CH−π Interactions in Glycan Recognition

Abstract

Carbohydrate recognition is crucial for biological processes ranging from development to immune system function to host–pathogen interactions. The proteins that bind glycans are faced with a daunting task: to coax these hydrophilic species out of water and into a binding site. Here, we examine the forces underlying glycan recognition by proteins. Our previous bioinformatic study of glycan-binding sites indicated that the most overrepresented side chains are electron-rich aromatic residues, including tyrosine and tryptophan. These findings point to the importance of CH−π interactions for glycan binding. Studies of CH−π interactions show a strong dependence on the presence of an electron-rich π system, and the data indicate binding is enhanced by complementary electronic interactions between the electron-rich aromatic ring and the partial positive charge of the carbohydrate C–H protons. This electronic dependence means that carbohydrate residues with multiple aligned highly polarized C–H bonds, such as β-galactose, form strong CH−π interactions, whereas less polarized residues such as α-mannose do not. This information can guide the design of proteins to recognize sugars and the generation of ligands for proteins, small molecules, or catalysts that bind sugars.

Tryptophan, more than just an interfacial amino acid in the membrane activity of cationic cell-penetrating and antimicrobial peptides

“…Additionally, it is now well-documented that aromatic amino acids can establish C-H-π interactions, by the combination of electronic and hydrophobic forces (Kiessling and Diehl, 2021). Of utmost interest is that these C-H-π bonds are crucial in glycan/protein interactions, such as for the case of lectins (Gabius et al ., 2011).…”

“…As already mentioned, thanks to its particular structure, Trp can be involved in both hydrophobic interactions and electrostatic interactions (Khemaissa et al , 2021). For instance, it can interact with positive partial charges from carbohydrates C-H protons through C-H-π bonds (Kiessling and Diehl, 2021). This suggests a better interaction between Trp and polarised C-H sugar bonds such as β -galactose whereas less polarised carbohydrates including α -mannose are not able to establish such interactions.…”

Novel Synthesis Methods of New Imidazole-Containing Coordination Compounds Tc(IV, V, VII)—Reaction Mechanism, Xrd and Hirshfeld Surface Analysis

“…In this case, the distance between the hydrogen atom and the center of the aromatic ring is the shortest in the case of the hydrogen of the imidazole ring. Although the CH-π interactions are often considered weaker than the hydrogen bonds, they are one of the factors that determine the molecular structure within a crystal and can be used for recognition [ 34 , 35 ].…”

Engineering the Ligand Specificity of the Human Galectin‐1 by Incorporation of Tryptophan Analogues

“…Water networks are also important players in the carbohydrate recognition by Gal‐1 [31] . Furthermore, as classically observed in protein‐carbohydrate interaction, [32,33] the ligand is stabilized by CH‐π interactions between the Gal ring and the aromatic ring of tryptophan W68. Several lines of experimental evidence (NMR, UV resonance Raman spectroscopy) and molecular dynamics simulations agree on the crucial role of W68 in stabilizing the Gal moiety in complex with Gal‐1 [29,34,35] .…”