Síntesis y análisis conformacional de glicopéptidos que incorporan ß-glucosa y a-N-acetilgalactosamina

Abstract

In the last two decades, the glycobiology field, which comprises the study of carbohydrates, glycopeptides and glycoproteins, has attracted considerable attention due to these molecules are involved in many fundamental processes of the life. One of these processes is known as molecular recognition of ligands by receptors. In particular, this interaction is tightly related to the 3D structure they adopt. In this context, this Thesis focuses on searching new non?natural glycosylamino acids that display different conformations from those that adopt glycosylated natural amino acids. In this sense, several glycosylamino acids have been synthesized, which incorporate ?,??disubstituted amino acids. The structural preferences of these new compounds were elucidated, combining NMR experiments and Molecular Dynamics simulations. As a result, the synthetic modifications made in the amino acid moiety can be regarded as a tool to develop glycosylated derivatives with conformations a la cartè. Another issue which this Thesis focuses on, is to find out why glucose only appear linked to serine, when it is incorporated in a certain peptide sequence (consensus sequence). In particular, in this work, we studied the consensus sequence for ??O?glycosylation with glucose. For this purpose, two peptides and one glycopeptide were synthesized. As a first approaching, we calculated the spatial distribution of the hydroxyl group of serine, that later will be glycosylated, and interestingly it is exposed to the solvent, therefore the glycosylation would be easier. On the other hand, this Thesis tries to shed some light to the controversial about the role that peptide moiety plays in the molecular recognition of glycopeptides by lectins. In this regard, two glycine rich glycopeptides were synthesized, Gly?Gly?Xxx?Gly?Gly, where Xxx was replaced by Thr/Ser(??OGalNac). Besides, conformational studies both in the free and bound?states were developed. In addition, thermodynamic parameters corresponding to molecular recognition of each glycopeptides by two specific lectins were obtained by microcalorimetry. All this work shows the importance of the amino acid linked to the carbohydrate plays in the molecular recognition process. In fact, it is not a mere spectator but it develops a role as modulator agent.