Quantitative predictions of binding free energy changes in drug-resistant influenza neuraminidase.

Quantitatively predicting changes in drug sensitivity associated with residue mutations is a major challenge in structural biology. By expanding the limits of free energy calculations, we successfully identified mutations in influenza neuraminidase (NA) that confer drug resistance to two antiviral d...
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Autor*in:	Daniel R Ripoll [verfasserIn] Ilja V Khavrutskii [verfasserIn] Sidhartha Chaudhury [verfasserIn] Jin Liu [verfasserIn] Robert A Kuschner [verfasserIn] Anders Wallqvist [verfasserIn] Jaques Reifman [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2012

Übergeordnetes Werk:	In: PLoS Computational Biology - Public Library of Science (PLoS), 2005, 8(2012), 8, p e1002665
Übergeordnetes Werk:	volume:8 ; year:2012 ; number:8, p e1002665

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc Journal toc

DOI / URN:	10.1371/journal.pcbi.1002665

Katalog-ID:	DOAJ065925009

Internformat


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520			\|a Quantitatively predicting changes in drug sensitivity associated with residue mutations is a major challenge in structural biology. By expanding the limits of free energy calculations, we successfully identified mutations in influenza neuraminidase (NA) that confer drug resistance to two antiviral drugs, zanamivir and oseltamivir. We augmented molecular dynamics (MD) with Hamiltonian Replica Exchange and calculated binding free energy changes for H274Y, N294S, and Y252H mutants. Based on experimental data, our calculations achieved high accuracy and precision compared with results from established computational methods. Analysis of 15 micros of aggregated MD trajectories provided insights into the molecular mechanisms underlying drug resistance that are at odds with current interpretations of the crystallographic data. Contrary to the notion that resistance is caused by mutant-induced changes in hydrophobicity of the binding pocket, our simulations showed that drug resistance mutations in NA led to subtle rearrangements in the protein structure and its dynamics that together alter the active-site electrostatic environment and modulate inhibitor binding. Importantly, different mutations confer resistance through different conformational changes, suggesting that a generalized mechanism for NA drug resistance is unlikely.
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912			\|a GBV_ILN_213
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912			\|a GBV_ILN_285
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912			\|a GBV_ILN_4335
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Indexfelder

