-bond 1H,1H, 1H,13C and 13C,13C-coupling constants. The population distribution for the glycosidic ω torsion angle in α-d-Manp-(1→6)-α-d-Manp-OMe for gt/gg/tg was equal to 45:50:5, whereas in α-d-Manp-OMe it was determined to be 56:36:8. The dynamic model that was generated for β-d-GlcpNAc-(1→6)-α-d-Manp-OMe by MD simulations employing the PARM22/SU01 CHARMM-based force field was in very good agreement with experimental observations. β-d-GlcpNAc-(1→6)-α-d-Manp-OMe is described by an equilibrium of populated states in which the ϕ torsion angle has the exo-anomeric conformation, the ψ torsion angle an extended antiperiplanar conformation and the ω torsion angle a distribution of populations predominantly between the gauchetrans and the gauchegauche conformational states (i.e., gt/gg/tg) is equal to 60:35:5, respectively. The use of site-specific 13C labelling in these disaccharides leads to increased spectral dispersion, thereby making NMR spectroscopy based conformational analysis possible that otherwise might be difficult to attain.

  • 5. Plazinski, Wojciech
    et al.
    Roslund, Mattias U.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Säwén, Elin
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Engström, Olof
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Tähtinen, Petri
    Widmalm, Göran
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Tautomers of N-acetyl-d-allosamine: an NMR and computational chemistry study2021In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 19, no 33, p. 7190-7201Article in journal (Refereed)
    Abstract [en]

    D-Allosamine is a rare sugar in Nature but its pyranoid form has been found α-linked in the core region of the lipopolysaccharide from the Gram-negative bacterium Porphyromonas gingivalis and in the chitanase inhibitor allosamidin, then β-linked and N-acetylated. In water solution the monosaccharide N-acetyl-D-allosamine (D-AllNAc) shows a significant presence of four tautomers arising from pyranoid and furanoid ring forms and anomeric configurations. The furanoid ring forms both showed 3JH1,H2 ≈ 4.85 Hz and to differentiate the anomeric configurations a series of chemical shift anisotropy/dipole–dipole cross-correlated relaxation NMR experiments was performed in which the α-anomeric form showed notable different relaxation rates for its components of the H1 doublet, thereby making it possible to elucidate the anomeric configuration of each of the furanoses. The conformational preferences of the different forms of D-AllNAc were investigated by 3JHH, 2JCH and 3JCH coupling constants from NMR experiments, molecular dynamics simulations and density functional theory calculations. The pyranose form resides in the 4C1 conformation and the furanose ring form has the majority of its conformers located on the South–East region of the pseudorotation wheel, with a small population in the Northern hemisphere. The tautomeric equilibrium was quite sensitive to changes in temperature, where the β-anomer of the pyranoid ring form decreased upon a temperature increase while the other forms increased

  • 6.
    Roslund, Mattias U.
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Säwén, Elin
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Landström, Jens
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Rönnols, Jerk
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Jonsson, K. Hanna M.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Lundborg, Magnus
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Svensson, Mona V.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Widmalm, Göran
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Complete 1H and 13C NMR chemical shift assignments of mono-, di-, and trisaccharides as basis for NMR chemical shift predictions of polysaccharides using the computer program CASPER2011In: Carbohydrate Research, ISSN 0008-6215, E-ISSN 1873-426X, Vol. 346, no 11, p. 1311-1319Article in journal (Refereed)
    Abstract [en]

    The computer program casper uses 1H and 13C NMR chemical shift data of mono- to trisaccharides for the prediction of chemical shifts of oligo- and polysaccharides. In order to improve the quality of these predictions the 1H and 13C, as well as 31P when applicable, NMR chemical shifts of 30 mono-, di-, and trisaccharides were assigned. The reducing sugars gave two distinct sets of NMR resonances due to the α- and β-anomeric forms. In total 35 1H and 13C NMR chemical shift data sets were obtained from the oligosaccharides. One- and two-dimensional NMR experiments were used for the chemical shift assignments and special techniques were employed in some cases such as 2D 1H,13C-HSQC Hadamard Transform methodology which was acquired approximately 45 times faster than a regular t1 incremented 1H,13C-HSQC experiment and a 1D 1H,1H-CSSF-TOCSY experiment which was able to distinguish spin-systems in which the target protons were only 3.3 Hz apart. The 1H NMR chemical shifts were subsequently refined using total line-shape analysis with the PERCH NMR software. The acquired NMR data were then utilized in the casper program (http://www.casper.organ.su.se/casper/) for NMR chemical shift predictions of the O-antigen polysaccharides from Klebsiella O5, Shigella flexneri serotype X, and Salmonella arizonae O62. The data were compared to experimental data of the polysaccharides from the two former strains and the lipopolysaccharide of the latter strain showing excellent agreement between predicted and experimental 1H and 13C NMR chemical shifts.

