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Analysis of Glycosyl-Enzyme Intermediate Formation in the Catalytic Mechanism of Influenza Virus Neuraminidase Using Molecular Modeling

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Abstract

Using classical molecular dynamics, constant-pH molecular dynamics simulation, metadynamics, and combined quantum mechanical and molecular mechanical approach, we identified an alternative pathway of glycosyl-enzyme intermediate formation during oligosaccharide substrate conversion by the influenza H5N1 neuraminidase. The Asp151 residue located in the enzyme mobile loop plays a key role in catalysis within a wide pH range due to the formation of a network of interactions with water molecules. Considering that propagation of influenza virus takes place in the digestive tract of birds at low pH values and in the human respiratory tract at pH values close to neutral, the existence of alternative reaction pathways functioning at different medium pH can explain the dual tropism of the virus and circulation of H5N1 viral strains capable of transmission from birds to humans.

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Abbreviations

QM/MM:

combined quantum mechanics and molecular mechanics

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Acknowledgements

The study was performed using equipment from the Center of Collective Use of super high-performance computational resources of the Lomonosov Moscow State University [29].

Funding

This work was supported by the Russian Foundation for Basic Research (project No. 18-34-00953).

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Authors and Affiliations

  1. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991, Moscow, Russia

    E. M. Kirilin & V. K. Švedas

  2. Lomonosov Moscow State University, Faculty of Bioengineering and Bioinformatics, 119991, Moscow, Russia

    V. K. Švedas

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  1. E. M. Kirilin
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Correspondence to E. M. Kirilin or V. K. Švedas.

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This article does not contain studies with human participants or animals performed by any of the authors. The authors declare that they have no conflict of interest.

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Kirilin, E., Švedas, V. Analysis of Glycosyl-Enzyme Intermediate Formation in the Catalytic Mechanism of Influenza Virus Neuraminidase Using Molecular Modeling. Biochemistry Moscow 85, 490–498 (2020). https://doi.org/10.1134/S0006297920040094

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