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

E. M. Kirilin1,a and V. K. Švedas1,2,b*

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

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

* To whom correspondence should be addressed.

Received February 3, 2020; Revised March 2, 2020; Accepted March 2, 2020
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.
KEY WORDS: influenza, neuraminidase, glycosyl-enzyme

DOI: 10.1134/S0006297920040094