  • 7.
    Rönnols, Jerk
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Engström, Olof
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Schnupf, Udo
    Säwén, Elin
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Brady, John W.
    Widmalm, Göran
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Inter-residual Hydrogen Bonding in Carbohydrates Unraveled by NMR Spectroscopy and Molecular Dynamics Simulations2019In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 20, p. 2519-2528Article in journal (Refereed)
    Abstract [en]

    Carbohydrates, also known as glycans in biological systems, are omnipresent in nature where they as glycoconjugates occur as oligo- and polysaccharides linked to lipids and proteins. Their three-dimensional structure is defined by two or three torsion angles at each glycosidic linkage. In addition, transglycosidic hydrogen bonding between sugar residues may be important. Herein we investigate the presence of these inter-residue interactions by NMR spectroscopy in D2O/[D-6]DMSO (70:30) or D2O and by molecular dynamics (MD) simulations with explicit water as solvent for disaccharides with structural elements alpha-d-Manp-(1 -> 2)-d-Manp, beta-d-GlcpNAc-(1 -> 2)-d-Manp, and alpha-d-Glcp-(1 -> 4)-beta-d-Glcp, all of which have been suggested to exhibit inter-residue hydrogen bonding. For the disaccharide beta-d-GlcpNAc-(1 -> 2)-beta-d-Manp-OMe, the large extent of O5 '...HO3 hydrogen bonding as seen from the MD simulation is implicitly supported by the H-1 NMR chemical shift and (3)J(HO3,H3) value of the hydroxy proton. In the case of alpha-d-Glcp-(1 -> 4)-beta-d-Glcp-OMe, the existence of a transglycosidic hydrogen bond O2 '...HO3 was proven by the presence of a cross-peak in H-1,C-13 HSQC-TOCSY experiments as a result of direct TOCSY transfer between HO3 of the reducing end residue and H2 ' (detected at C2 ') of the terminal residue. The occurrence of inter-residue hydrogen bonding, albeit transient, is judged important for the stabilization of three-dimensional structures, which may be essential in maintaining a conformational state for carbohydrate-protein interactions of glycans to take place in biologically important environments.

  • 8.
    Rönnols, Jerk
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Pendrill, Robert
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Fontana, Carolina
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Hamark, Christoffer
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Angles d'Ortoli, Thibault
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Engström, Olof
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Ståhle, Jonas
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Zaccheus, Mona V.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Säwén, Elin
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Hahn, Liljan E.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Iqbal, Shahzad
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Widmalm, Göran
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Complete H-1 and C-13 NMR chemical shift assignments of mono- to tetrasaccharides as basis for NMR chemical shift predictions of oligosaccharides using the computer program CASPER2013In: Carbohydrate Research, ISSN 0008-6215, E-ISSN 1873-426X, Vol. 380, p. 156-166Article in journal (Refereed)
    Abstract [en]

    H-1 and C-13 NMR chemical shift data are used by the computer program CASPER to predict chemical shifts of oligo- and polysaccharides. Three types of data are used, namely, those from monosaccharides, disaccharides, and trisaccharides. To improve the accuracy of these predictions we have assigned the H-1 and C-13 NMR chemical shifts of eleven monosaccharides, eleven disaccharides, twenty trisaccharides, and one tetrasaccharide; in total 43 compounds. Five of the oligosaccharides gave two distinct sets of NMR resonances due to the alpha- and beta-anomeric forms resulting in 48 H-1 and C-13 NMR chemical shift data sets. In addition, the pyranose ring forms of Neu5Ac were assigned at two temperatures, due to chemical shift displacements as a function of temperature. The H-1 NMR chemical shifts were refined using total line-shape analysis with the PERCH NMR software. H-1 and C-13 NMR chemical shift predictions were subsequently carried out by the CASPER program (http://www.casper.organ.su.se/casper/) for three branched oligosaccharides having different functional groups at their reducing ends, namely, a mannose-containing pentasaccharide, and two fucose-containing heptasaccharides having N-acetyllactosamine residues in the backbone of their structures. Good to excellent agreement was observed between predicted and experimental H-1 and C-13 NMR chemical shifts showing the utility of the method for structural determination or confirmation of synthesized oligosaccharides.

