Molecular dynamics simulations of galectin‐1‐oligosaccharide complexes reveal the molecular basis for ligand diversity

Abstract

Galectin-1 is a member of a protein family historically characterized by its ability to bind carbohydrates containing a terminal galactosyl residue. Galectin-1 is found in a variety of mammalian tissues as a homodimer of 14.5-kDa subunits. A number of developmental and regulatory processes have been attributed to the ability of galectin-1 to bind a variety of oligosaccharides containing the Gal-β-(1,4)-GlcNAc (LacNAc II ) sequence. To probe the origin of this permissive binding, solvated molecular dynamics (MD) simulations of several representative galectin-1-ligand complexes have been performed. Simulations of structurally defined complexes have validated the computational approach and expanded upon data obtained from X-ray crystallography and surface plasmon resonance measurements. The MD results indicate that a set of anchoring interactions between the galectin-1 carbohydrate recognition domain (CRD) and the LacNAc core are maintained for a diverse set of ligands and that substituents at the nonreducing terminus of the oligosaccharide extend into the remainder of a characteristic surface groove. The anionic nature of ligands exhibiting relatively high affinities for galectin-1 implicates electrostatic interactions in ligand selectivity, which is confirmed by a generalized Born analysis of the complexes. The results suggest that the search for a single endogenous ligand or function for this lectin may be inappropriate and instead support a more general role for galectin-1, in which the lectin is able to crosslink heterogeneous oligosaccharides displayed on a variety of cell surfaces. Such binding promiscuity provides an explanation for the variety of adhesion phenomena mediated by galectin-1.

Understanding the bacterial polysaccharide antigenicity ofStreptococcus agalactiaeversusStreptococcus pneumoniae

“…4) indicated that the complex had structurally converged by Ϸ5 ns. As noted previously for carbohydrate-lectin interactions (31,32), the favorable electrostatic and van der Waals interaction energies, Ϫ294.4 kcal⅐mol Ϫ1 , were largely offset by the positive solvation free energy, 211.9 kcal⅐mol Ϫ1 (Table 2). Despite the polar character of the antigen, van der Waals interactions contributed 43% (Ϫ126.9 kcal⅐mol Ϫ1 ) of the total molecular mechanical binding energy.…”

“…The MM-GBSA results compare well with those employing the more rigorous Poisson-Boltzmann implicit solvent approximation (43). Based on earlier work (31), as well as on limited preliminary trials with the current system, we selected the GB parameterization of Tsui and Case (44). Although the magnitude of the computed solvation free energy is dependent on the choice of implicit solvent model, the relative values for closely related ligands are less sensitive.…”

“…The approach taken followed closely that reported earlier for a similar, but smaller, carbohydrate-lectin complex (31). The free energies of the components were computed by separating the energies into molecular mechanical (electrostatic and van der Waals), solvation, and entropic components ⌬G ϭ ⌬E MM Ϫ T⌬S MM ϩ ⌬G Solvation .…”

Binding diversity of the two binding sites of ricin B lectin

“…Among the various protein-carbohydrate complexes, the lectin-carbohydrate complex is one of the most highly interesting systems ever studied. [1][2][3][4][5] Lectins are globular proteins, which bind carbohydrates with a high degree of configurational specificity. 6 Ricin, a plant lectin, extracted as a heterodimer from the seeds of the castor bean plant Ricinus communis, is a toxic glycoprotein.…”

Extended binding site of ricin B lectin for oligosaccharide recognition

“…Similar extension of the binding site has also been reported for a oligosaccharide binding by Galectin-1, which is also known to crosslink oligosaccharides on a variety of cell surfaces. 39 These additional contacts strengthen the ligand binding by extending the binding site. As the current study is performed in implicit solvent we are not able to detect water mediated hydrogen bonds.…”