A systematic study has been performed on neuraminidase (NA) mutations and NA-inhibitor docked complexes, with the aim to understand protein-ligand interactions and design broad-spectrum antiviral drugs with minimal resistances.The catalytic D151 residue is likely to mutate while others are relatively conserved.The NA active-site conformations are altered by mutations, but more alterations do not necessarily result in larger deviations to the binding properties.The effects of all related mutations have been discussed;e.g., for the arginine triad (R118, R292 and R371), it is found that residue R118 plays the most significant role during ligand binding.Generally, the calculated binding free energies agree well with the experimental observations.Susceptibility of influenza virus to NA inhibitors can be reinforced by some mutations;e.g., the binding free energies of ligands with N2 subtype increase from-18.0 to-42.1 kcal mol-1 by the E119D mutation.Mutations of the various NA subtypes often cause similar conformational and binding changes, explaining the occurrence of cross resistances;nonetheless, differences can be detected in some cases that correspond to subtype-specific resistances.For all NA subtypes, the electrostatic contributions are the major driving force for ligand binding and largely responsible for the binding differences between the wild-type and mutated NA proteins.