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NMR spectroscopy and MD simulations of carbohydrates
Stockholm University, Faculty of Science, Department of Organic Chemistry.
2011 (English)Doctoral 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.

Place, publisher, year, edition, pages
Stockholm: Department of Organic Chemistry, Stockholm University , 2011. , 75 p.
Keyword [en]
NMR specroscopy, MD simulations, carbohydrates
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-61569ISBN: 978-91-7447-348-3 (print)OAI: oai:DiVA.org:su-61569DiVA: diva2:436367
Public defence
2011-09-30, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
Opponent
Supervisors
Available from: 2011-09-08 Created: 2011-08-23 Last updated: 2011-08-23Bibliographically approved
List of papers
1. Synthesis and conformational analysis of carbasugar bioisosteres of alpha-L-iduronic acid and its methyl glycoside
Open this publication in new window or tab >>Synthesis and conformational analysis of carbasugar bioisosteres of alpha-L-iduronic acid and its methyl glycoside
2010 (English)In: Carbohydrate Research, ISSN 0008-6215, E-ISSN 1873-426X, Vol. 345, no 8, 984-993 p.Article in journal (Refereed) Published
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.

Keyword
Heparin, Conformational equilibrium, NMR, Molecular modelling
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-59758 (URN)10.1016/j.carres.2010.03.002 (DOI)000278747700001 ()
Available from: 2011-07-12 Created: 2011-07-12 Last updated: 2017-12-11Bibliographically approved
2. Conformational flexibility and dynamics of two (1→6)-linked disaccharides related to an oligosaccharide epitope expressed on malignant tumour cells
Open this publication in new window or tab >>Conformational flexibility and dynamics of two (1→6)-linked disaccharides related to an oligosaccharide epitope expressed on malignant tumour cells
2009 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 15, no 35, 8886-8894 p.Article in journal (Refereed) Published
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.

Keyword
carbohydrates, enzymes, molecular dynamics, NMR spectroscopy, torsion angles
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-29504 (URN)10.1002/chem.200900507 (DOI)000270045500030 ()
Available from: 2009-09-02 Created: 2009-09-02 Last updated: 2017-12-13Bibliographically approved
3. 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 glycoproteins
Open this publication in new window or tab >>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 glycoproteins
Show others...
2010 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 8, no 16, 3684-3695 p.Article in journal (Refereed) Published
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.

Keyword
Maximum entropy, Karplus relation, disaccharides
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-42005 (URN)10.1039/c003958f (DOI)000280527500015 ()
Available from: 2010-08-13 Created: 2010-08-13 Last updated: 2017-12-12Bibliographically approved
4. Structural analysis of the exopolysaccharide produced by Streptococcus thermophilus ST1 solely by NMR spectroscopy
Open this publication in new window or tab >>Structural analysis of the exopolysaccharide produced by Streptococcus thermophilus ST1 solely by NMR spectroscopy
Show others...
2010 (English)In: Journal of Biomolecular NMR, ISSN 0925-2738, E-ISSN 1573-5001, Vol. 47, no 2, 125-134 p.Article in journal (Refereed) Published
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.

Keyword
Carbohydrates, Polysaccharide, Biopolymer, NMR spectroscopy, Absolute configuration, Dynamic light scattering
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-39280 (URN)10.1007/s10858-010-9413-0 (DOI)000277602500004 ()
Available from: 2010-05-17 Created: 2010-05-17 Last updated: 2017-12-12Bibliographically approved
5. The dynamics of GATG glycodendrimers by NMR diffusion and quantitative 13C relaxation
Open this publication in new window or tab >>The dynamics of GATG glycodendrimers by NMR diffusion and quantitative 13C relaxation
Show others...
2010 (English)In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 12, no 25, 6587-6589 p.Article in journal (Refereed) Published
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.

National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-41935 (URN)10.1039/c003645p (DOI)000278824400005 ()
Available from: 2010-08-12 Created: 2010-08-12 Last updated: 2017-12-12Bibliographically approved

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