Theoretical insights into the molecular mechanism of I117V mutation in neuraminidase mediated reduction of oseltamivir drug susceptibility in A/H5N1 influenza virus

Mohini Yadav,Manabu Igarashi,Norifumi Yamamoto

doi:10.7717/peerj-pchem.19

Mohini Yadav, Manabu Igarashi + Show 1 more

Open Access

https://doi.org/10.7717/peerj-pchem.19

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Abstract

The substitution of Ile to Val at residue 117 (I117V) of neuraminidase (NA) reduces the susceptibility of the A/H5N1 influenza virus to oseltamivir (OTV). However, the molecular mechanism by which the I117V mutation affects the intermolecular interactions between NA and OTV has not been fully elucidated. In this study, we performed molecular dynamics (MD) simulations to analyze the characteristic conformational changes that contribute to the reduced binding affinity of NA to OTV after the I117V mutation. The results of MD simulations revealed that after the I117V mutation in NA, the changes in the secondary structure around the mutation site had a noticeable effect on the residue interactions in the OTV-binding site. In the case of the WT NA-OTV complex, the positively charged side chain of R118, located in the β-sheet region, frequently interacted with the negatively charged side chain of E119, which is an amino acid residue in the OTV-binding site. This can reduce the electrostatic repulsion of E119 toward D151, which is also a negatively charged residue in the OTV-binding site, so that both E119 and D151 simultaneously form hydrogen bonds with OTV more frequently, which greatly contributes to the binding affinity of NA to OTV. After the I117V mutation in NA, the side chain of R118 interacted with the side chain of E119 less frequently, likely because of the decreased tendency of R118 to form a β-sheet structure. As a result, the electrostatic repulsion of E119 toward D151 is greater than that of the WT case, making it difficult for both E119 and D151 to simultaneously form hydrogen bonds with OTV, which in turn reduces the binding affinity of NA to OTV. Hence, after the I117V mutation in NA, influenza viruses are less susceptible to OTV because of conformational changes in residues of R118, E119, and D151 around the mutation site and in the binding site.

Highlights

Influenza A viruses infect a variety of avian and mammalian species, including humans (Webster et al, 1992)
The results showed that after the I117V mutation in NA, the binding affinity between NA and OTV was reduced due to the conformational change of R118 adjacent to the mutation site, which affected the interactions of E119 and D151 with OTV
We theoretically investigated the molecular mechanism of reduced OTV drug susceptibility in the A/H5N1 influenza virus harboring the NA I117V mutation using molecular dynamics (MD) simulations

Summary

Introduction

Influenza A viruses infect a variety of avian and mammalian species, including humans (Webster et al, 1992). Influenza A viruses are divided into subtypes based on antigenic differences of two virus surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA) (Gamblin & Skehel, 2010). HA mediates virus entry into the host cell by binding to a terminal sialic acid on the host cell surface. NA is responsible for removing sialic acid to facilitate the release of progeny viruses from infected cells. Several NA inhibitors, such as oseltamivir (OTV), zanamivir, laninamivir, and peramivir, are currently available for the treatment of influenza virus infection (McKimm-Breschkin, 2012). OTV is the most widely used anti-influenza drug (Kim et al, 1997)

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