Quantifying the Role of Water in Protein−Carbohydrate Interactions

Abstract

Water-mediated interactions play a key role in carbohydrate-lectin binding, where the interactions involve a conserved water that is separated from the bulk solvent and present a bridge between the side chains of the protein and the carbohydrate ligand. To apply quantum mechanical methods to examine the role of conserved waters, we present an analysis in which the relevant carbohydrate atoms are modeled by methanol, and in which the protein is replaced by a limited number of amino acid side chains. Clusters containing a conserved water and a representative amino acid fragment were also examined to determine the influence of amino acid side chains on interaction energies. To quantify the differential binding energies of methanol versus water, quantum mechanical calculations were performed at the B3LYP/6-311++G(3df,3pd)//B3LYP/6-31+G(d) level in which either a methanol molecule was bound to the conserved water (liganded state) or in which a water molecule replaces the methanol (unliganded state). Not surprisingly, the binding of a water to clusters containing charged amino acid side chains was more favorable by 1.55 to 7.23 kcal/mol than that for the binding of a water to the corresponding pure water clusters. In contrast, the binding energy of water to clusters containing polar-uncharged amino acid side chains ranged from 4.35 kcal/mol less favorable to 4.72 kcal/mol more favorable than for binding to the analogous pure water clusters. The overall trend for the binding of methanol versus water, in any of the clusters, favored methanol by an average value of 1.05 kcal/mol. To extend these studies to a complex between a protein (Concanavalin A) and its carbohydrate ligand, a cluster was examined that contained the side chains of three key amino acids, namely asparagine, aspartate, and arginine, as well as a key water molecule, arranged as in the X-ray diffraction structure of Con A. Again, using methanol as a model for the endogenous carbohydrate ligand, energies of -5.94 kcal/mol and -5.70 kcal/mol were obtained for the binding of methanol and water, respectively, to the Con A-water cluster. The extent to which cooperativity enhanced the binding energies has been quantified in terms of nonadditive three-body contributions. In general, the binding of water or methanol to neutral dimers formed cooperative clusters; in contrast, the cooperativity in charged clusters depended on the overall geometry as well as the charge.

Structure and binding analysis of Polyporus squamosus lectin in complex with the Neu5Acα2-6Galβ1-4GlcNAc human-type influenza receptor

“…The direct electrostatic contribution from ligand binding (−67.1 kcal mol −1 ) was largely offset by the energy (58.2 kcal mol −1 ) required to desolvate the polar residues in the binding interface. This is not unexpected given that the electrostatic interactions arise predominantly from hydrogen bonds involving hydroxyl groups in the glycan; hydrogen bonds which, depending on the polarity of the amino acid side chain involved, can be effectively equivalent in strength to those formed with water molecules (Tschampel and Woods 2003). Notably, the data in Table III lead to the conclusion that although hydrogen bonds are essential for binding specificity, a larger net contribution (−31.4 kcal mol −1 ) arises from van der Waals contacts.…”

Hydration of Sugars in the Gas Phase: Regioselectivity and Conformational Choice in N‐Acetyl Glucosamine and Glucose

“…[15][16][17] This can involve direct hydroxyl hydrogen-bonding and purely dispersive "CH-p" binding, [18][19][20] both of which may, or may not displace the water molecules surrounding the carbohydrate or the protein [21] or binding may alternatively be mediated by bound water molecules. [22,23] In all of these scenarios it is likely that the carbohydrate conformations associated with complexed or explicitly, and sometimes only partially, hydrated structures in the gas phase might provide a more precise model than dynamical structures in aqueous solution.…”

Binding energies of water to lithiated valine: Formation of solution-phase structure in vacuo

“…From measurements of hydration free energies, information about peptide structures can be inferred [8 -11]. Such hydration studies provide useful insight into effects of water on molecular structure and how water molecules interact with biomolecules [12][13][14][15][16].…”