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Conformational Dynamics of a Central Trisaccharide Fragment of the LeaLex Tumor Associated Antigen Studied by NMR Spectroscopy and Molecular Dynamics Simulations
Stockholm University, Faculty of Science, Department of Organic Chemistry.
Stockholm University, Faculty of Science, Department of Organic Chemistry.
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2012 (English)In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, no 25, 4705-4715 p.Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
2012. no 25, 4705-4715 p.
Keyword [en]
Carbohydrates, Conformation analysis, NMR spectroscopy, Molecular dynamics
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-81235DOI: 10.1002/ejoc.201200569ISI: 000307937800008OAI: oai:DiVA.org:su-81235DiVA: diva2:561431
Funder
Swedish Research CouncilKnut and Alice Wallenberg Foundation
Note

AuthorCount:6;

Available from: 2012-10-18 Created: 2012-10-15 Last updated: 2017-12-07Bibliographically approved
In thesis
1. Conformations of Flexible Oligosaccharides: Molecular Simulations and NMR spectroscopy
Open this publication in new window or tab >>Conformations of Flexible Oligosaccharides: Molecular Simulations and NMR spectroscopy
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The conformational preferences of several oligosaccharides are investigated herein using a combination of NMR spectroscopy and molecular dynamics (MD) simulations, focusing on the torsion angles associated with the glycosidic linkages.

Strategies for obtaining usable J-HMBC spectra for carbons with an adjacent 13C label are described. By employing a selective pulse or a constant time modification, spectra free from interferences are obtained for site-specifically 13C labeled oligosaccharides.

Intermolecular hydrogen bonding in sucrose is investigated using MD simulations performed at different concentrations. One of the most frequent intermolecular hydrogen bonds in the simulations, O3f∙∙∙HO3g, was detected using the HSQC-TOCSY NMR experiment.

Based on MD simulations and NMR spectroscopy, the conformational ensemble for a trisaccharide segment of the LeaLex hexasaccharide is proposed to feature conformational exchange between conformations with positive and negative values for the ψ3 torsion angle in the β-D-GlcpNAc-(1→3)-β-D-Galp linkage.

Using MD simulations, the conformation of the N-acetyl group is shown to influence the glycosidic conformation at a nearby linkage in two oligosaccharides.

Short (1→6)-linked oligosaccharides are shown to exhibit conformational exchange at the ω and ψ torsion angles. Notably, the former torsion angle populates states with ψ ≈ ±90°. Conformationally sensitive homo- and heteronuclear coupling constants are determined using various NMR experiments. The experimental data, including effective distances from NOESY obtained for two of the compounds, is used to improve the representation of the ω torsion angle in the CHARMM36 force field.

Place, publisher, year, edition, pages
Stockholm: Department of Organic Chemistry, Stockholm University, 2013. 78 p.
Keyword
Carbohydrates, Oligosaccharide, Conformation, NMR spectroscopy, MD simulations
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-95480 (URN)978-91-7447-808-2 (ISBN)
Public defence
2013-12-13, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 1: Manuscript. Paper 5: Accepted. Paper 6: Manuscript.

Available from: 2013-11-21 Created: 2013-10-29 Last updated: 2015-10-06Bibliographically approved
2. Structural and Conformational Studies of Oligo- and Polysaccharides
Open this publication in new window or tab >>Structural and Conformational Studies of Oligo- and Polysaccharides
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The focus of this thesis is to examine the structural properties of polysaccharides produced by bacteria, as well as the dynamic and conformational behavior of a synthetically derived oligosaccharide.

The primary structures of the O-polysaccharide repeating units of four different Escherichia coli (E. coli) strains, namely O175, O177, O103 and TD2158, as well as the first report of a capsular polysaccharide produced by lactic acid bacteria Leuconostoc mesenteroides ssp. cremoris PIA2 are reported in paper I–V. Structural analyses have been performed using a combination of nuclear magnetic resonance spectroscopy and chemical component analysis.

The elucidated structures in paper I–III, as well as paper V, are composed of linear repeating units of varying composition and length. In paper IV, the structure of the O-polysaccharide repeating unit of E. coli TD2158 is determined to be a branched hexasaccharide structure with a heterogeneous substitution pattern, with either a β-GlcpNAc or β-Glcp residue branching to the backbone chain. Incubation with bacteriophage HK620 tailspike protein shows that the polysaccharide is selectively cleaved at the α-GlcpNAc-(1→2)-α-Rhap-linkage of the backbone chain, yielding a 9:1 ratio of β-GlcpNAc/β-Glcp containing hexasaccharides after digestion.

In paper VI the conformational properties of a trisaccharide, which constitutes an internal epitope of the LeaLex hexasaccharide over-expressed on the surface of squamous lung cancer cells, have been analyzed using NMR spectroscopy and molecular dynamics simulations. The β-(1→3)-linkage of the trisaccharide was shown to be highly flexible.

Place, publisher, year, edition, pages
Stockholm: Department of Organic Chemistry, Stockholm University, 2012. 54 p.
Keyword
NMR spectroscopy, structural analysis, conformational analysis, carbohydrates, polysaccharides
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-75050 (URN)978-91-7447-457-2 (ISBN)
Public defence
2012-05-04, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 4: Submitted. Paper 6: Submitted.

Available from: 2013-04-09 Created: 2012-04-03 Last updated: 2013-11-18Bibliographically approved

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