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Structural analysis of glycans by NMR chemical shift prediction
Stockholm University, Faculty of Science, Department of Organic Chemistry.
Stockholm University, Faculty of Science, Department of Organic Chemistry.
2011 (English)In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 83, no 5, 1514-1517 p.Article in journal (Refereed) Published
Abstract [en]

Structural determination of N- and O-linked glycans as well as polysaccharides is hampered by the limited spectral dispersion. The computerized approach CASPER, an acronym for computer assisted spectrum evaluation of regular polysaccharides, uses liquid state NMR data to elucidate carbohydrate structure based on agreement with predicted 1H and 13C chemical shifts. We here demonstrate developments based on multiple through-bond J-based correlations that significantly enhance the credence to the sequence connectivities proposed in the analysis exemplified by an oligosaccharide and a bacterial polysaccharide. The approach is also suitable for predicting 1H and 13C NMR chemical shifts of synthesized oligosaccharides and glycoconjugates, thereby corroborating a proposed structure.

Place, publisher, year, edition, pages
2011. Vol. 83, no 5, 1514-1517 p.
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-55136DOI: 10.1021/ac1032534ISI: 000287685800006OAI: oai:DiVA.org:su-55136DiVA: diva2:401376
Funder
Swedish Research CouncilKnut and Alice Wallenberg Foundation
Available from: 2011-03-02 Created: 2011-03-02 Last updated: 2017-12-11Bibliographically approved
In thesis
1. Computer-Assisted Carbohydrate Structural Studies and Drug Discovery
Open this publication in new window or tab >>Computer-Assisted Carbohydrate Structural Studies and Drug Discovery
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Carbohydrates are abundant in nature and have functions ranging from energy storage to acting as structural components. Analysis of carbohydrate structures is important and can be used for, for instance, clinical diagnosis of diseases as well as in bacterial studies. The complexity of glycans makes it difficult to determine their structures. NMR spectroscopy is an advanced method that can be used to examine carbohydrates at the atomic level, but full assignments of the signals require much work. Reliable automation of this process would be of great help. Herein studies of Escherichia coli O-antigen polysaccharides are presented, both a structure determination by NMR and also research on glycosyltransferases which assemble the polysaccharides. The computer program CASPER has been improved to assist in carbohydrate studies and in the long run make it possible to automatically determine structures based only on NMR data.

Detailed computer studies of glycans can shed light on their interactions with proteins and help find inhibitors to prevent unwanted binding. The WaaG glycosyltransferase is important for the formation of E. coli lipopolysaccharides. Molecular docking analyses of structures confirmed to bind this enzyme have provided information on how inhibitors could be composed. Noroviruses cause gastroenteritis, such as the winter vomiting disease, after binding human histo-blood group antigens. In one of the projects, fragment-based docking, followed by molecular dynamics simulations and binding free energy calculations, was used to find competitive binders to the P domain of the capsid of the norovirus VA387. These novel structures have high affinity and are a very good starting point for developing drugs against noroviruses. The protein targets in these two projects are carbohydrate binding, but the techniques are general and can be applied to other research projects.

Place, publisher, year, edition, pages
Stockholm: Department of Organic Chemistry, Stockholm University, 2011. 78 p.
Keyword
Carbohydrates, molecular docking, molecular dynamics simulation, fragment-based virtual screening, NMR spectroscopy, computer-aided drug design, computer-aided structure elucidation, glycosyltransferases, Escherichia coli
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-56411 (URN)978-91-7447-245-5 (ISBN)
Public defence
2011-05-25, 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 5: Manuscript. Paper 6. Manuscript.Available from: 2011-05-03 Created: 2011-04-15 Last updated: 2012-07-03Bibliographically approved

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