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A tool for the prediction of structures of complex sugars

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Abstract

In two recent back to back articles(Xia et al., J Chem Theory Comput 3:1620–1628 and 1629–1643, 2007a, b) we have started to address the problem of complex oligosaccharide conformation and folding. The scheme previously presented was based on exhaustive searches in configuration space in conjunction with Nuclear Overhauser Effect (NOE) calculations and the use of a complex rotameric library that takes branching into account. NOEs are extremely useful for structural determination but only provide information about short range interactions and ordering. Instead, the measurement of residual dipolar couplings (RDC), yields information about molecular ordering or folding that is long range in nature. In this article we show the results obtained by incorporation RDC calculations into our prediction scheme. Using this new approach we are able to accurately predict the structure of six human milk sugars: LNF-1, LND-1, LNF-2, LNF-3, LNnT and LNT. Our exhaustive search in dihedral configuration space combined with RDC and NOE calculations allows for highly accurate structural predictions that, because of the non-ergodic nature of these molecules on a time scale compatible with molecular dynamics simulations, are extremely hard to obtain otherwise (Almond et al., Biochemistry 43:5853–5863, 2004). Molecular dynamics simulations in explicit solvent using as initial configurations the structures predicted by our algorithm show that the histo-blood group epitopes in these sugars are relatively rigid and that the whole family of oligosaccharides derives its conformational variability almost exclusively from their common linkage (β-d-GlcNAc-(1→3)-β-d-Gal) which can exist in two distinct conformational states. A population analysis based on the conformational variability of this flexible glycosidic link indicates that the relative population of the two distinct states varies for different human milk oligosaccharides.

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References

  • Allinger NL, Yuh YH, Lii JH (1989) Molecular mechanics—the mm3 force-field for hydrocarbons.1. J Am Chem Soc 111(23):8551–8566

    Article  Google Scholar 

  • Allinger NL, Chen KS, Rahman M, Pathiaseril A (1991) Molecular mechanics (mm3) calculations on aldehydes and ketones. J Am Chem Soc 113(12):4505–4517

    Article  Google Scholar 

  • Almond A (2005) Towards understanding the interaction between oligosaccharides and water molecules. Carbohydr Res 340(5):907–920

    Article  Google Scholar 

  • Almond A, Axelsen JB (2002) Physical interpretation of residual dipolar couplings in neutral aligned media. J Am Chem Soc 124(34):9986–9987

    Article  Google Scholar 

  • Almond A, Duus JO (2001) Quantitative conformational analysis of the core region of n-glycans using residual dipolar couplings, aqueous molecular dynamics, and steric alignment. J Biomol NMR 20(4):351–363

    Article  Google Scholar 

  • Almond A, Bunkenborg J, Franch T, Gotfredsen CH, Duus JO (2001) Comparison of aqueous molecular dynamics with nmr relaxation and residual dipolar couplings favors internal motion in a mannose oligosaccharide. J Am Chem Soc 123(20):4792–4802

    Article  Google Scholar 

  • Almond A, Petersen BO, Duus JO (2004) Oligosaccharides implicated in recognition are predicted to have relatively ordered structures. Biochemistry 43(19):5853–5863

    Article  Google Scholar 

  • Azurmendi HF, Bush CA (2002) Tracking alignment from the moment of inertia tensor (tramite) of biomolecules in neutral dilute liquid crystal solutions. J Am Chem Soc 124(11):2426–2427

    Article  Google Scholar 

  • Basma M, Sundara S, Calgan D, Vernali T, Woods RJ (2001) Solvated ensemble averaging in the calculation of partial atomic charges. J Comput Chem 22(11):1125–1137

    Article  Google Scholar 

  • Berendsen HJC, Postma JPM, van Gunsteren WF, Hermans J (1981) In: Pullman B (ed) Intermolecular forces. Reidel, Dordrecht, Holland, pp 331–342

  • Berendsen HJC, Postma JPM, Vangunsteren WF, Dinola A, Haak JR (1984) Molecular-dynamics with coupling to an external bath. J Chem Phys 81(8):3684–3690

