Remarkable Loop Flexibility in Avian Influenza N1 and Its Implications for Antiviral Drug Design

The emergence and continuing global spread of the highly virulent avian influenza H5N1 has raised concerns of a possible human pandemic. Several approved anti-influenza drugs effectively target the neuraminidase (NA), a surface glycoprotein that cleaves terminal sialic acid residues and facilitates the release of viral progeny from infected cells. The first crystal structures of group-1 NAs revealed that although the binding pose of oseltamivir was similar to that seen in previous crystallographic complexes, the 150-loop adopted a distinct conformation, opening a new cavity adjacent to the active site. Here we show that the 150-loop is able to open into significantly wider conformations than seen in the crystal structures, through explicitly solvated MD simulations of the apo and oseltamivir-bound forms of tetrameric N1. We find that motion in the 150-loop is coupled to motion in the neighboring 430-loop, which expands the active site cavity even further. Furthermore, in simulations of the oseltamivir-bound system, the 150-loop approaches the closed conformation, suggesting that the loop switching motion may be more rapid than previously observed.