Journal of Organic Chemistry 2009-12-18

Conformational effects of the non-natural alpha-methylserine on small peptides and glycopeptides.

Alberto Fernández-Tejada, Francisco Corzana, Jesús H Busto, Alberto Avenoza, Jesús M Peregrina

Index: J. Org. Chem. 74(24) , 9305-13, (2009)

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Abstract

The synthesis and the conformational analysis in aqueous solution of a peptide and a glycopeptide containing the sequence threonine-alanine-alanine (Thr-Ala-Ala) are reported. Furthermore, the threonine residue has been replaced by the quaternary amino acid alpha-methylserine (MeSer) and their corresponding non-natural peptide and glycopeptide are also studied. The conformational analysis in aqueous solution combines NOEs and coupling constants data with Molecular Dynamics (MD) simulations with time-averaged restraints. The study reveals that the beta-O-glycosylation produces a remarkable and completely different effect on the backbone of the peptide derived from Thr and MeSer. In the former, the beta-O-glycosylation is responsible for the experimentally observed shift from extended conformations (peptide) to folded ones (glycopeptide). In contrast, the beta-O-glycosylation of the MeSer-containing peptide, which clearly shows two main conformations in aqueous solution [extended ones (70%) and beta-turn (30%)], causes a high degree of flexibility for the backbone.