Skip to main content
SpringerLink
Log in

Unified picture for the conformation and stabilization of the O-glycosidic linkage in glycopeptide model structures

  • Original Research
  • Published:
Structural Chemistry Aims and scope Submit manuscript

Abstract

Glycoproteins play a central role in the immune response. In this study, we focus on the core of the common O-linked mucin-type glycopeptides. It has been observed that glycosylation stabilizes the protein in a stiffened, extended structure. We provide a unified picture for the conformation and stabilization of the O-glycosidic linkage using O-(2-acetylamino-2-deoxy-α- or -β-d-galacto- or -mannopyranosyl)-N-acetyl-l-serinamide model structures. We have calculated equilibrium geometries of the model structures with the B3LYP/6-31G(2df,p) method suggested in the Gaussian-4 theory. According to the relative energies, we confirm that the GalNAc-Ser linkage is more stable than its mannose analogues. The natural preference for the α-GalNAc-Ser over the β-GalNAc-Ser anomers can be explained by entropic effects. We explored the hydrogen bonding patterns on the carbohydrate unit calculating highly accurate dRPA@PBE0.25 and dRPA75 energies and found that in some cases, the acetamido group can be fixed by hydrogen bonding from the (O3Carb)H atom, but in most of the cases, it can rotate more freely. The torsion angles in the glycosidic linkage show that the linkage is stiffened more in the α-anomers and the most in the α-GalNAc-Ser structure because of the steric strains in the axial position and by two or three intramolecular hydrogen bonds. We also found that although, in our gas-phase model geometries, the peptide backbone prefers to be in a γ L-turn, a structural water molecule can stabilize a polyproline II helix of a proline-rich sequence, a β-sheet, or more likely random coils.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Lis H, Sharon N (1993) Protein glycosylation. Structural and functional aspects. Eur J Biochem 218:1–27

    Article  CAS  Google Scholar 

  2. Vliegenthart JF, Casset F (1998) Novel forms of protein glycosylation. Curr Opin Struct Biol 8:565–571

    Article  CAS  Google Scholar 

  3. Khoury GA, Baliban RC, Floudas CA (2011) Proteome-wide post-translational modification statistics: frequency analysis and curation of the swiss-prot database. Sci Rep. doi:10.1038/srep00090

    Google Scholar 

  4. Caramelo JJ, Parodi AJ (2015) A sweet code for glycoprotein folding. FEBS Lett. doi:10.1016/j.febslet.2015.07.021

    Google Scholar 

  5. Varki A, Cummings RD, Esko JD, Freeze HH, Stanley P, Bertozzi CR, Hart GW, Etzler ME (2009) Essentials of glycobiology. Cold Spring Harbor Laboratory Press, Cold Spring Harbor

    Google Scholar 

  6. Gamblin DP, Scanlan EM, Davis BG (2009) Glycoprotein synthesis: an update. Chem Rev 109:131–163

    Article  CAS  Google Scholar 

  7. Ambrosi M, Cameron NR, Davis BG (2005) Lectins: tools for the molecular understanding of the glycocode. Org Biomol Chem 3:1593–1608

    Article  CAS  Google Scholar 

  8. Rudd PM, Dwek RA (1997) Glycosylation: heterogeneity and the 3D structure of proteins. Crit Rev Biochem Mol Biol 32:1–100

    Article  CAS  Google Scholar 

  9. Kornfeld R, Kornfeld S (1976) Comparative aspects of glycoprotein structure. Annu Rev Biochem 45:217–237

    Article  CAS  Google Scholar 

  10. Yasukata T (1999) Structure–activity relationship. Glycopeptide antibiotics. Nippon Yakuzaishikai Zasshi 51:215–221

    CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  12. Bertozzi CR, Kiessling LL (2001) Chemical glycobiology. Science 291:2357–2364

    Article  CAS  Google Scholar 

  13. Cohen-Anisfeld ST, Lansbury PT (1993) A practical, convergent method for glycopeptide synthesis. J Am Chem Soc 115:10531–10537

