The Conformation Space of Oligosaccharides, Natural Information Coding Leading to Molecular Recognition

Gábor I. Csonka^*, Carlos P. Sosa, Imre G. Csizmadia

Department of Inorganic Chemistry, Budapest University of Technology, H-1521 Budapest, Silicon Graphics Inc. 655 E. Lone Oak Dr. Eagan, MN 55123, USA, Department of Chemistry, University of Toronto, Toronto, Ontario, Canada M5S 3H6

1. Carbohydrate recognition in the Nature
2. Lectins
3. Experimental techniques
4. Computational chemistry - Lewis X
5. Rapid Estimation of Basis Set Error and Correlation Energy

As carriers of information, oligosaccharides have far greater potential than nucleic acids or proteins.

Figure 1
 
Carbohydrate recognition in nature

1. Enzymes - bind and transform carbohydrates
2. Antibodies - over 70% directed towards oligosaccharide epitope.
3. Lectins - recognition of cell-surface oligosaccharides, adhesion (in animals, plants, bacteria and viruses)
4. Bacterial periplasmic proteins –high binding constants to monosaccharides

1. bacterial and viral lectins initiate the infection of the target cells (e.g. influenza haemagglutinin)
2. collectins (e.g. mannose binding protein) as part of an antibody-independent immune response
3. selectins mediate the recruitment of leukocytes into inflammatory tissue sites

Carbohydrates in their pyranose and furanose forms are characterized by an array of polar functional groups. Most are OH groups – donation and acceptance of hydrogen bonds

Carbohydrate recognition: surround these groups with complementary H-bonds donor or acceptor functionality. – Nature: glucose in intermolecular complex.

Experimental techniques

Crystal structures

• packing forces distort the hydrogen bonds (and H positions are uncertain)
• provide precise test possibilities for force fields applied for solid-phase
• CCDC 55 structures of un-substituted di-, 17 tri-, 4 tetrasaccharides (out of 160k)
• PDB – cocrystallization of lectins with oligosaccharides (less rigid structure!)
• 3D-structures for lectins.

WebLab ViewerLite (PC, Mac) is necessary to visualize the structures.

NMR structures

• in solution (no intramolecular H-bonds)
• imprecisions, NOE results
• complex structures 

Calorimetric studies

• complexation enthalpy
• complexation entropy
• K

Computational Chemistry

• MM + Monte Carlo or dynamics – problems with force fields
• Ab initio HF/6-31G(d) good energetic results for monosaccharides

Example

Lewis^x (Le^x, Gal-b-1,4-[Fuc-a-1,3]-GlcNAc) and its analogs.

• Seach in the conformational space: MM2* - SUMM
• HF/6-31G(d) optimization of the individual rotamers

Ab initio results Published on the internet

Problem with MM2* Statistical analysis

Conclusions

1. ‘Stacked’ conformation  In this arrangement the plane of the fucose ring is nearly parallel with the plane of the galactose ring.
2. The key torsion angles for Fuc-a-1,3-GlcNAc and Gal-b-1,4-GlcNAc glycosidic bonds   mostly keep their value in the different environments (solid-, liquid-, gas-phase).
3. The ab initio torsion angles agree considerably better with the experimental results.
4. The ab initio results  provide better differentiation of the rotamers.
5. In the strongly bound sLe^x E-selectin complex both glycosidic linkage (four glycosidic torsions) were distorted considerably relative to the ab initio results.
6. In the less strongly bound sLe^x L-selectin complex only the Gal-b-1,4-GlcNAc linkage (two glycosidic torsions) was distorted.
7. In the weakly bound sLe^x P-selectin complex only a single glycosidic torsion angle was slightly distorted.

References

Recent reviews for further reading

Imberty A, Perez S
Structure, conformation, and dynamics of bioactive oligosaccharides: Theoretical approaches and experimental validations
CHEM REV 100 (12): 4567-4588 DEC 2000

Davis AP, Wareham RS
Carbohydrate recognition through noncovalent interactions: A challenge for biomimetic and supramolecular chemistry
ANGEW CHEM INT EDIT 38 (20): 2979-2996 1999

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