author_variant	d r r drr i v k ivk s c sc j l jl r a k rak a w aw j r jr
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publishDate	2012
allfields	10.1371/journal.pcbi.1002665 doi (DE-627)DOAJ065925009 (DE-599)DOAJc990e87185354733a26e436e70ef2d5b DE-627 ger DE-627 rakwb eng QH301-705.5 Daniel R Ripoll verfasserin aut Quantitative predictions of binding free energy changes in drug-resistant influenza neuraminidase. 2012 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Quantitatively predicting changes in drug sensitivity associated with residue mutations is a major challenge in structural biology. By expanding the limits of free energy calculations, we successfully identified mutations in influenza neuraminidase (NA) that confer drug resistance to two antiviral drugs, zanamivir and oseltamivir. We augmented molecular dynamics (MD) with Hamiltonian Replica Exchange and calculated binding free energy changes for H274Y, N294S, and Y252H mutants. Based on experimental data, our calculations achieved high accuracy and precision compared with results from established computational methods. Analysis of 15 micros of aggregated MD trajectories provided insights into the molecular mechanisms underlying drug resistance that are at odds with current interpretations of the crystallographic data. Contrary to the notion that resistance is caused by mutant-induced changes in hydrophobicity of the binding pocket, our simulations showed that drug resistance mutations in NA led to subtle rearrangements in the protein structure and its dynamics that together alter the active-site electrostatic environment and modulate inhibitor binding. Importantly, different mutations confer resistance through different conformational changes, suggesting that a generalized mechanism for NA drug resistance is unlikely. Biology (General) Ilja V Khavrutskii verfasserin aut Sidhartha Chaudhury verfasserin aut Jin Liu verfasserin aut Robert A Kuschner verfasserin aut Anders Wallqvist verfasserin aut Jaques Reifman verfasserin aut In PLoS Computational Biology Public Library of Science (PLoS), 2005 8(2012), 8, p e1002665 (DE-627)491436017 (DE-600)2193340-6 15537358 nnns volume:8 year:2012 number:8, p e1002665 https://doi.org/10.1371/journal.pcbi.1002665 kostenfrei https://doaj.org/article/c990e87185354733a26e436e70ef2d5b kostenfrei http://europepmc.org/articles/PMC3431292?pdf=render kostenfrei https://doaj.org/toc/1553-734X Journal toc kostenfrei https://doaj.org/toc/1553-7358 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 8 2012 8, p e1002665
spelling	10.1371/journal.pcbi.1002665 doi (DE-627)DOAJ065925009 (DE-599)DOAJc990e87185354733a26e436e70ef2d5b DE-627 ger DE-627 rakwb eng QH301-705.5 Daniel R Ripoll verfasserin aut Quantitative predictions of binding free energy changes in drug-resistant influenza neuraminidase. 2012 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Quantitatively predicting changes in drug sensitivity associated with residue mutations is a major challenge in structural biology. By expanding the limits of free energy calculations, we successfully identified mutations in influenza neuraminidase (NA) that confer drug resistance to two antiviral drugs, zanamivir and oseltamivir. We augmented molecular dynamics (MD) with Hamiltonian Replica Exchange and calculated binding free energy changes for H274Y, N294S, and Y252H mutants. Based on experimental data, our calculations achieved high accuracy and precision compared with results from established computational methods. Analysis of 15 micros of aggregated MD trajectories provided insights into the molecular mechanisms underlying drug resistance that are at odds with current interpretations of the crystallographic data. Contrary to the notion that resistance is caused by mutant-induced changes in hydrophobicity of the binding pocket, our simulations showed that drug resistance mutations in NA led to subtle rearrangements in the protein structure and its dynamics that together alter the active-site electrostatic environment and modulate inhibitor binding. Importantly, different mutations confer resistance through different conformational changes, suggesting that a generalized mechanism for NA drug resistance is unlikely. Biology (General) Ilja V Khavrutskii verfasserin aut Sidhartha Chaudhury verfasserin aut Jin Liu verfasserin aut Robert A Kuschner verfasserin aut Anders Wallqvist verfasserin aut Jaques Reifman verfasserin aut In PLoS Computational Biology Public Library of Science (PLoS), 2005 8(2012), 8, p e1002665 (DE-627)491436017 (DE-600)2193340-6 15537358 nnns volume:8 year:2012 number:8, p e1002665 https://doi.org/10.1371/journal.pcbi.1002665 kostenfrei https://doaj.org/article/c990e87185354733a26e436e70ef2d5b kostenfrei http://europepmc.org/articles/PMC3431292?pdf=render kostenfrei https://doaj.org/toc/1553-734X Journal toc kostenfrei https://doaj.org/toc/1553-7358 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 8 2012 8, p e1002665
allfields_unstemmed	10.1371/journal.pcbi.1002665 doi (DE-627)DOAJ065925009 (DE-599)DOAJc990e87185354733a26e436e70ef2d5b DE-627 ger DE-627 rakwb eng QH301-705.5 Daniel R Ripoll verfasserin aut Quantitative predictions of binding free energy changes in drug-resistant influenza neuraminidase. 2012 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Quantitatively predicting changes in drug sensitivity associated with residue mutations is a major challenge in structural biology. By expanding the limits of free energy calculations, we successfully identified mutations in influenza neuraminidase (NA) that confer drug resistance to two antiviral drugs, zanamivir and oseltamivir. We augmented molecular dynamics (MD) with Hamiltonian Replica Exchange and calculated binding free energy changes for H274Y, N294S, and Y252H mutants. Based on experimental data, our calculations achieved high accuracy and precision compared with results from established computational methods. Analysis of 15 micros of aggregated MD trajectories provided insights into the molecular mechanisms underlying drug resistance that are at odds with current interpretations of the crystallographic data. Contrary to the notion that resistance is caused by mutant-induced changes in