    Article  CAS  Google Scholar 

  14. Meldal M, Bock K (1994) A general approach to the synthesis of O- and N-linked glycopeptides. Glycoconj J 11:59–63

    Article  CAS  Google Scholar 

  15. Sears P, Wong CH (1998) Enzyme action in glycoprotein synthesis. Cell Mol Life Sci 54:223–252

    Article  CAS  Google Scholar 

  16. Seitz O (2000) Glycopeptide synthesis and the effects of glycosylation on protein structure and activity. Chem Bio Chem 1:214–246

    Article  CAS  Google Scholar 

  17. Davis BG (2002) Synthesis of glycoproteins. Chem Rev 102:579–601. doi:10.1021/cr0004310

    Article  CAS  Google Scholar 

  18. Spain SG, Gibson MI, Cameron NR (2007) Recent advances in the synthesis of well-defined glycopolymers. J Polym Sci A Polym Chem 45:2059–2072

    Article  CAS  Google Scholar 

  19. Helenius A, Aebi M (2001) Intracellular functions of N-linked glycans. Science 291:2364–2369

    Article  CAS  Google Scholar 

  20. Imperiali B, O’Connor SE (1999) Effect of N-linked glycosylatian on glycopeptide and glycoprotein structure. Curr Opin Chem Biol 3:643–649

    Article  CAS  Google Scholar 

  21. Van den Steen P, Rudd PM, Dwek RA, Opdenakker G (1998) Concepts and principles of O-linked glycosylation. Crit Rev Biochem Mol Biol 33:151–208

    Article  Google Scholar 

  22. Hounsell EF, Davies MJ, Renouf DV (1996) O-linked protein glycosylation structure and function. Glycoconj J 13:19–26

    Article  CAS  Google Scholar 

  23. Strous GJ, Dekker J (1992) Mucin-type glycoproteins. Crit Rev Biochem Mol Biol 27:57–92

    Article  CAS  Google Scholar 

  24. Hang HC, Bertozzi CR (2005) The chemistry and biology of mucin-type O-linked glycosylation. Bioorganic Med Chem 13:5021–5034

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  26. Danishefsky SJ, Allen JR (2000) From the laboratory to the clinic: a retrospective on fully synthetic carbohydrate-based anticancer vaccines. Angew Chemie Int Ed 39:836–863

    Article  CAS  Google Scholar 

  27. Davis BG (2004) Mimicking posttranslational modifications of proteins. Science 303:480–482

    Article  CAS  Google Scholar 

  28. Wang L, Schultz PG (2005) Expanding the genetic code. Angew Chemie Int Ed 44:34–66

    Article  CAS  Google Scholar 

  29. Dube DH, Prescher JA, Quang CN, Bertozzi CR (2006) Probing mucin-type O-linked glycosylation in living animals. Proc Natl Acad Sci USA 103:4819–4824

    Article  CAS  Google Scholar 

  30. Nicolaou KC, Boddy CNC, Bräse S, Winssinger N (1999) Chemistry, biology, and medicine of the glycopeptide antibiotics. Angew Chemie Int Ed 38:2096–2152

    Article  Google Scholar 

  31. Donadio S, Sosio M, Stegmann E, Weber T, Wohlleben W (2005) Comparative analysis and insights into the evolution of gene clusters for glycopeptide antibiotic biosynthesis. Mol Genet Genomics 274:40–50

    Article  CAS  Google Scholar 

  32. Wolter F, Schoof S, Süssmuth R (2007) Synopsis of structural, biosynthetic, and chemical aspects of glycopeptide antibiotics. In: Wittmann V (ed) Glycopeptides and glycoproteins. Springer, Berlin, pp 143–185

    Google Scholar 

  33. James RC, Pierce JG, Okano A, Xie J, Boger DL (2012) Redesign of glycopeptide antibiotics: back to the future. ACS Chem Biol 7:797–804

    Article  CAS  Google Scholar 

  34. Tsung-Lin L, Yu-Chen L, Syue-Yi L (2012) Combining biocatalysis and chemoselective chemistries for glycopeptide antibiotics modification. Curr Opin Chem Biol 16:170–178

