Exploring the conformational space for the interactions of aromatic residue analogs with biologically important saccharides

Abstract

Proteins interacting with carbohydrate ligands are getting a great deal of attention because of its important role in various biological processes. The crystal structures of several lectin-saccharide complexes have shown the presence of an aromatic residue in the binding site. The C-H hydrophobic patch of saccharide “stacks” against pi-cloud of aromatic residues forming CH-pi interactions, which are governed by dispersive and charge transfer interactions. The energetics of saccharide - aromatic residue interactions are dictated by their mutual position-orientations. It is conceivable that there exist low-energy position-orientations other than those found in the limited number of crystal structures of protein-carbohydrate complexes known to date. Hence, we have explored the conformational space for the interactions of 3-methylindole (3-MeIn), p-hydroxytoluene (p-OHTol) and toluene (Tol) (analogs of tryptophan, tyrosine and phenylalanine, respectively) with six saccharides. A Monte Carlo conformational search method was used to explore the features of the molecular potential energy surfaces. We found that the saccharides are densely populated above and below the pi-cloud of the aromatic ring of the amino acid residue but not along the edges. Clustering of conformers indicate the aromatic residues are spread out when interacting with C-H atoms as compared to that with -OH groups. The saccharides were capable of sliding on the surface of the aromatic residue. Four C-H groups can simultaneously participate in CH-pi interaction in 3-MeIn systems owing to its larger surface area. The β-D-Galactose and β-L-Fucose have been found to interact only through their b- and a-faces, respectively. Our ability to understand molecular flexibility through conformational search will further lead to advances in the design of drugs and to understand the advantages of selective choice of aromatic residues viz. tryptophan, tyrosine or phenylalanine in different carbohydrate binding proteins.