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Homology modeling and examination of the effect of the D92E mutation on the H5N1 nonstructural protein NS1 effector domain

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Abstract

Virulent H5N1 strains of influenza virus often harbor a D92E point mutation in the nonstructural protein NS1. This crucial mutation has been correlated with increased virulence and/or cytokine resistance, but the structural implications of such a change are still unclear. Furthermore, NS1 protein could also be a potential target for the development of novel antiviral agents against H5N1 strains. Therefore, a reasonable 3D model of H5N1 NS1 is important for the understanding of the molecular basis of increased virulence and the design of novel antiviral agents. Based on the crystal structure of a non-H5N1 NS1 protein, a model of H5N1 NS1 was developed by homology modeling, molecular mechanics and molecular dynamics simulations. It was found that the D92E mutation could result in weakened interactions of the carboxylate side chain with other phosphorylated residues, thereby activating phosphorylation of NS1.

Superposition of snapshots picked from the two molecular dynamic (MD) trajectories: a H5N1 NS1 homology model and b non-H5N1 NS1 crystal structure after 0 (green ribbon), 5 (blue ribbon) and 10 ns (pink ribbon) MD simulation

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Acknowledgments

Financial support from the Georgia Cancer Coalition, Georgia Research Alliance, and the National Institutes of Health (CA123329, CA113917) is gratefully acknowledged. We also thank Mr. Victor Bolet for his technical support on computation.

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Authors and Affiliations

  1. Department of Chemistry and Center for Biotechnology and Drug Design, Georgia State University, Atlanta, GA, 30302-4098, USA

    Minyong Li & Binghe Wang

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  1. Minyong Li
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  2. Binghe Wang
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Correspondence to Binghe Wang.

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Li, M., Wang, B. Homology modeling and examination of the effect of the D92E mutation on the H5N1 nonstructural protein NS1 effector domain. J Mol Model 13, 1237–1244 (2007). https://doi.org/10.1007/s00894-007-0245-0

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  • DOI: https://doi.org/10.1007/s00894-007-0245-0

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