    Article  Google Scholar 

  35. Carlstedt I, Sheehan JK, Corfield AP, Gallagher JT (1985) Mucous glycoproteins: a gel of a problem. Essays Biochem 20:40–76

    CAS  Google Scholar 

  36. Shogren R, Gerken TA, Jentoft N (1989) Role of glycosylation on the conformation and chain dimensions of O-linked glycoproteins: light-scattering studies of ovine submaxillary mucin. Biochemistry 28:5525–5536

    Article  CAS  Google Scholar 

  37. Cyster JG, Shotton DM, Williams AF (1991) The dimensions of the T lymphocyte glycoprotein leukosialin and identification of linear protein epitopes that can be modified by glycosylation. EMBO J 10:893–902

    CAS  Google Scholar 

  38. Gerken TA, Butenhof KJ, Shogren R (1989) Effects of glycosylation on the conformation and dynamics of O-linked glycoproteins: carbon-13 NMR studies of ovine submaxillary mucin. Biochemistry 28:5536–5543

    Article  CAS  Google Scholar 

  39. Li F, Erickson HP, James JA, Moore KL, Cummings RD, McEver RP (1996) Visualization of P-selectin glycoprotein ligand-1 as a highly extended molecule and mapping of protein epitopes for monoclonal antibodies. J Biol Chem 271:6342–6348

    Article  CAS  Google Scholar 

  40. Maeji NJ, Inoue Y, Chujo R (1987) Conformational-determining role for the N-acetyl group in the O-glycosidic linkage, a-galNAc-Thr. Biopolymers 26:1753–1767

    Article  CAS  Google Scholar 

  41. Maeji NJ, Inoue Y, Chuio R (1987) Conformational study of 0-glycosylated threonine containing peptide models. Int J Pept Protein Res 29:699–1987

    Article  CAS  Google Scholar 

  42. Naganagowda GA, Gururaja TL, Satyanarayana J, Levine MJ (1999) NMR analysis of human salivary mucin (MUC7) derived O-linked model glycopeptides: comparison of structural features and carbohydrate–peptide interactions. J Pept Res 54:290–310

    Article  CAS  Google Scholar 

  43. Live DH, Williams LJ, Kuduk SD, Schwarz JB, Glunz PW, Chen XT, Sames D, Kumar RA, Danishefsky SJ (1999) Probing cell-surface architecture through synthesis: an NMR-determined structural motif for tumor-associated mucins. Proc Natl Acad Sci USA 96:3489–3493

    Article  CAS  Google Scholar 

  44. Coltart DM, Royyuru AK, Williams LJ, Glunz PW, Sames D, Koduk SD, Schwarz JB, Chen XT, Danishefsky SJ, Live DH (2002) Principles of mucin architecture: structural studies on synthetic glycopeptides bearing clustered mono-, di-, tri-, and hexasaccharide glycodomains. J Am Chem Soc 124:9833–9844

    Article  CAS  Google Scholar 

  45. Csonka GI, Schubert G, Perczel A, Sosa CP, Csizmadia IG (2002) Ab initio conformational space study of model compounds of O-glycosides of serine diamide. Chem Eur J 8:4718–4733

    Article  CAS  Google Scholar 

  46. Corzana F, Busto JH, Jiménez-Osés G, Asensio JL, Jiménez-Barbero J, Peregrina JM, Avenoza A (2006) New insights into α-GalNAc-Ser motif: influence of hydrogen bonding versus solvent interactions on the preferred conformation. J Am Chem Soc 128:14640–14648

    Article  CAS  Google Scholar 

  47. Corzana F, Busto JH, Jiménez-Osés G, De Luis MG, Asensio JL, Jiménez-Barbero J, Peregrina JM, Avenoza A (2007) Serine versus threonine glycosylation: the methyl group causes a drastic alteration on the carbohydrate orientation and on the surrounding water shell. J Am Chem Soc 129:9458–9467

    Article  CAS  Google Scholar 

  48. Corzana F, Busto JH, Engelsen SB, Jiménez-Barbero J, Asensio JL, Peregrina JM, Avenoza A (2006) Effect of beta-O-glucosylation on L-Ser and L-Thr diamides: a bias toward alpha-helical conformations. Chem Eur J 12:7864–7871

