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Conformational Studies of Oligosaccharides.

ABSTRACT: The conformation of a molecule strongly affects its function, as demonstrated for peptides and nucleic acids. This correlation is much less established for carbohydrates, the most abundant organic materials in nature. Recent advances in synthetic and analytical techniques have enabled the study of carbohydrates at the molecular level. Recurrent structural features were identified as responsible for particular biological activities or material properties. In this Minireview, recent achievements in the structural characterization of carbohydrates, enabled by systematic studies of chemically defined oligosaccharides, are discussed. These findings can guide the development of more potent glycomimetics. Synthetic carbohydrate materials by design can be envisioned.

SUBMITTER: Yu Y

PROVIDER: S-EPMC7496230 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Conformational Studies of Oligosaccharides.

Yu Yang Y Delbianco Martina M

Chemistry (Weinheim an der Bergstrasse, Germany) 20200709 44

The conformation of a molecule strongly affects its function, as demonstrated for peptides and nucleic acids. This correlation is much less established for carbohydrates, the most abundant organic materials in nature. Recent advances in synthetic and analytical techniques have enabled the study of carbohydrates at the molecular level. Recurrent structural features were identified as responsible for particular biological activities or material properties. In this Minireview, recent achievements i ...[more]

PMID: 32329095

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Project description:Cholera is caused by Vibrio cholerae and is an example of a blood-group-dependent disease. Recent studies suggest that the receptor-binding B subunit of the cholera toxin (CT) binds histo-blood group antigens at a secondary binding site. Herein, we studied the conformational dynamics of Lewis Y (LeY) oligosaccharides, H-tetrasaccharides and A-pentasaccharides, in aqueous solution by conducting accelerated molecular dynamics (aMD) simulations. The flexible nature of both oligosaccharides was displayed in aMD simulations. Furthermore, aMD simulations revealed that for both oligosaccharides in the free form, 4C1 and 1C4 puckers were sampled for all but GalNAc monosaccharides, while either the 4C1 (GlcNAc, Gal, GalNAc) or 1C4 (Fuc2, Fuc3) pucker was sampled in the CT-bound forms. In aMD, the complete transition from the 4C1 to 1C4 pucker was sampled for GlcNAc and Gal in both oligosaccharides. Further, we have observed a transition from the open to closed conformer in the case of A-pentasaccharide, while H-tetrasaccharide remains in the open conformation throughout the simulation. Both oligosaccharides adopted an open conformation in the CT binding site. Moreover, we have investigated the molecular basis of recognition of LeY oligosaccharides by the B subunit of the cholera toxin of classical and El Tor biotypes using the molecular mechanics generalized Born surface area (MM/GBSA) scheme. The O blood group determinant, H-tetrasaccharide, exhibits a stronger affinity to both biotypes compared to the A blood group determinant, A-pentasaccharide, which agrees with the experimental data. The difference in binding free energy between O and A blood group determinants mainly arises due to the increased entropic cost and desolvation energy in the case of A-pentasaccharide compared to that of H-tetrasaccharide. Our study also reveals that the terminal Fuc3 contributes most to the binding free energy compared to other carbohydrate residues as it forms multiple hydrogen bonds with CT. Overall, our study might help in designing glycomimetic drugs targeting the cholera toxin.

Dataset Information

Conformational Studies of Oligosaccharides.

Publications

Conformational Studies of Oligosaccharides.

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