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  • 9.
    Säwén, Elin
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Conformational Studies of Carbohydrates with NMR Spectroscopy and Molecular Dynamics Simulations2008Licentiate thesis, comprehensive summary (Other academic)
  • 10.
    Säwén, Elin
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    NMR spectroscopy and MD simulations of carbohydrates2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Knowledge about the structure, conformation and dynamics of carbohydrates is important in our understanding of the way carbohydrates function in biological systems, for example in intermolecular signaling and recognition. This thesis is a summary of five papers studying these properties in carbohydrate-containing molecules with NMR spectroscopy and molecular dynamics simulations.

    In paper I, the ring-conformations of the six-membered rings of two carbaiduronic analogs were investigated. These carbasugars could potentially be used as hydrolytically stable mimics of iduronic acid in drugs. The study showed that the equilibrium is entirely shifted towards the 4C1 conformation.

    Paper II is an investigation of the conformational flexibility and dynamics of two (1→6)-linked disaccharides related to an oligosaccharide epitope expressed on malignant tumor cells.

    In paper III, the conformational space of the glycosidic linkage of an alfa-(1→2) linked mannose disaccharide present in N- and O-linked glycoproteins, was studied. A maximum entropy analysis using different priors as background information was used and four new Karplus equations for 3JC,C and 3JC,H coupling constants, related to the glycosidic linkage, were presented.

    Paper IV describes a structural elucidation of the exopolysaccharide (EPS) produced by Streptococcus thermophilus ST1, a major dairy starter used in yoghurt and cheese production. The EPS contains a hexasaccharide repeating unit of d-galactose and d-glucose residues, which is a new EPS structure of the S. thermophilus species.

    In paper V, the dynamics of three generations of glycodendrimers were investigated by NMR diffusion and 13C NMR relaxation studies. Three different correlations times were identified, one global correlation time describing the rotation of the dendrimer as a whole, one local correlation time describing the reorientation of the C-H vectors, and one correlation time describing the pulsation of a dendrimer branch.

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  • 11.
    Säwén, Elin
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Hinterholzinger, Florian
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Landersjö, Clas
    Widmalm, Göran
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Conformational studies of lacto-N-fucocopentaose 2 by NMR spectroscopy and molecular dynamic simulations2009In: Abstracts of Papers, 238th ACS National Meeting, Washington, DC, United States, August 16-20, 2009, American Chemical Society , 2009Conference paper (Other academic)
  • 12.
    Säwén, Elin
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Huttunen, Eine
    Zhang, Xue
    Yang, Zhennai
    Widmalm, Göran
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Structural analysis of the exopolysaccharide produced by Streptococcus thermophilus ST1 solely by NMR spectroscopy2010In: Journal of Biomolecular NMR, ISSN 0925-2738, E-ISSN 1573-5001, Vol. 47, no 2, p. 125-134Article in journal (Refereed)
    Abstract [en]

    The use of lactic acid bacteria in fermentation of milk results in favorable physical and rheological properties due to in situ exopolysaccharide (EPS) production. The EPS from S. thermophilus ST1 produces highly viscous aqueous solutions and its structure has been investigated by NMR spectroscopy. Notably, all aspects of the elucidation of its primary structure including component analysis and absolute configuration of the constituent monosaccharides were carried out by NMR spectroscopy. An array of techniques was utilized including, inter alia, PANSY and NOESY-HSQC TILT experiments. The EPS is composed of hexasaccharide repeating units with the following structure: → 3)[α-d-Glcp-(1 → 4)]-β-d-Galp-(1 → 4)-β-d-Glcp-(1 → 4)[β-d-Galf-(1 → 6)]-β-d-Glcp-(1 → 6)-β-d-Glcp-(1 →, in which the residues in square brackets are terminal groups substituting backbone sugar residues that consequently are branch-points in the repeating unit of the polymer. Thus, the EPS consists of a backbone of four sugar residues with two terminal sugar residues making up two side-chains of the repeating unit. The molecular mass of the polymer was determined using translational diffusion experiments which resulted in Mw = 62 kDa, corresponding to 64 repeating units in the EPS.