    Article  ADS  Google Scholar 

  • Bohne A, Lang E, von der Lieth CW (1998) W3-sweet: carbohydrate modeling by internet. J Mol Model 4(1):33–43

    Article  Google Scholar 

  • Brady JW, Schmidt RK (1993) The role of hydrogen-bonding in carbohydrates—molecular-dynamics simulations of maltose in aqueous-solution. J Phys Chem 97(4):958–966

    Article  Google Scholar 

  • Bush CA, Martin-Pastor M, Imberty A (1999) Structure and conformation of complex carbohydrates of glycoproteins, glycolipids, and bacterial polysaccharides. Annu Rev Biophys Biomol Struct 28:269–293

    Article  Google Scholar 

  • Case DA, Cheatham TE, Darden T, Gohlke H, Luo R, Merz KM, Onufriev A, Simmerling C, Wang B, Woods RJ (2005) The amber biomolecular simulation programs. J Comput Chem 26(16):1668–1688

    Article  Google Scholar 

  • Case D, Darden T, Cheatham T III, Simmerling CL, Wang J, Duke RE, Luo R, Merz KM, Pearlman DA, Crowley M, Walker R, Zhang W, Wang B, Hayik S, Roitberg A, Seabra G, Wong KF, Paesani F, Wu X, Brozell S, Tsui V, Gohlke H, Yang L, Tan C, Mongan J, Hornak V, Cui G, Beroza P, Mathews DH, Schafmeister C, Ross WS, Kollman PA (2006) Amber 9

  • Cheatham TE, Young MA (2000) Molecular dynamics simulation of nucleic acids: successes, limitations, and promise. Biopolymers 56(4):232–256

    Article  Google Scholar 

  • Cumming DA, Carver JP (1987a) Reevaluation of rotamer populations for 1,6 linkages—reconciliation with potential-energy calculations. Biochemistry 26(21):6676–6683

    Article  Google Scholar 

  • Cumming DA, Carver JP (1987b) Virtual and solution conformations of oligosaccharides. Biochemistry 26(21):6664–6676

    Article  Google Scholar 

  • Damm W, Frontera A, TiradoRives J, Jorgensen WL (1997) Opls all-atom force field for carbohydrates. J Comput Chem 18(16):1955–1970

    Article  Google Scholar 

  • Duus JO, Gotfredsen CH, Bock K (2000) Carbohydrate structural determination by nmr spectroscopy: modern methods and limitations. Chem Rev 100(12):4589–4614

    Article  Google Scholar 

  • Dwek RA (1996) Glycobiology: toward understanding the function of sugars. Chem Rev 96(2):683–720

    Article  Google Scholar 

  • Eklund R, Widmalm G (2003) Molecular dynamics simulations of an oligosaccharide using a force field modified for carbohydrates. Carbohydr Res 338(5):393–398

    Article  Google Scholar 

  • Engelsen SB, Cros S, Mackie W, Perez S (1996) A molecular builder for carbohydrates: application to polysaccharides and complex carbohydrates. Biopolymers 39(3):417–433

    Article  Google Scholar 

  • French AD, Brady JW (eds) (1990) Computer modelling of carbohydrate molecules, ACS symposium series. American Chemical Society, Washington

    Google Scholar 

  • Galonic DP, Gin DY (2007) Chemical glycosylation in the synthesis of glycoconjugate antitumour vaccines. Nature 446(7139):1000–1007

    Article  ADS  Google Scholar 

  • Hawkins GD, Cramer CJ, Truhlar DG (1996) Parametrized models of aqueous free energies of solvation based on pairwise descreening of solute atomic charges from a dielectric medium. J Phys Chem 100(51):19824–19839

    Article  Google Scholar 

  • Hoover WG (1985) Canonical dynamics—equilibrium phase-space distributions. Phys Rev A 31(3):1695–1697

    Article  ADS  Google Scholar 

  • Imberty A, Perez S (2000) Structure, conformation, and dynamics of bioactive oligosaccharides: theoretical approaches and experimental validations. Chem Rev 100(12):4567–4588

