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I223R/H275Y double mutant neuraminidase

 

Hua Tan,^ab Kun Wei,^c Jiguang Bao^b and Xiaobo Zhou^d

 

^a College of Global Change and Earth System Science, Beijing Normal University, Beijing 100875, P. R. China;

^b School of Mathematical Sciences, Beijing Normal University, Beijing 100875, P. R. China;

^c College of Information & Technology, Beijing University of Chemical Technology, Beijing 100029, P. R. China;

^d Center for Bioinformatics & Systems Biology, Department of Radiology,

Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.

 

ABSTRACT

It was recently reported that an I223R/H275Y double mutant of neuraminidase (NA) creates a multidrug-resistant form of the pandemic influenza A (H1N1) virus. However, a comprehensive understanding of the molecular mechanisms is still lacking. We conducted a systematic in silico study to explore the structural basis underlying this multidrug resistance. By molecular docking analyses and molecular dynamics (MD) simulations, we compared various biochemical and biophysical properties of the wild type, the I223R single mutant and the I223R/H275Y double mutant NA with two inhibitors, zanamivir (ZMR) and oseltamivir (G39). The binding free energy of oseltamivir with all types of NA was substantially lower than its zanamivir counterpart. On the other hand, the binding free energy of each inhibitor with wild type NA was generally higher than that with mutant NAs. MD simulation outcomes exemplify distinct patterns for oseltamivir and zanamivir with all types of NA. In particular, the stronger resistance of the double mutant NA relative to the wild and single mutant types can be ascribed to the overall looser but locally more compact structure of the former. Specifically, as a whole the double mutant NA adapts to the larger gyration radius and greater distance between charged atom groups, which is contrary to the pattern in the local binding site region. The enhanced resistance of all types of NA to oseltamivir rather than zanamivir might be accounted for similarly. We expect these findings to provide significant insights into improving inhibitors for the multidrug-resistant neuraminidase of H1N1 influenza viruses.

 

PUBLISHED IN: MOLECULAR BIOSYSTEMS, 2013, 9 (11): 2764-2774.

 

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