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Delineating the conformational flexibility of trisaccharides from NMR spectroscopy experiments and computer simulations
Stockholm University, Faculty of Science, Department of Organic Chemistry.
Stockholm University, Faculty of Science, Department of Organic Chemistry.
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2016 (English)In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 18, no 28, 18776-18794 p.Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
2016. Vol. 18, no 28, 18776-18794 p.
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-133040DOI: 10.1039/c6cp02970aISI: 000379939100017OAI: oai:DiVA.org:su-133040DiVA: diva2:956308
Available from: 2016-08-29 Created: 2016-08-29 Last updated: 2016-09-05Bibliographically approved
In thesis
1. Assembling and Unraveling Carbohydrates Structures: Conformational analysis of synthesized branched oligosaccharides
Open this publication in new window or tab >>Assembling and Unraveling Carbohydrates Structures: Conformational analysis of synthesized branched oligosaccharides
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Advances in the elaboration of vaccines and enzyme inhibitors rely on acquiring more knowledge about protein-carbohydrate binding events. Furthermore, the relationships between biological function and the three-dimensional properties of large glycans can be studied by focusing on the structural components they contained, namely, by scaling down the system under analysis. Chemical methods are useful assets as they allow the isolation and determination of epitopes; these small and recognizable fragments that lead to very specific interactions. In this thesis, biologically relevant saccharides were obtained using recently developed concepts in carbohydrate synthesis and NMR spectroscopy was used to unravel their conformational preferences.

In paper I, the convergent synthesis of the tetrasaccharide found in the natural product solaradixine is described. Reactivity enhanced disaccharide glycosyl donors were coupled to a disaccharide acceptor in a 2 + 2 fashion. The computer program CASPER was subsequently used to verify the synthesized structure.

The conformation arming concept employed in paper I was further investigated in paper II. An NMR-based methodology enabled the determination of the ring conformations of a set of donors. Subsequently, glycosylation reactions were performed and yields were correlated to donors ring shapes. Perturbations in the rings shape caused by bulky silyl ether protective groups were sufficient to boost the potency of several donors. As a matter of fact, complex branched oligosaccharides could be obtained in good to excellent yields.

In paper III, NMR spectroscopy observables were measured to elucidate the ring shape, the mutual orientation of the rings across the glycosidic bond and the positions of the side chains of 5 trisaccharides found in larger structures. With the aid of molecular dynamics simulations, their overall conformational propensities were revealed.

Finally, the software CASPER prediction skills were improved by adding, inter alia, NMR information of synthesized mono- and disaccharides to its database. Unassigned chemical shifts from polysaccharides served as input to challenge its ability to solve large carbohydrate structures.

Place, publisher, year, edition, pages
Stockholm: Department of Organic Chemistry, Stockholm University, 2016. 85 p.
Keyword
Convergent carbohydrate synthesis, Super-armed donors, Glycosylation, Conformational analysis, NMR, Chemical shift prediction
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-133106 (URN)978-91-7649-473-8 (ISBN)
Public defence
2016-10-21, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
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Note

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Manuscript. Paper 4: Manuscript.

Available from: 2016-09-28 Created: 2016-08-31 Last updated: 2016-09-16Bibliographically approved

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Angles d'Ortoli, ThibaultWidmalm, Göran
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