Effect of protonation of the N-acetyl neuraminic acid residue of sialyl Lewis^X: A molecular orbital study with insights into its binding properties toward the carbohydrate recognition domain of E-selectin

Semiempirical molecular orbital (MO) calculations with an implicit treatment of the water environment were employed in order to assess whether the sialyl Lewis^X (sLe^X) tetrasaccharide binds to E-selectin in the anionic or neutral (i.e., protonated) state. The analysis of the frontier molecular orbitals, electrostatic potential surfaces, and conformational behavior of the sugar indicates that its neutral form possesses the necessary characteristics for binding. In particular, the LUMO level of the neutral sLe^X molecule is localized both on the carboxylic group of the N-acetyl neuraminic acid (NeuNAc) residue and on the nearby glycosidic linkage. These two moieties interact with the Arg97 residue of E-selectin, as revealed by a recent crystal structure analysis of the E-selectin/sLe^X complex. The energetics of this specific interaction was investigated with the aid of ab initio Hartree-Fock MO calculations, which resulted in a BSSE-corrected binding energy of 16.63 kcal/mol. Our observations could open up new perspectives in the design of sLe^X mimics.