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The Nature and Sequence of the Amino Acid Aglycone Strongly Modulates the Conformation and Dynamics Effects of Tn Antigen's Clusters
Author(s) -
Corzana Francisco,
Busto Jesús H.,
García de Luis Marisa,
JiménezBarbero Jesús,
Avenoza Alberto,
Peregrina Jesús M.
Publication year - 2009
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200801777
Subject(s) - threonine , glycopeptide , moiety , chemistry , serine , epitope , glycosidic bond , residue (chemistry) , peptide , stereochemistry , oligosaccharide , peptide sequence , biochemistry , biology , phosphorylation , antigen , genetics , gene , enzyme , antibiotics
All in a cluster : The selected sequence has a crucial influence on both the orientation and flexibility of the carbohydrate moiety in mucin‐type glycopeptides (see picture). This feature can be explained through the varied conformational behavior of the glycosidic linkage of the Thr residue when compared with the Ser residue (see figure). On this basis, and taking into account that these carbohydrates presumably interact with components of the immune system, these findings could be helpful in the design of new cancer vaccines.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.