Synthesis and Conformational Analysis of a Conformationally Constrained Trisaccharide, and Complexation Properties with Concanavalin A

Abstract

Abstract:The trisaccharide b-dGlcNAc(1 32)a-d-Man(1 33)d-Man is a fragment of a biantennary glycan that is recognized by a-d-Man-specific lectins such as concanavalin A (ConA), Lathyrus ochrus lectin, lentil lectin, and can adopt several conformations upon binding. To probe the importance of loss of flexibility of a saccharide during binding with ConA this trisaccharide has been synthesized in a conformationally constrained form where a methylene acetal bridge mimics a GlcNAc ± O-6''´´´Man ± O-4 intramolecular hydrogen bond. Microcalorimetry measurements revealed that the conformationally constrained compound has a more favorable entropy term but this term is offset by a smaller enthalpy term. NMR spectroscopic studies have shown that the cyclic compound is indeed considerably less flexible than the linear compound and both compounds adopt mainly one conformation. SYBYL software together with energy parameters appropriate for carbohydrates was used for a systematic conformational search. The linear compound is very flexible. A clustering method determined seven main conformational families. Six possible conformational families were identified for the cyclic compound when considering the orientations of the bGlcNAc(1 32)Man and abMan-(1 33)Man glycosidic bonds. The central mannose residue was docked in the binding site of ConA and the complex was refined. The results are compared with crystal structures of legume lectin ± oligosaccharide complexes and with the NMR and thermodynamic data.

Experimental Evidence for the Existence of Non-exo-Anomeric Conformations in Branched Oligosaccharides: NMR Analysis of the Structure and Dynamics of Aminoglycosides of the Neomycin Family

“…[19] These ions were placed in the most favorable locations by using Coulombic potential terms with the LEAP module. [22] All simulations were performed using periodic boundary conditions and the particle-mesh Ewald approach [16] to introduce longrange electrostatic effects. The SHAKE algorithm [23] for hydrogen atoms, which allows the use of 2 fs time step, was employed.…”

“…[16] Thus, in some cases, sugar rigidification upon binding is known to make a significant contribution to the entropic barrier of the process. This effect has been suggested to be at the origin of the enthalpy/entropy compensation phenomenon usually observed for this kind of interactions.…”

“…This effect has been suggested to be at the origin of the enthalpy/entropy compensation phenomenon usually observed for this kind of interactions. [16] Nevertheless, up to now, no detailed studies on the role of carbohydrate flexibility in their recognition by RNA have been reported. A proper understanding of the driving forces behind neomycin B recognition by its target RNA requires a detailed knowledge of the structure and dynamical behavior of the ligand in both the free and bound states.…”

Lectins: Tools for the Molecular Understanding of the Glycocode

“…Attempts to overcome certain thermodynamic barriers through the planning of the glycoconjugate structure may not always result in the expected high-affinity association, due to the offset of different contributions. 89 …”

Hydroquinones with Conformationally Constrained Substituents: Synthesis, Characterization, and Evaluation as Calcium–ATPase Inhibitors

“…However, the relative loss of conformational entropy upon binding is lower for the rigid ligand. This concept of optimizing ligand affinity by constraining conformational entropy is well-known and has been evaluated in various systems with ligands such as peptides or carbohydrates [16]- [18].…”