Computational analysis of carbohydrate recognition based on hybrid QM/MM modeling: a case study of norovirus capsid...

Norovirus is a major pathogen of nonbacterial acute gastroenteritis in humans and animals. Carbohydrate recognition between norovirus capsid proteins and Lewis antigens is considered to play a critical role in initiating infection of eukaryotic cells. In this article, we first report a detailed atomistic simulation study of the norovirus capsid protein in complex with the Lewis antigen based on ab initio QM/MM combined with MD-FEP simulations. To understand the mechanistic details of ligand binding, we analyzed and compared the carbohydrate recognition mechanism of the wild-type P domain protein with a mutant protein. Small structural differences between two capsid proteins are observed on the weak interaction site of residue 389, which is located on the solvent exposed surface of the P domain. To further clarify affinity differences in ligand binding, we directly evaluated free energy changes of the ligand binding process. Although the mutant protein loses its interaction energy with the Lewis antigen, this small amount of energy penalty is compensated for by an increase in the solvation stability, which is induced by structural reorganization at the ligand binding site on the protein surface. As a sum of these opposite energy components, the mutant P domain obtains a slightly enhanced binding affinity for the Lewis antigen. The present computational study clearly demonstrated that a detailed free energy balance of the interaction energy between the capsid protein and the surrounding aqueous solvent is the mechanistic basis of carbohydrate recognition in the norovirus capsid protein.