    Article  CAS  Google Scholar 

  49. Fernández-Tejada A, Corzana F, Busto JH, Jiménez-Osés G, Jiménez-Barbero J, Avenoza A, Peregrina JM (2009) Insights into the geometrical features underlying β-O-GIcNAc glycosylation: water pockets drastically modulate the interactions between the carbohydrate and the peptide backbone. Chem Eur J 15:7297–7301

    Article  Google Scholar 

  50. Pratt MR, Bertozzi CR (2005) Synthetic glycopeptides and glycoproteins as tools for biology. Chem Soc Rev 34:58–68

    Article  CAS  Google Scholar 

  51. Cocinero EJ, Stanca-Kaposta EC, Dethlefsen M, Liu B, Gamblin DP, Davis BG, Simons JP (2009) Hydration of sugars in the gas phase: regioselectivity and conformational choice in N-acetyl glucosamine and glucose. Chem Eur J 15:13427–13434

    Article  CAS  Google Scholar 

  52. Mallajosyula SS, MacKerell AD Jr (2011) Influence of solvent and intramolecular hydrogen bonding on the conformational properties of O-linked glycopeptides. J Phys Chem B 115:11215–11229

    Article  CAS  Google Scholar 

  53. Fernández-Tejada A, Corzana F, Busto JH, Jiménez-Osés G, Peregrina JM, Avenoza A (2008) Non-natural amino acids as modulating agents of the conformational space of model glycopeptides. Chem Eur J 14:7042–7058

    Article  Google Scholar 

  54. Corzana F, Busto JH, Marcelo F, Garcíadeluis M, Asensio JL, Martín-Santamaría S, Jiménez-Barbero J, Avenoza A, Peregrina JM (2011) Engineering O-glycosylation points in non-extended peptides: implications for the molecular recognition of short tumor-associated glycopeptides. Chem Eur J 17:3105–3110

    Article  CAS  Google Scholar 

  55. Curtiss LA, Redfern PC, Raghavachari K (2007) Gaussian-4 theory. J Chem Phys 126:084108

    Article  Google Scholar 

  56. Perdew JP, Burke K, Ernzerhof M (1996) Generalized gradient approximation made simple. Phys Rev Lett 77:3865–3868

    Article  CAS  Google Scholar 

  57. Adamo C, Barone V (1999) Toward reliable density functional methods without adjustable parameters: the PBE0 model. J Chem Phys 110:6158

    Article  CAS  Google Scholar 

  58. Heßelmann A (2012) Random-phase-approximation correlation method including exchange interactions. Phys Rev A 85:012517

    Article  Google Scholar 

  59. Kállay M (2014) A systematic way for the cost reduction of density fitting methods. J Chem Phys 141:244113

    Article  Google Scholar 

  60. Mezei PD, Csonka GI, Ruzsinszky A, Kállay M (2015) Construction and application of a new dual-hybrid random phase approximation. J Chem Theory Comput, submitted

  61. Mezei PD, Csonka GI, Kállay M (2015) Accurate Diels-Alder reaction energies from efficient density functional calculations. J Chem Theory Comput 11:2879–2888

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This project is supported by the Grants TÁMOP-4.2.1/B-09/1/KMR-2010-0002 and TÁMOP-4.2.2.B-10/1–2010-0009. The authors thank the Hungarian National Higher Education and Research Network for the computer time.

Author information

Authors and Affiliations

  1. Department of Inorganic and Analytical Chemistry, Budapest University of Technology and Economics, Budapest, 1521, Hungary

    Pál D. Mezei & Gábor I. Csonka

Authors
  1. Pál D. Mezei
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gábor I. Csonka
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Pál D. Mezei.

Additional information

Dedicated to Professor Magdolna Hargittai on the occasion of her 70th birthday.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 32 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mezei, P.D., Csonka, G.I. Unified picture for the conformation and stabilization of the O-glycosidic linkage in glycopeptide model structures. Struct Chem 26, 1367–1376 (2015). https://doi.org/10.1007/s11224-015-0666-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11224-015-0666-9

Keywords

Search

Navigation