Structural and binding studies of 2'- and 3-fucosyllactose and its complexes with norovirus capsid protein by molecular dynamics simulations

Human breast milk contains free oligosaccharides (Human Milk Oligosaccharides-HMOs) that help to protect breastfed infants against a variety of infectious diseases and act as decoy receptors. In breast milk, HMOs are the third most abundant compounds after lactose and lipids. Structural and conformational models of HMOs are quite crucial to studying the interaction with proteins and molecular recognition phenomenon. Molecular dynamics simulations for two trisaccharides HMOs (2'-FL and 3-FL) were carried out for 250 ns and the conformational models were subsequently substantiated by three replicate simulations. The conformer models of HMOs 2'-FL and 3-FL were deposited in the 3-Dimensional Structural Database for Sialic acid-containing CARbohydrates (3DSDSCAR) database website (www.3dsdscar.in). HMOs were then docked into the active site of norovirus capsid protein and are simulated for 100 ns duration. Each complex system was stabilized by direct and water-mediated hydrogen bonding interactions. Binding free energy calculations predict two possible binding modes for each complex system. The conformational flexibility and binding stability of the complex systems were calculated. The protein folding/unfolding and compactness seem to be better for the two HMOs. From a general perspective, we found that both 2'-FL and 3-FL exhibited higher binding efficacy towards norovirus capsid protein and according to the structural stability, 3-FL might be used as a preventive inhibitor for norovirus infection.