hydrophobicity of the binding pocket, our simulations showed that drug resistance mutations in NA led to subtle rearrangements in the protein structure and its dynamics that together alter the active-site electrostatic environment and modulate inhibitor binding. Importantly, different mutations confer resistance through different conformational changes, suggesting that a generalized mechanism for NA drug resistance is unlikely. Biology (General) Ilja V Khavrutskii verfasserin aut Sidhartha Chaudhury verfasserin aut Jin Liu verfasserin aut Robert A Kuschner verfasserin aut Anders Wallqvist verfasserin aut Jaques Reifman verfasserin aut In PLoS Computational Biology Public Library of Science (PLoS), 2005 8(2012), 8, p e1002665 (DE-627)491436017 (DE-600)2193340-6 15537358 nnns volume:8 year:2012 number:8, p e1002665 https://doi.org/10.1371/journal.pcbi.1002665 kostenfrei https://doaj.org/article/c990e87185354733a26e436e70ef2d5b kostenfrei http://europepmc.org/articles/PMC3431292?pdf=render kostenfrei https://doaj.org/toc/1553-734X Journal toc kostenfrei https://doaj.org/toc/1553-7358 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 8 2012 8, p e1002665
allfieldsGer	10.1371/journal.pcbi.1002665 doi (DE-627)DOAJ065925009 (DE-599)DOAJc990e87185354733a26e436e70ef2d5b DE-627 ger DE-627 rakwb eng QH301-705.5 Daniel R Ripoll verfasserin aut Quantitative predictions of binding free energy changes in drug-resistant influenza neuraminidase. 2012 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Quantitatively predicting changes in drug sensitivity associated with residue mutations is a major challenge in structural biology. By expanding the limits of free energy calculations, we successfully identified mutations in influenza neuraminidase (NA) that confer drug resistance to two antiviral drugs, zanamivir and oseltamivir. We augmented molecular dynamics (MD) with Hamiltonian Replica Exchange and calculated binding free energy changes for H274Y, N294S, and Y252H mutants. Based on experimental data, our calculations achieved high accuracy and precision compared with results from established computational methods. Analysis of 15 micros of aggregated MD trajectories provided insights into the molecular mechanisms underlying drug resistance that are at odds with current interpretations of the crystallographic data. Contrary to the notion that resistance is caused by mutant-induced changes in hydrophobicity of the binding pocket, our simulations showed that drug resistance mutations in NA led to subtle rearrangements in the protein structure and its dynamics that together alter the active-site electrostatic environment and modulate inhibitor binding. Importantly, different mutations confer resistance through different conformational changes, suggesting that a generalized mechanism for NA drug resistance is unlikely. Biology (General) Ilja V Khavrutskii verfasserin aut Sidhartha Chaudhury verfasserin aut Jin Liu verfasserin aut Robert A Kuschner verfasserin aut Anders Wallqvist verfasserin aut Jaques Reifman verfasserin aut In PLoS Computational Biology Public Library of Science (PLoS), 2005 8(2012), 8, p e1002665 (DE-627)491436017 (DE-600)2193340-6 15537358 nnns volume:8 year:2012 number:8, p e1002665 https://doi.org/10.1371/journal.pcbi.1002665 kostenfrei https://doaj.org/article/c990e87185354733a26e436e70ef2d5b kostenfrei http://europepmc.org/articles/PMC3431292?pdf=render kostenfrei https://doaj.org/toc/1553-734X Journal toc kostenfrei https://doaj.org/toc/1553-7358 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 8 2012 8, p e1002665
allfieldsSound	10.1371/journal.pcbi.1002665 doi (DE-627)DOAJ065925009 (DE-599)DOAJc990e87185354733a26e436e70ef2d5b DE-627 ger DE-627 rakwb eng QH301-705.5 Daniel R Ripoll verfasserin aut Quantitative predictions of binding free energy changes in drug-resistant influenza neuraminidase. 2012 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Quantitatively predicting changes in drug sensitivity associated with residue mutations is a major challenge in structural biology. By expanding the limits of free energy calculations, we successfully identified mutations in influenza neuraminidase (NA) that confer drug resistance to two antiviral drugs, zanamivir and oseltamivir. We augmented molecular dynamics (MD) with Hamiltonian Replica Exchange and calculated binding free energy changes for H274Y, N294S, and Y252H mutants. Based on experimental data, our calculations achieved high accuracy and precision compared with results from established computational methods. Analysis of 15 micros of aggregated MD trajectories provided insights into the molecular mechanisms underlying drug resistance that are at odds with current interpretations of the crystallographic data. Contrary to the notion that resistance is caused by mutant-induced changes in hydrophobicity of the binding pocket, our simulations showed that drug resistance mutations in NA led to subtle rearrangements in the protein structure and its dynamics that together alter the active-site electrostatic environment and modulate inhibitor binding. Importantly, different mutations confer resistance through different conformational changes, suggesting that a generalized mechanism for NA drug resistance is unlikely. Biology (General) Ilja V Khavrutskii verfasserin aut Sidhartha Chaudhury verfasserin aut Jin Liu verfasserin aut Robert A Kuschner verfasserin aut Anders Wallqvist verfasserin aut Jaques Reifman verfasserin aut In PLoS Computational Biology Public Library of Science (PLoS), 2005 8(2012), 8, p e1002665 (DE-627)491436017 (DE-600)2193340-6 15537358 nnns volume:8 year:2012 number:8, p e1002665 https://doi.org/10.1371/journal.pcbi.1002665 kostenfrei https://doaj.org/article/c990e87185354733a26e436e70ef2d5b kostenfrei http://europepmc.org/articles/PMC3431292?pdf=render kostenfrei https://doaj.org/toc/1553-734X Journal toc kostenfrei https://doaj.org/toc/1553-7358 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 8 2012 8, p e1002665
language	English
source	In PLoS Computational Biology 8(2012), 8, p e1002665 volume:8 year:2012 number:8, p e1002665
sourceStr	In PLoS Computational Biology 8(2012), 8, p e1002665 volume:8 year:2012 number:8, p e1002665
