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

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 elucid...

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Autores principales:	Mohini Yadav, Manabu Igarashi, Norifumi Yamamoto
Formato:	article
Lenguaje:	EN
Publicado:	PeerJ Inc. 2021
Materias:	Influenza virus Reduced drug susceptibility Oseltamivir Neuraminidase Drug resistance Infectious disease Physical and theoretical chemistry QD450-801
Acceso en línea:	https://doaj.org/article/2ec2189464f945cbaa831c4abf17bdf6
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spelling	oai:doaj.org-article:2ec2189464f945cbaa831c4abf17bdf62021-11-24T15:05:16ZTheoretical insights into the molecular mechanism of I117V mutation in neuraminidase mediated reduction of oseltamivir drug susceptibility in A/H5N1 influenza virus10.7717/peerj-pchem.192689-7733https://doaj.org/article/2ec2189464f945cbaa831c4abf17bdf62021-11-01T00:00:00Zhttps://peerj.com/articles/pchem-19.pdfhttps://peerj.com/articles/pchem-19/https://doaj.org/toc/2689-7733The 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.Mohini YadavManabu IgarashiNorifumi YamamotoPeerJ Inc.articleInfluenza virusReduced drug susceptibilityOseltamivirNeuraminidaseDrug resistanceInfectious diseasePhysical and theoretical chemistryQD450-801ENPeerJ Physical Chemistry, Vol 3, p e19 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Influenza virus Reduced drug susceptibility Oseltamivir Neuraminidase Drug resistance Infectious disease Physical and theoretical chemistry QD450-801
spellingShingle	Influenza virus Reduced drug susceptibility Oseltamivir Neuraminidase Drug resistance Infectious disease Physical and theoretical chemistry QD450-801 Mohini Yadav Manabu Igarashi Norifumi Yamamoto Theoretical insights into the molecular mechanism of I117V mutation in neuraminidase mediated reduction of oseltamivir drug susceptibility in A/H5N1 influenza virus
description	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.
format	article
author	Mohini Yadav Manabu Igarashi Norifumi Yamamoto
author_facet	Mohini Yadav Manabu Igarashi Norifumi Yamamoto
author_sort	Mohini Yadav
title	Theoretical insights into the molecular mechanism of I117V mutation in neuraminidase mediated reduction of oseltamivir drug susceptibility in A/H5N1 influenza virus
title_short	Theoretical insights into the molecular mechanism of I117V mutation in neuraminidase mediated reduction of oseltamivir drug susceptibility in A/H5N1 influenza virus
title_full	Theoretical insights into the molecular mechanism of I117V mutation in neuraminidase mediated reduction of oseltamivir drug susceptibility in A/H5N1 influenza virus
title_fullStr	Theoretical insights into the molecular mechanism of I117V mutation in neuraminidase mediated reduction of oseltamivir drug susceptibility in A/H5N1 influenza virus
title_full_unstemmed	Theoretical insights into the molecular mechanism of I117V mutation in neuraminidase mediated reduction of oseltamivir drug susceptibility in A/H5N1 influenza virus
title_sort	theoretical insights into the molecular mechanism of i117v mutation in neuraminidase mediated reduction of oseltamivir drug susceptibility in a/h5n1 influenza virus
publisher	PeerJ Inc.
publishDate	2021
url	https://doaj.org/article/2ec2189464f945cbaa831c4abf17bdf6
work_keys_str_mv	AT mohiniyadav theoreticalinsightsintothemolecularmechanismofi117vmutationinneuraminidasemediatedreductionofoseltamivirdrugsusceptibilityinah5n1influenzavirus AT manabuigarashi theoreticalinsightsintothemolecularmechanismofi117vmutationinneuraminidasemediatedreductionofoseltamivirdrugsusceptibilityinah5n1influenzavirus AT norifumiyamamoto theoreticalinsightsintothemolecularmechanismofi117vmutationinneuraminidasemediatedreductionofoseltamivirdrugsusceptibilityinah5n1influenzavirus
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Theoretical insights into the molecular mechanism of I117V mutation in neuraminidase mediated reduction of oseltamivir drug susceptibility in A/H5N1 influenza virus

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