Sugars and Proteins: the role of dynamics in molecular interactions

Glycans are among the most varied and complex molecules in biological systems. The different branches of the tree of life could be differentiated on the basis of the glycan composition of the own glycoconjugate molecules. However, how much we already know about glycans and glycoconjugate function and distribution is still an open question. Not so many years ago our knowledge about protein N-glycosylation was considerably scarce. In fact, while protein N-glycosylation was once believed to be limited to eukaryotes, it is now firmly established that this complex modification also occurs in bacteria and archaea. Consequently, in the past 10 years, the field of protein glycosylation has witnessed enormous strides in the discovery of new and unusual carbohydrates, in the elucidation of the enzymes involved in glycan assembly and processing, and in the understanding the biological impact that these glycan modifications have on the structure and function of target protein. The reason for this “late” discovery probably lies in the intrinsic structural complexity, heterogeneity and flexibility of glycans. As counterweight, numerous and exhaustive works in glycomics have demonstrated that it is due to their structural complexity, heterogeneity and flexibility why glycans have been selected as key intermediates for cell proliferation, differentiation, adhesion, infection, communication, etc. With this thesis we have tried to look inside into glycan structure, with the aim to reconcile their structural features at the atomic level with the reasons of their molecular flexibility at a more complex scale. When glycans are recognized by their receptors, their intrinsic flexibility and the plasticity of the whole system has enormous effects in the molecular recognition phenomenon. In fact, both partners involved in the intermolecular interaction could adapt their contact surface in a way that enhances enthalpy-based favourable intermolecular interactions. Alternatively or simultaneously, the glycan and the receptor could strategically keep internal molecular motions, even in the bound state, in a way that minimizes the entropy penalty to the binding event. As consequence, the role of enthalpic/entropic compensation is not easy to predict and even, to assess. Along this thesis we have explored these features, focusing our attention on sugar protein interactions, starting from the sugar flexibility at the monosaccharide level, passing then to the study of disaccharides, and later investigating the complex motions within a sugar receptor. Finally, CH/ intermolecular interactions, which essentially contribute to the stability of sugar-protein complexes, have also been discussed and a new strategy for their direct detection has been proposed...