Dynamic residue interaction network analysis of the oseltamivir binding site of N1 neuraminidase and its H274Y mutation site conferring drug resistance in influenza A virus

PeerJ. 2021 Jun 2;9:e11552. doi: 10.7717/peerj.11552. eCollection 2021.


Background: Oseltamivir (OTV)-resistant influenza virus exhibits His-to-Tyr mutation at residue 274 (H274Y) in N1 neuraminidase (NA). However, the molecular mechanisms by which the H274Y mutation in NA reduces its binding affinity to OTV have not been fully elucidated.

Methods: In this study, we used dynamic residue interaction network (dRIN) analysis based on molecular dynamics simulation to investigate the correlation between the OTV binding site of NA and its H274Y mutation site.

Results: dRIN analysis revealed that the OTV binding site and H274Y mutation site of NA interact via the three interface residues connecting them. H274Y mutation significantly enhanced the interaction between residue 274 and the three interface residues in NA, thereby significantly decreasing the interaction between OTV and its surrounding loop 150 residues. Thus, we concluded that such changes in residue interactions could reduce the binding affinity of OTV to NA, resulting in drug resistant influenza viruses. Using dRIN analysis, we succeeded in understanding the characteristic changes in residue interactions due to H274Y mutation, which can elucidate the molecular mechanism of reduction in OTV binding affinity to influenza NA. Finally, the dRIN analysis used in this study can be widely applied to various systems such as individual proteins, protein-ligand complexes, and protein-protein complexes, to characterize the dynamic aspects of the interactions.

Keywords: Drug resistance; Influenza neuraminidase; Molecular dynamics simulation; Residue interaction network.

Grant support

This work has received financial support from the Joint Usage/Research Center Program at Research Center for Zoonosis Control, Hokkaido University, Sapporo, Japan. The molecular simulations were carried out on the TSUBAME supercomputer, Tokyo Institute of Technology, Tokyo, Japan, under the TSUBAME Encouragement Program for Young/Female Users. Mohini Yadav received support for living expenses and tuition fees from the Watanuki International Scholarship Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.