NS2B/NS3 protease: allosteric effect of mutations associated with the pathogenicity of tick-borne encephalitis virus

Abstract

The sequences of the protease domain of the tick-borne encephalitis (TBE) virus NS3 protein have two amino acid substitutions, 16 R→K and 45 S→F, in the highly pathogenic and poorly pathogenic strains of the virus, respectively. Two models of the NS2B-NS3 protease complex for the highly pathogenic and poorly pathogenic strains of the virus were constructed by homology modeling using the crystal structure of West Nile virus NS2B-NS3 protease as a template; 20 ns molecular dynamic simulations were performed for both models, the trajectories of the dynamic simulations were compared, and the averaged distance between the two models was calculated for each residue. Conformational differences between two models were revealed in the identified pocket. The different conformations of the pocket resulted in different orientations of the NS2B segment located near the catalytic triad. In the model of the highly pathogenic TBE virus the identified pocket had a more open conformation compared to the poorly pathogenic model. We propose that conformational changes in the active protease center, caused by two amino acid substitutions, can influence enzyme functioning and the virulence of the virus.

Keywords:

• flaviviral protease
• amino acid substitution
• pathogenicity
• conformational analysis
• molecular dynamic

Acknowledgments

This work was funded in part by the Russian Ministry of Science and Education (State Contract No. 14.740.12.0819 and State Contract No. P389), Grant ISTC No. 4006, the interdisciplinary integration project of SB RAS No. 141, and the joint projects of BRFFR and SB RAS No. 14. The authors thank Mr Colin H. Brown and Mr Dmitry Mukha for their help during this work.