    Article  Google Scholar 

  • Imberty A, Gerber S, Tran V, Perez S (1990a) Data-bank of 3-dimensional structures of disaccharides, a tool to build 3-d structures of oligosaccharides.1. oligo-mannose type n-glycans. Glycoconj J 7(1):27–54

    Article  Google Scholar 

  • Imberty A, Tran V, Perez S (1990b) Relaxed potential-energy surfaces of n-linked oligosaccharides—the mannose-alpha(1-3)-mannose case. J Comput Chem 11(2):205–216

    Article  Google Scholar 

  • Imberty A, Delage MM, Bourne Y, Cambillau C, Perez S (1991) Data-bank of 3-dimensional structures of disaccharides. 2. n-acetyllactosaminic type n-glycans—comparison with the crystal-structure of a biantennary octasaccharide. J Comput Chem 8(6):456–483

    Article  Google Scholar 

  • Jorgensen WL, Maxwell DS, TiradoRives J (1996) Development and testing of the opls all-atom force field on conformational energetics and properties of organic liquids. J Am Chem Soc 118(45):11225–11236

    Article  Google Scholar 

  • Kaminski GA, Friesner RA, Tirado-Rives J, Jorgensen WL (2001) Evaluation and reparametrization of the opls-aa force field for proteins via comparison with accurate quantum chemical calculations on peptides. J Phys Chem B 105(28):6474–6487

    Article  Google Scholar 

  • Kiddle GR, Homans SW (1998) Residual dipolar couplings as new conformational restraints in isotopically c-13-enriched oligosaccharides. FEBS Lett 436(1):128–130

    Article  Google Scholar 

  • Kirschner KN, Woods RJ (2001) Solvent interactions determine carbohydrate conformation. Proc Natl Acad Sci USA 98(19):10541–10545

    Article  ADS  Google Scholar 

  • Klyosov AA, Witczak ZJ, Platt D (eds) (2006) Carbohydrate drug design, ACS symposium series. American Chemical Society, Washington

    Google Scholar 

  • Koca J (1998) Travelling through conformational space: an approach for analyzing the conformational behaviour of flexible molecules. Prog Biophys Mol Biol 70(2):137–173

    Article  Google Scholar 

  • Landersjo C, Hoog C, Maliniak A, Widmalm G (2000) Nmr investigation of a tetrasaccharide using residual dipolar couplings in dilute liquid crystalline media: effect of the environment. J Phys Chem B 104(23):5618–5624

    Article  Google Scholar 

  • Landersjo C, Jansson JLM, Maliniak A, Widmalm G (2005) Conformational analysis of a tetrasaccharide based on nmr spectroscopy and molecular dynamics simulations. J Phys Chem B 109(36):17320–17326

    Article  Google Scholar 

  • Lindahl E, Hess B, van der Spoel D (2001) Gromacs 3.0: a package for molecular simulation and trajectory analysis. J Mol Model 7(8):306–317

    Google Scholar 

  • Liu Q, Schmidt RK, Teo B, Karplus PA, Brady JW (1997) Molecular dynamics studies of the hydration of alpha,alpha-trehalose. J Am Chem Soc 119(33):7851–7862

    Article  Google Scholar 

  • Mackerell AD (2004) Empirical force fields for biological macromolecules: overview and issues. J Comput Chem 25(13):1584–1604

    Article  Google Scholar 

  • MacKerell AD, Bashford D, Bellott M, Dunbrack RL, Evanseck JD, Field MJ, Fischer S, Gao J, Guo H, Ha S, Joseph-McCarthy D, Kuchnir L, Kuczera K, Lau FTK, Mattos C, Michnick S, Ngo T, Nguyen DT, Prodhom B, Reiher WE, Roux B, Schlenkrich M, Smith JC, Stote R, Straub J, Watanabe M, Wiorkiewicz-Kuczera J, Yin D, Karplus M (1998) All-atom empirical potential for molecular modeling and dynamics studies of proteins. J Phys Chem B 102(18):3586–3616

    Article  Google Scholar 

  • Martin-Pastor M, Bush CA (2000a) Conformational studies of human milk oligosaccharides using h-1-c-13 one-bond nmr residual dipolar couplings. Biochemistry 39(16):4674–4683