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Biology (General)
isfreeaccess_bool	true
container_title	PLoS Computational Biology
authorswithroles_txt_mv	Daniel R Ripoll @@aut@@ Ilja V Khavrutskii @@aut@@ Sidhartha Chaudhury @@aut@@ Jin Liu @@aut@@ Robert A Kuschner @@aut@@ Anders Wallqvist @@aut@@ Jaques Reifman @@aut@@
publishDateDaySort_date	2012-01-01T00:00:00Z
hierarchy_top_id	491436017
id	DOAJ065925009
language_de	englisch
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callnumber-first	Q - Science
author	Daniel R Ripoll
spellingShingle	Daniel R Ripoll misc QH301-705.5 misc Biology (General) Quantitative predictions of binding free energy changes in drug-resistant influenza neuraminidase.
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topic_title	QH301-705.5 Quantitative predictions of binding free energy changes in drug-resistant influenza neuraminidase
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title	Quantitative predictions of binding free energy changes in drug-resistant influenza neuraminidase.
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title_full	Quantitative predictions of binding free energy changes in drug-resistant influenza neuraminidase
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title_sort	quantitative predictions of binding free energy changes in drug-resistant influenza neuraminidase
callnumber	QH301-705.5
title_auth	Quantitative predictions of binding free energy changes in drug-resistant influenza neuraminidase.
abstract	Quantitatively predicting changes in drug sensitivity associated with residue mutations is a major challenge in structural biology. By expanding the limits of free energy calculations, we successfully identified mutations in influenza neuraminidase (NA) that confer drug resistance to two antiviral drugs, zanamivir and oseltamivir. We augmented molecular dynamics (MD) with Hamiltonian Replica Exchange and calculated binding free energy changes for H274Y, N294S, and Y252H mutants. Based on experimental data, our calculations achieved high accuracy and precision compared with results from established computational methods. Analysis of 15 micros of aggregated MD trajectories provided insights into the molecular mechanisms underlying drug resistance that are at odds with current interpretations of the crystallographic data. Contrary to the notion that resistance is caused by mutant-induced changes in hydrophobicity of the binding pocket, our simulations showed that drug resistance mutations in NA led to subtle rearrangements in the protein structure and its dynamics that together alter the active-site electrostatic environment and modulate inhibitor binding. Importantly, different mutations confer resistance through different conformational changes, suggesting that a generalized mechanism for NA drug resistance is unlikely.
abstractGer	Quantitatively predicting changes in drug sensitivity associated with residue mutations is a major challenge in structural biology. By expanding the limits of free energy calculations, we successfully identified mutations in influenza neuraminidase (NA) that confer drug resistance to two antiviral drugs, zanamivir and oseltamivir. We augmented molecular dynamics (MD) with Hamiltonian Replica Exchange and calculated binding free energy changes for H274Y, N294S, and Y252H mutants. Based on experimental data, our calculations achieved high accuracy and precision compared with results from established computational methods. Analysis of 15 micros of aggregated MD trajectories provided insights into the molecular mechanisms underlying drug resistance that are at odds with current interpretations of the crystallographic data. Contrary to the notion that resistance is caused by mutant-induced changes in hydrophobicity of the binding pocket, our simulations showed that drug resistance mutations in NA led to subtle rearrangements in the protein structure and its dynamics that together alter the active-site electrostatic environment and modulate inhibitor binding. Importantly, different mutations confer resistance through different conformational changes, suggesting that a generalized mechanism for NA drug resistance is unlikely.
abstract_unstemmed	Quantitatively predicting changes in drug sensitivity associated with residue mutations is a major challenge in structural biology. By expanding the limits of free energy calculations, we successfully identified mutations in influenza neuraminidase (NA) that confer drug resistance to two antiviral drugs, zanamivir and oseltamivir. We augmented molecular dynamics (MD) with Hamiltonian Replica Exchange and calculated binding free energy changes for H274Y, N294S, and Y252H mutants. Based on experimental data, our calculations achieved high accuracy and precision compared with results from established computational methods. Analysis of 15 micros of aggregated MD trajectories provided insights into the molecular mechanisms underlying drug resistance that are at odds with current interpretations of the crystallographic data. Contrary to the notion that resistance is caused by mutant-induced changes in hydrophobicity of the binding pocket, our simulations showed that drug resistance mutations in NA led to subtle rearrangements in the protein structure and its dynamics that together alter the active-site electrostatic environment and modulate inhibitor binding. Importantly, different mutations confer resistance through different conformational changes, suggesting that a generalized mechanism for NA drug resistance is unlikely.
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title_short	Quantitative predictions of binding free energy changes in drug-resistant influenza neuraminidase.
url	https://doi.org/10.1371/journal.pcbi.1002665 https://doaj.org/article/c990e87185354733a26e436e70ef2d5b http://europepmc.org/articles/PMC3431292?pdf=render https://doaj.org/toc/1553-734X https://doaj.org/toc/1553-7358
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up_date	2024-07-03T17:18:41.879Z
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Quantitative predictions of binding free energy changes in drug-resistant influenza neuraminidase.

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