Abstract
The conformations and dynamics of gangliosides GM1, GM2, 6′-GM2 and GM4 have been studied by computational means, and the results compared to NMR data. Unconstrained conformational searches were run using the AMBER* force field augmented by MNDO derived parameters for the Neu5Ac anomeric torsion, the GB/SA water solvation model, and the MC/EM alogorithm; extended (10–12[emsp4 ]ns) dynamic simulations in GB/SA water were performed with the MC/SD protocol, and the stored structures were minimized. The overall mobility of the Neu5Acα2,3Gal linkage and the position of its minimum energy conformation have been shown to depend mainly on the presence or the absence of a GalNAc residue at the adjacent position. The best quantitative agreement with the available NOE data was achieved after minimization of the structures stored during the MC/SD dynamic runs. The latter protocol appears to reproduce satisfactorily the available experimental data, and can be used with confidence to build three-dimensional models of ganglioside headgroups.
Similar content being viewed by others
References and notes
Karlsson K-A, Animal glycosphingolipids as membrane attachment sites for bacteria, Ann Rev Biochem 58, 309-50 (1989).
Hakomori S-I, Bifunctional role of glycosphingolipids, J Biol Chem 265, 18713-6 (1990).
Nagai Y, Ganglioside reasearch: new trends and reflections, Pure & Appl Chem 70, 533-8 (1998).
For leading references see: Rao VSR, Qasba PK, Baloyi PV, Chandrasekaran R, Conformation of carbohydrates. Harwood Academic Publishers (1998).
Poppe L, Dabrowski J, von der Lieth CW, Numata M, Ogawa T, Solution conformation of sialosylcerebroside (GM4) and its NeuAc(α2-3)Galβ sugar component, Eur J Biochem 180, 337-42(1989).
Siebert HC, Reuter G, Schauer R, von der Lieth CW, Dabrowski J, Solution conformation of GM3 gangliosides containing different sialic acid residues as revealed by NOE based distance mapping, molecular mechanics and molecular dynamics calculations, Biochemistry 31, 6962-71 (1992).
Sabesan S, Block K, Lemieux RU, The conformational properties of the gangliosides GM2 and GM1 based on 1H and 13C nuclear magnetic resonance, Can J Chem 62, 1034-45 (1984).
Li Y-T, Li S-C, Hasegawa A, Ishida H, Kiso M, Bernardi A, Brocca P, Raimondi L, Sonnino S, Structural basis for the resistance of Tay-Sachs ganglioside GM2 to enzymatic degradation, J Biol Chem 274, 10014-8 (1999).
Acquotti D, Poppe L, Dabrowski J, von der Lieth CW, Sonnino S, Tettamanti G, Three-dimensional structure of the oligosaccharide chain of ganglioside revealed by distance mapping procedure: a rotating and laboratory frame nuclear Overhauser enhancement investigation of native glycolipid in dimethyl sulfoxide and in water-dodecylphosphocoline solution, J Am Chem Soc 112, 7772-8 (1990).
Brocca P, Berthault P, Sonnino S, Conformation of the oligosaccharide chain of GM1 ganglioside in a carbohydrate-enriched surface, Biophys J 74, 309-18 (1998).
Poppe L, van Halbeek H, Acquotti D, Sonnino S, Carbohydrate dynamics at a micellar surface: GD1a headgroup transformations revealed by NMR spectroscopy, Biophys J 66, 1642-52 (1994).
Aubin Y, Ito Y, Paulson JC, Prestegard JH, Structure and dynamics of the sialic acid moiety of GM3-ganglioside at the surface of a magnetically oriented membrane, Biochemistry 32, 13405-13 (1993).
Barber KR, Hamilton KS, Rigby AC, Grant CWM, Behaviour of complex oligosaccharides at a bilayer membrane surface probed by 2H-NMR, Biochem Biophys Acta 1190, 376-84 (1994).
Singh DM, Shan X, Davis JH, Jones DH, Grant CWM, Oligosaccharide behavior of complex natural glycosphingolipids in multicomponent model membrane, Biochemistry 34, 451-63 (1995).
Jones DH, Barber KR, Grant CWM, Minor influence of sialic acid on conformation of a membrane-bound oligosaccharide recognition site, Biochemistry 35, 4803-11 (1996).
Breg J, Kroon-Batenburg LMJ, Strecker G, Montreuil J, Vliegenthart JFG, Conformational analysis of the sialylα(2-3)Nacetyllactosamine structural element occurring in glycoproteins, by two-dimensional NOE1H-NMR spectroscopy in combination with energy calculations by hard-sphere exo-anomeric and molecular mechanics force fields with H-bonding potentials, Eur J Biochem 178, 727-39 (1989).
Sabesan S, Bock K, Paulson JC, Conformational analysis of sialyloligosaccharides, Carb Res 218, 27-54 (1991).
Scardsale JN, Prestegard JH, Yu RK, NMR and computational studies of interaction between remote residues in gangliosides, Biochemistry 20, 9843-55 (1990).
Bernardi A, Raimondi L, Conformational analysis of GMI oligosaccharides in water solution with a new set of parameters for the Neu5Ac moiety, J Org Chem 60, 3370-7 (1995).
