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.Communicated by Ramaswamy H. Sarma.

N1 neuraminidase of H5N1 avian influenza A virus complexed with sialic acid and zanamivir - A study by molecular docking and molecular dynamics simulation.

Development of antiviral drugs is an urgent need to control and prevent the presently circulating H5N1 avian influenza virus which is affects the human respiratory tract. The complex crystal structure of N1-N-acetylneuranamic acid (sialic acid, SIA) is not available as complex and hence SIA and zanamivir (ZMR) are docked into the binding site of N1 neuraminidase. Based on the analysis, the initial complex structures have been simulated for 120 ns to get insight into the binding modes and interaction between protein-ligand complex systems. NAMD pair interaction energy and MM-PBSA binding free energy are calculated and show that there are two possible binding modes (BM1 and BM2) for N1-SIA and a single binding mode (BM1) for and N1-ZMR complex structures respectively. BM1 of N1-SIA is the most preferred binding mode. On contrary to the currently available drugs in which the chair conformation is distorted, in both the binding modes of N1-SIA, the binding pocket of N1 neuraminidase is able to accommodate SIA in 2C5 chair conformation which is the preferred conformation of SIA in solution state. In N1-ZMR complex, ZMR is bind in a distorted chair conformation. The neuraminidase binding pocket is also able to accommodate galactose of SIAα(2→3)GAL and SIAα(2→6)GAL. RMSD, RMSF and hydrogen bonding analyses have been carried out to identify the conformational flexibility and structural stability of each complex system. All the analyses show that SIA can be used as an inhibitor for N1 neuraminidase of H5N1 influenza viral infection. Communicated by Ramaswamy H. Sarma.

Molecular dynamics simulation studies on influenza A virus H5N1 complexed with sialic acid and fluorinated sialic acid.

Abbreviations HA Hemagglutinin MD Molecular Dynamics MM-PBSA Molecular Mechanics Poisson-Boltzmann Surface Area NA Neuraminidase NAMD Nanoscale Molecular Dynamic Simulation PMEMD Particle Mesh Ewald Molecular Dynamics RMSD Root-Mean-Square Deviation RMSF Root-Mean-Square Fluctuation SIA sialic acid VMD Visual Molecular Dynamics Communicated by Ramaswamy H. Sarma.