    Article  Google Scholar 

  • Martin-Pastor M, Bush CA (2000b) The use of nmr residual dipolar couplings in aqueous dilute liquid crystalline medium for conformational studies of complex oligosaccharides. Carbohydr Res 323(1–4):147–155

    Article  Google Scholar 

  • Martin-Pastor M, Canales A, Corzana F, Asensio JL, Jimenez-Barbero J (2005) Limited flexibility of lactose detected from residual dipolar couplings using molecular dynamics simulations and steric alignment methods. J Am Chem Soc 127(10):3589–3595

    Article  Google Scholar 

  • Nahmany A, Strino F, Rosen J, Kemp GJL, Nyholm PG (2005) The use of a genetic algorithm search for molecular mechanics (mm3)-based conformational analysis of oligosaccharides. Carbohydr Res 340(5):1059–1064

    Article  Google Scholar 

  • Naidoo KJ, Brady JW (1999) Calculation of the ramachandran potential of mean force for a disaccharide in aqueous solution. J Am Chem Soc 121(10):2244–2252

    Article  Google Scholar 

  • Neuhaus D, Williamson M (1989) The Nuclear Overhauser Effect in structural and conformational analysis. VCH Publishers, INC, New York

    Google Scholar 

  • Newburg DS (2005) Innate immunity and human milk. J Nutr 135(5):1308–1312

    Google Scholar 

  • Newburg DS, Ruiz-Palacios GM, Morrow AL (2005) Human milk glycans protect infants against enteric pathogens. Annu Rev Nutr 25:37–58

    Article  Google Scholar 

  • Nose S (1984) A molecular-dynamics method for simulations in the canonical ensemble. Mol Phys 52(2):255–268

    Article  ADS  MathSciNet  Google Scholar 

  • Pearlman DA, Case DA, Caldwell JW, Ross WS, Cheatham TE, Debolt S, Ferguson D, Seibel G, Kollman P (1995) Amber, a package of computer-programs for applying molecular mechanics, normal-mode analysis, molecular-dynamics and free-energy calculations to simulate the structural and energetic properties of molecules. Comput Phys Commun 91(1–3):1–41

    Article  MATH  ADS  Google Scholar 

  • Peters T, Pinto BM (1996) Structure and dynamics of oligosaccharides: nmr and modeling studies. Curr Opin Struct Biol 6(5):710–720

    Article  Google Scholar 

  • Peters T, Meyer B, Stuikeprill R, Somorjai R, Brisson JR (1993) A monte-carlo method for conformational-analysis of saccharides. Carbohydr Res 238:49–73

    Article  Google Scholar 

  • Ponder JW (2004) Tinker: Software tools for molecular design

  • Ponder JW, Case DA (2003) Force fields for protein simulations. Adv Protein Chem 66:27–85

    Article  Google Scholar 

  • Ponder JW, Richards FM (1987) An efficient newton-like method for molecular mechanics energy minimization of large molecules. J Comput Chem 8(7):1016–1024

    Article  Google Scholar 

  • Prestegard JH, Al-Hashimi HM, Tolman JR (2000) Nmr structures of biomolecules using field oriented media and residual dipolar couplings. Q Rev Biophys 33(4):371–424

    Article  Google Scholar 

  • Prestegard JH, Bougault CM, Kishore AI (2004) Residual dipolar couplings in structure determination of biomolecules. Chem Rev 104(8):3519–3540

    Article  Google Scholar 

  • Ren P, Ponder JW (2003) Polarizable atomic multipole water model for molecular mechanics simulation. J Phys Chem B 107(24):5933–5947

    Article  Google Scholar 

  • Rudd PM, Elliott T, Cresswell P, Wilson IA, Dwek RA (2001) Glycosylation and the immune system. Science 291(5512):2370–2376

    Article  ADS  Google Scholar 

  • Seeberger PH, Werz DB (2005) Automated synthesis of oligosaccharides as a basis for drug discovery. Nat Rev Drug Discov 4(9):751–763