Mukhopadhyay C, Bush CA, Molecular dynamics simulations of oligosaccharides containing N-acetylneuraminic acid, Biopolymers 34, 11-20 (1994).
Woods RJ, Computational carbohydrate chemistry: what theoretical methods can tell us, Glycoconj J 15, 209-16 (1998).
For a discussion see: Rubinstenn G, Sinay P, Berthault P, Evidence of conformational heterogeneity for carbohydrate mimetics. NMR study of β-methyl-C-lactoside in aqueous solution, J Phys Chem A 101, 2536-40 (1997).
Bernardi A, Checchia A, Brocca P, Sonnino S, Zuccotto F, Sugar mimics: an artificial receptor for Cholera Toxin, J Am Chem Soc 121, 2032–6 (1999).
For a review on carbohydrate mimetics see: Sears P, Wong C-H, Carbohydrate mimetics: a new strategy for tackling the problem of carbohydrate-mediated biological recognition, Angew Chem Int Ed 38, 2300–24 (1999).
Guarnieri F, Still WC, A rapidly convergent simulation method: mixed Monte Carlo/stochastic dynamics, J Comput Chem 15, 1302–10 (1994).
For an application of this protocol to the study of solution conformation of oligosaccharides, see Bernardi A, Raimondi L, Zanferrari D, Conformational analysis of saccharides with Monte Carlo/stochastic dynamics simulations, J Mol Struct (THEOCHEM) 395–396, 361–73 (1997).
Still WC. Tempzyk A, Hawley R, Hendrickson T, Semianalytical treatment of solvation for molecular mechanics and dynamics, J Am Chem Soc 112, 6127–9 (1990).
Mohamadi F, Richards NGJ, Guida WC, Liskamp R, Lipton M, Caufield C, Chang G, Hendrickson T, Still WC, MacroModel-An integrated software system for modeling organic and bioorganic molecules using molecular mechanics, J Comp Chem 11, 440–67 (1990).
Senderowitz H, Still WC, A quantummechanically derived all-atom force field for pyranose oligosaccharides. AMBER* parameters and free energy simulations, J Org Chem 62, 1427–38 (1997).
Stewart JJP, MOPAC 6.0. QCPE Program N. 455 (1990).
Chang G, Guida WC, Still WC, An internal coordinate Monte Carlo method for searching conformational space, J Am Chem Soc 111, 4379–86 (1989).
Brown EB, Brey WS, Weltner W Jr, Cell-surface carbohydrates and their interactions I. NMR of N-acetylneuraminic acid, Biochim Biophys Acta 399, 124–30 (1975).
Bernardi A, Raimondi L, Zuccotto F, Simulation of protein-sugar interactions: a computational model of the complex between ganglioside GM1 and the Heat-Labile Enterotoxin of Escherchia coli., J Med Chem 40, 1855–62 (1997).
Ponder JW, Richards FM, An efficient Newton-like method for molecular mechanics energy minimizations of large molecules, J Comp Chem 8, 1016–24 (1987).
Merritt EA, Sarfaty S, Van den Akker F, L'Hoir C, Martial JA, Hol WGJ, Crystal structure of Cholera Toxin B-pentamer bound to receptor (GM1) pentasaccharide, Protein Sci 3, 166–75 (1994).
Acquotti D, Cantu’ L, Ragg E, Sonnino S, Geometrical and conformational properties of ganglioside GalNAc-GD1a, IV4 GalNAcIV3 Neu5AcII3 Neu5AcGgOse4 Cer, Eur J Biochem 225, 271–88 (1994).
Harris R, Kiddle GR, Field RA, Milton MJ, Ernst B, Magnani JL, Homans W, Stable-isotope-assisted NMR studies on 13C-enriched sialyl Lewis X in solution and bound to E selectin, J Am Chem Soc 121, 2546–51 (1999).
Peters T, Meyer B, Stuike-Prill R, Somorjai R, Brisson J-R, A Monte Carlo method for conformational analysis of saccharides, J Carboh Res 238, 49–73 (1993).
Cramer CJ, Truhlar DG, Quantum chemical correlation analysis of 1,2-ethanediol: correlation and solvation effects on the tendency to form internal hydrogen bonds in the gas phase and in aqueous solution, J Am Chem Soc 116, 3892–900 (1994) and references therein.
Cornell WD, Cieplak P, Bayly CI, Kollman PA, Application of RESP charges to calculate conformational energies, hydrogen bond energies and free energies of solvation, J Am Chem Soc 115, 9620–31 (1993).
Rockwell GD, Grindley TB, Conformational analysis of cyclohexane-1,2-diol derivatives and MM3 parameter improvement, Aust J Chem 49, 379–90 (1996).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Brocca, P., Bernardi, A., Raimondi, L. et al. Modeling ganglioside headgroups by conformational analysis and molecular dynamics. Glycoconj J 17, 283–299 (2000). https://doi.org/10.1023/A:1007161319700
Issue Date:
DOI: https://doi.org/10.1023/A:1007161319700