Recent advances in employing molecular modelling to determine the specificity of glycan-binding proteins

Abstract

Impressive improvements in docking performance can be achieved by applying energy bonuses to poses in which glycan hydroxyl groups occupy positions otherwise preferred by bound waters. In addition, inclusion of glycosidic conformational energies allows unlikely glycan conformations to be appropriately penalized. A method for predicting the binding specificity of glycan-binding proteins has been developed, which is based on grafting glycan branches onto a minimal binding determinant in the binding site. Grafting can be used either to screen virtual libraries of glycans, such as the known glycome, or to identify docked poses of minimal binding determinants that are consistent with specificity data. The reviewed advances allow accurate modelling of carbohydrate-protein 3D co-complexes, but challenges remain in ranking the affinity of congeners.

Figure 1

Partial structural mimicry among monosaccharides (Neu5Ac, top; GlcNAc, bottom;) can confuse MBD assignments, and is challenging to detect, in part because of nomenclature limitations and established structure representation preferences.

Figure 2

Calculated glycosidic torsion rotational energies (solid lines) versus distributions of related torsion angles from glycans in the PDB [30].

Figure 3

Left: solvent accessible surface of the lentil lectin Concanavalin A (light blue) in complex with the natural trisaccharide ligand (PDB: 1CVN). Waters of crystallization are shown as red spheres. Superimposed are the waters of crystallization (dark blue) from the ligand-free structure (PDB: 1GKB). Key waters, which appear to be displaced by the ligand, as well as a conserved water molecule (Wat40), are shown as larger spheres [57]. Right: results from docking a hyaluronan tetrasaccharide to CD44 (orange, ribbon model) using the water-site biased docking method. The top ranked pose (ball and stick model) has an RMSD of 0.7 Å from the reference ligand position (stick model) [63].