Understanding the Selectivity Mechanism of the Human Asialoglycoprotein Receptor (ASGP-R) toward Gal- and Man-type Ligands for Predicting Interactions with Exogenous Sugars

摘要

A practical approach for addressing the computer simulation of protein-carbohydrate interactions is described here. An articulated computational protocol was set up and validated by checking its ability to predict experimental data, available in the literature, and concerning the selectivity shown by the Carbohydrate Recognition Domain (CRD) of the human asialoglycoprotein receptor (ASGP-R) toward Gal-type ligands. Some required features responsible for the interactions were identified. Subsequently the same protocol was applied to monomer sugar molecules that constitute the building blocks for alginates and ulvans. Such sugar polymers may supply a low-cost source of rare sugars with a potential impact on several industrial applications, from pharmaceutical to fine chemical industry. An example of their applicative exploitation could be given by their use in developing biomaterial with adhesion properties toward hepatocytes, through interaction with the ASGP-R. Such a receptor has been already proposed as a target for exogenous molecules, specifically in the case of hepatocytes, for diagnostic and therapeutic purposes. The DOCK5.2 program was used to search optimal locations of the above ligands of interest into CRD binding site and to roughly estimate interaction energies. Finally, the binding ΔG of theoretical protein-ligand complexes was estimated by using the DelPhi program in which the solvation free energy is accounted for with a continuum solvent model, by solving the Poisson-Boltzmann equation. The structure analysis of the obtained complexes and their ΔG values suggest that one of the sugar monomers of interest shows the desired characteristics.