    Article  Google Scholar 

  • Strino F, Nahmany A, Rosen J, Kemp GJL, Sa-correia I, Nyholm PG (2005) Conformation of the exopolysaccharide of burkholderia cepacia predicted with molecular mechanics (mm3) using genetic algorithm search. Carbohydr Res 340(5):1019–1024

    Article  Google Scholar 

  • Tjandra N, Bax A (1997) Direct measurement of distances and angles in biomolecules by nmr in a dilute liquid crystalline medium. Science 278(5340):1111–1114

    Article  ADS  Google Scholar 

  • Tolman JR, Ruan K (2006) Nmr residual dipolar couplings as probes of biomolecular dynamics. Chem Rev 106(5):1720–1736

    Article  Google Scholar 

  • Van der Spoel D, Lindahl E, Hess B, Groenhof G, Mark AE, Berendsen HJC (2005) Gromacs: fast, flexible, and free. J Comput Chem 26(16):1701–1718

    Article  Google Scholar 

  • Van der Spoel D, Lindahl E, Hess B, van Buuren AR, Apol E, Meulenhoff PJ, Tieleman DP, Sijbers ALTM, Feenstra KA, van Drunen R, Berendsen HJC (2006) Gromacs: Groningen machine for chemical simulations

  • Veluraja K, Margulis CJ (2005) Conformational dynamics of sialyl lewis(x) in aqueous solution and its interaction with selectine. A study by molecular dynamics. J Biomol Struct Dyn 23(1):101–111

    Google Scholar 

  • Vliegenthart JFG, Woods RJ (eds) (2006) NMR spectroscopy and computer modeling of carbohydrates: recent advances, ACS symposium series. American Chemical Society, Washington

    Google Scholar 

  • Wong CH (ed) (2003) Carbohydrate-based drug discovery. Wiley-VCH, Weinheim

    Google Scholar 

  • Woods RJ (1996) The application of molecular modeling techniques to the determination of oligosaccharide solution conformations. In: Lipkowitz kB, Boyd DB (eds) Review in computational chemistry, vol 9. VCH Publishers, New York, pp 129–165

    Chapter  Google Scholar 

  • Woods RJ (1998) Computational carbohydrate chemistry: what theoretical methods can tell us. Glycoconj J 15(3):209–216

    Article  Google Scholar 

  • Woods RJ, Chappelle R (2000) Restrained electrostatic potential atomic partial charges for condensed-phase simulations of carbohydrates. J Mol Struct Theochem 527:149–156

    Article  Google Scholar 

  • Woods RJ, Dwek RA, Edge CJ, Fraserreid B (1995) Molecular mechanical and molecular dynamical simulations of glycoproteins and oligosaccharides. 1. glycam-93 parameter development. J Phys Chem 99(11):3832–3846

    Article  Google Scholar 

  • Wormald MR, Petrescu AJ, Pao YL, Glithero A, Elliott T, Dwek RA (2002) Conformational studies of oligosaccharides and glycopeptides: complementarity of nmr, x-ray crystallography, and molecular modelling. Chem Rev 102(2):371–386

    Article  Google Scholar 

  • Xia JC, Daly RP, Chuang FC, Parker L, Jensen JH, Margulis CJ (2007a) Sugar folding: a novel structural prediction tool for oligosaccharides and polysaccharides. J Chem Theory Comput 3(4):1620–1628

    Article  Google Scholar 

  • Xia JC, Daly RP, Chuang FC, Parker L, Jensen JH, Margulis CJ (2007b) Sugar folding: a novel structural prediction tool for oligosaccharides and polysaccharides. J Chem Theory Comput 3(4):1629–1643

    Article  Google Scholar 

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Acknowledgment

This research was funded by Grant#05-2182 from the Roy J. Carver Charitable Trust awarded to CJM.

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  1. Department of Chemistry, University of Iowa, Iowa City, IA, 52242, USA

    Junchao Xia & Claudio Margulis

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  1. Junchao Xia
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Correspondence to Claudio Margulis.

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Xia, J., Margulis, C. A tool for the prediction of structures of complex sugars. J Biomol NMR 42, 241–256 (2008). https://doi.org/10.1007/s10858-008-9279-6

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