title: The nature and sequence of the amino acid aglycone strongly modulates the conformation and dynamics effects of Tn antigen's clusters.
abstract: Synthetic oligosaccharide vaccines based on carbohydrate epitopes are currently being evaluated as potential immunotherapeutics in the treatment of cancer. In an effort to study the role that the amino acid moiety (L-serine and/or L-threonine residues) plays on the global shape of the resulting glycopeptides and on the dynamics of the carbohydrate moiety, diverse glycopeptides based on the Tn antigen have been synthesized and studied in aqueous solution by combining NMR spectroscopic experiments and molecular dynamics simulations. Our results demonstrate that although the effect of the clustering of Tn on the peptide backbone is not remarkable, it substantially modifies the dynamics, and thus, the presentation features of the carbohydrate moiety. In fact, the selected sequence has a crucial influence on both the orientation and flexibility of the sugar region. Thus, although a serine-threonine pair shows a well-defined spatial disposition of the Tn epitopes, its analogue sequence threonine-serine allows a certain degree of mobility that could favor the interaction with a diversity of receptors without a major energy penalty. These features can be explained by attending to the different conformational behavior of the glycosidic linkage of threonine-containing glycopeptides when compared with those of the serine analogues. On this basis, and taking into account that these carbohydrates interact with components of the immune system, these findings could have implications for further design of new cancer vaccines.
authors.affiliation: Departamento de Química, Universidad de La Rioja, Grupo de Síntesis Química de La Rioja, UA-CSIC. Madre de Dios 51, 2006 Logroño, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Corzana
authors.forename: Jesús H
authors.initials: JH
authors.lastname: Busto
authors.forename: Marisa
authors.initials: M
authors.lastname: García de Luis
authors.forename: Jesús
authors.initials: J
authors.lastname: Jiménez-Barbero
authors.forename: Alberto
authors.initials: A
authors.lastname: Avenoza
authors.forename: Jesús M
authors.initials: JM
authors.lastname: Peregrina
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000737:chemistry* / Q000276:immunology*; D003198:Computer Simulation; D004317:Doxorubicin / Q000737:chemistry*; D006020:Glycopeptides / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation
chemical_list: D000596:Amino Acids; D015295:Antigens, Tumor-Associated, Carbohydrate; D006020:Glycopeptides; C040286:Tn antigen; D004317:Doxorubicin