title: Carbohydrate-Aromatic Interactions in Proteins.
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.
authors.affiliation: School of Chemistry, University of Bristol , Bristol BS8 1TS, United Kingdom.
authors.forename: Kieran L
authors.initials: KL
authors.lastname: Hudson
authors.affiliation: School of Chemistry, University of Bristol , Bristol BS8 1TS, United Kingdom.
authors.forename: Gail J
authors.initials: GJ
authors.lastname: Bartlett
authors.affiliation: Department of Biochemistry, University of Wisconsin-Madison , Madison, Wisconsin 53706, United States.
authors.forename: Roger C
authors.initials: RC
authors.lastname: Diehl
authors.affiliation: York Structural Biology Laboratory, Department of Chemistry, University of York , Heslington YO10 5DD, United Kingdom.
authors.forename: Jon
authors.initials: J
authors.lastname: Agirre
authors.affiliation: School of Chemistry, University of Bristol , Bristol BS8 1TS, United Kingdom.
authors.forename: Timothy
authors.initials: T
authors.lastname: Gallagher
authors.affiliation: Department of Biochemistry, University of Wisconsin-Madison , Madison, Wisconsin 53706, United States.|Department of Chemistry, University of Wisconsin-Madison , Madison, Wisconsin 53706, United States.
authors.forename: Laura L
authors.initials: LL
authors.lastname: Kiessling
authors.affiliation: School of Chemistry, University of Bristol , Bristol BS8 1TS, United Kingdom.|School of Biochemistry, University of Bristol , Bristol BS8 1TD, United Kingdom.|BrisSynBio, University of Bristol , Life Sciences Building, Bristol BS8 1TQ, United Kingdom.
authors.forename: Derek N
authors.initials: DN
authors.lastname: Woolfson
mesh_terms: D024322:Amino Acids, Aromatic / Q000737:chemistry; D002241:Carbohydrates / Q000737:chemistry*; D018360:Crystallography, X-Ray; D030562:Databases, Protein; D011506:Proteins / Q000737:chemistry*
chemical_list: D024322:Amino Acids, Aromatic; D002241:Carbohydrates; D011506:Proteins