H5N1 is a subtype of the influenza A virus that can cause disease in humans and 
many other animal species. Oseltamivir (Tamiflu) is a potent and selective 
antiviral drug employed to fight the flu virus in infected individuals by 
inhibiting neuraminidase (NA), a flu protein responsible for the release and 
spread of the progeny virions. However, oseltamivir resistance has become a 
critical problem. In particular, influenza strains with a R292K NA mutation are 
highly resistant to the oseltamivir. Though the biological functions of the 
mutations have previously been characterized, the structural basis behind the 
reduced catalytic activity and reduced protein level is not clear. In this 
study, molecular docking and molecular dynamics (MD) approach were employed to 
investigate the structural and dynamical effects throughout the protein 
structure and specifically, at the drug-binding pocket. Furthermore, potential 
of mean force was analyzed using explicit solvent MD simulations with the 
umbrella sampling method to explore the free energy of binding. It is believed 
that this study provides valuable guidance for the resistance management of 
oseltamivir and designing of more potent antiviral inhibitor.