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

article

Mohini Yadav¹  Manabu Igarashi²  Norifumi Yamamoto¹ 

[1]Department of Applied Chemistry, Faculty of Engineering, Chiba Institute of Technology

[2]Division of Global Epidemiology, Research Center for Zoonosis Control, Hokkaido University

[3]International Collaboration Unit, Research Center for Zoonosis Control, Hokkaido University

关键词: Residue interaction network;    Molecular dynamics simulation;    Drug resistance;    Influenza neuraminidase;   

DOI  :  10.7717/peerj.11552

学科分类：社会科学、人文和艺术（综合）

来源: Inra

【 摘 要 】

BackgroundOseltamivir (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.MethodsIn 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.ResultsdRIN 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.

【 授权许可】

CC BY