Abstract
Protein–carbohydrate interactions play pivotal roles in health and disease. However, defining and manipulating these interactions has been hindered by an incomplete understanding of the underlying fundamental forces. To elucidate common and discriminating features in carbohydrate recognition, we have analyzed quantitatively X-ray crystal structures of proteins with noncovalently bound carbohydrates. Within the carbohydrate-binding pockets, aliphatic hydrophobic residues are disfavored, whereas aromatic side chains are enriched. The greatest preference is for tryptophan with an increased prevalence of 9-fold. Variations in the spatial orientation of amino acids around different monosaccharides indicate specific carbohydrate C–H bonds interact preferentially with aromatic residues. These preferences are consistent with the electronic properties of both the carbohydrate C–H bonds and the aromatic residues. Those carbohydrates that present patches of electropositive saccharide C–H bonds engage more often in CH−π interactions involving electron-rich aromatic partners. These electronic effects are also manifested when carbohydrate–aromatic interactions are monitored in solution: NMR analysis indicates that indole favorably binds to electron-poor C–H bonds of model carbohydrates, and a clear linear free energy relationships with substituted indoles supports the importance of complementary electronic effects in driving protein–carbohydrate interactions. Together, our data indicate that electrostatic and electronic complementarity between carbohydrates and aromatic residues play key roles in driving protein–carbohydrate complexation. Moreover, these weak noncovalent interactions influence which saccharide residues bind to proteins, and how they are positioned within carbohydrate-binding sites.
Highlights
There is growing appreciation of the fundamental roles of protein−carbohydrate interactions in biologically and medically important processes
The importance of hydrogen bonds between the carbohydrate hydroxyl groups and polar moieties of amino acids in the binding of carbohydrates by proteins is well recognized.[5−7] the role played by hydrophobic aliphatic and aromatic side chains in binding water-soluble carbohydrates is more obscure, with emphasis placed on interactions with carbohydrate C−H groups through the hydrophobic effect.[8]
These fundamental studies establish the importance of carbohydrate−aromatic interactions, but some gaps in knowledge remain: The relative propensities of specific monosaccharides and aromatic residues to participate in carbohy
Summary
There is growing appreciation of the fundamental roles of protein−carbohydrate interactions in biologically and medically important processes. The importance of hydrogen bonds between the carbohydrate hydroxyl groups and polar moieties of amino acids in the binding of carbohydrates by proteins is well recognized.[5−7] the role played by hydrophobic aliphatic and aromatic side chains in binding water-soluble carbohydrates is more obscure, with emphasis placed on interactions with carbohydrate C−H groups through the hydrophobic effect.[8] Aromatic residues have long been implicated in binding carbohydrates.[5,9] Carbohydrate-aromatic interactions are increasingly the subject of study in their own right,[10] and an underlying contributer to affinity is the CH−π interaction, i.e., the interaction of an aromatic π-system with a C−H bond.[11,12] carbohydrate−aromatic interactions have been examined in model systems using a variety of methods, including computational studies; investigation of the folding of synthetic glycopeptides designed to form intramolecular interactions; and the interrogation of small-molecule systems by solution-phase NMR studies.[10,13−25] These fundamental studies establish the importance of carbohydrate−aromatic interactions, but some gaps in knowledge remain: The relative propensities of specific monosaccharides and aromatic residues to participate in carbohy-. This analysis is supported by determination of linear free energy relationships using substituted indoles and methyl glycosides, which highlight a key role for electronic effects in CH−π interactions
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