Abstract
The emergence of a novel H7N9 avian influenza that infects humans is a serious cause for concern. Of the genome sequences of H7N9 neuraminidase available, one contains a substitution of arginine to lysine at position 292, suggesting a potential for reduced drug binding efficacy. We have performed molecular dynamics simulations of oseltamivir, zanamivir and peramivir bound to H7N9, H7N9-R292K, and a structurally related H11N9 neuraminidase. They show that H7N9 neuraminidase is structurally homologous to H11N9, binding the drugs in identical modes. The simulations reveal that the R292K mutation disrupts drug binding in H7N9 in a comparable manner to that observed experimentally for H11N9-R292K. Absolute binding free energy calculations with the WaterSwap method confirm a reduction in binding affinity. This indicates that the efficacy of antiviral drugs against H7N9-R292K will be reduced. Simulations can assist in predicting disruption of binding caused by mutations in neuraminidase, thereby providing a computational ‘assay.'
Highlights
The emergence of a novel H7N9 avian influenza that infects humans is a serious cause for concern
We have performed computational assays involving multiple 70 nanosecond molecular dynamics simulations of oseltamivir, zanamivir and peramivir bound to H11N9, H7N9 and H7N9-R292K neuraminidase, together with absolute binding free energy calculations using the WaterSwap method[23]
A computational assay involving nine molecular dynamics simulations was performed using these models: oseltamivir, zanamivir and peramivir bound to H11N9, H7N9 and H7N9-R292K neuraminidase
Summary
The emergence of a novel H7N9 avian influenza that infects humans is a serious cause for concern. Absolute binding free energy calculations with the WaterSwap method confirm a reduction in binding affinity This indicates that the efficacy of antiviral drugs against H7N9-R292K will be reduced. Knowledge of the sequence alone does not provide sufficient information to predict the magnitude of any reduction in binding affinity To answer these questions, we have performed computational assays involving multiple 70 nanosecond (ns) molecular dynamics simulations of oseltamivir, zanamivir and peramivir bound to H11N9, H7N9 and H7N9-R292K neuraminidase, together with absolute binding free energy calculations using the WaterSwap method[23]. The results indicate that molecular dynamics simulations coupled with binding affinity calculations with WaterSwap can provide a rapid and cheap predictive assay to detect disrupted drug binding in neuraminidase in emerging influenza strains
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