  • 13.
    Säwén, Elin
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Massad, Tariq
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Landersjö, Clas
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Damberg, Peter
    Widmalm, Göran
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Population distribution of flexible molecules from maximum entropy analysisusing different priors as background information: application to the phi,psi-conformational space of the a-(1→2)-linked mannose disaccharide presentin N- and O-linked glycoproteins2010In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 8, no 16, p. 3684-3695Article in journal (Refereed)
    Abstract [en]

    The conformational space available to the flexible molecule a-D-Manp-(1→2)-a-D-Manp-OMe, amodel for the a-(1→2)-linked mannose disaccharide in N- or O-linked glycoproteins, is determinedusing experimental data and molecular simulation combined with a maximum entropy approach thatleads to a converged population distribution utilizing different input information. A database survey ofthe Protein Data Bank where structures having the constituent disaccharide were retrieved resulted inan ensemble with >200 structures. Subsequent filtering removed erroneous structures and gave thedatabase (DB) ensemble having three classes of mannose-containing compounds, viz., N- and O-linkedstructures, and ligands to proteins. A molecular dynamics (MD) simulation of the disaccharide revealeda two-state equilibrium with a major and a minor conformational state, i.e., the MD ensemble. Thesetwo different conformation ensembles of the disaccharide were compared to measured experimentalspectroscopic data for the molecule in water solution. However, neither of the two populations werecompatible with experimental data from optical rotation, NMR 1H,1H cross-relaxation rates as well ashomo- and heteronuclear 3J couplings. The conformational distributions were subsequently used asbackground information to generate priors that were used in a maximum entropy analysis. Theresulting posteriors, i.e., the population distributions after the application of the maximum entropyanalysis, still showed notable deviations that were not anticipated based on the prior information.Therefore, reparameterization of homo- and heteronuclear Karplus relationships for the glycosidictorsion angles f and y were carried out in which the importance of electronegative substituents on thecoupling pathway was deemed essential resulting in four derived equations, two 3JCOCC and two 3JCOCHbeing different for the f and y torsions, respectively. These Karplus relationships are denotedJCX/SU09. Reapplication of the maximum entropy analysis gave excellent agreement between theMD- and DB-posteriors. The information entropies show that the current reparametrization of theKarplus relationships constitutes a significant improvement. The fH torsion angle of the disaccharide isgoverned by the exo-anomeric effect and for the dominating conformation fH = -40◦ and yH = 33◦.The minor conformational state has a negative yH torsion angle; the relative populations of the majorand the minor states are ~3 : 1. It is anticipated that application of the methodology will be useful toflexible molecules ranging from small organic molecules to large biomolecules.

  • 14.
    Säwén, Elin
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Roslund, Mattias
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Cumpstey, Ian
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Widmalm, Göran
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Synthesis and conformational analysis of carbasugar bioisosteres of alpha-L-iduronic acid and its methyl glycoside2010In: Carbohydrate Research, ISSN 0008-6215, E-ISSN 1873-426X, Vol. 345, no 8, p. 984-993Article in journal (Refereed)
    Abstract [en]

    The synthesis of two novel carbasugar analogues of α-l-iduronic acid is described in which the ring-oxygen is replaced by a methylene group. In analogy with the conformational equilibrium described for α-l-IdopA, the conformation of the carbasugars was investigated by 1H and 13C NMR spectroscopy. Hadamard transform NMR experiments were utilised for rapid acquisition of 1H,13C-HSQC spectra and efficient measurements of heteronuclear long-range coupling constants. Analysis of 1H NMR chemical shifts and JH,H coupling constants extracted by a total-lineshape fitting procedure in conjunction with JH,C coupling constants obtained by three different 2D NMR experiments, viz., 1H,13C-HSQC-HECADE, J-HMBC and IPAP-HSQC-TOCSY-HT, as well as effective proton–proton distances from 1D 1H,1H T-ROE and NOE experiments showed that the conformational equilibrium 4C12S5a1C4 is shifted towards 4C1 as the predominant or exclusive conformation. These carbasugar bioisosteres of α-l-iduronic acid do not as monomers show the inherent flexibility that is anticipated to be necessary for biological activity.

  • 15.
    Säwén, Elin
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Stevensson, Baltzar
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Physical Chemistry.
    Östervall, Jennie
    Stockholm University, Faculty of Science, Department of Organic Chemistry. Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Physical Chemistry.
    Maliniak, Arnold
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Physical Chemistry.
    Widmalm, Göran
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Molecular conformations in the pentasaccharide LNF-1 derived from NMR spectroscopy and molecular dynamics simulations2011In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 115, no 21, p. 7109-7121Article in journal (Refereed)
    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.

  • 16. Yang, Mingjun
    et al.
    Angles d'Ortoli, Thibault
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Säwén, Elin
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Jana, Madhurima
    Widmalm, Göran
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    MacKerell, Jr., Alexander D.
    Delineating the conformational flexibility of trisaccharides from NMR spectroscopy experiments and computer simulations2016In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 18, no 28, p. 18776-18794Article in journal (Refereed)
    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.

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