Mutation-induced loop opening and energetics for binding of tamiflu to influenza N8 neuraminidase.
Identifieur interne : 000146 ( PubMed/Corpus ); précédent : 000145; suivant : 000147Mutation-induced loop opening and energetics for binding of tamiflu to influenza N8 neuraminidase.
Auteurs : Parimal Kar ; Volker KnechtSource :
- The journal of physical chemistry. B [ 1520-5207 ] ; 2012.
English descriptors
- KwdEn :
- Antiviral Agents (metabolism), Catalytic Domain, Enzyme Stability, Influenza A Virus, H1N1 Subtype (enzymology), Influenza A Virus, H2N2 Subtype (enzymology), Influenza A Virus, H5N1 Subtype (enzymology), Influenza A virus (enzymology), Molecular Dynamics Simulation, Mutation, Neuraminidase (chemistry), Neuraminidase (genetics), Neuraminidase (metabolism), Oseltamivir (metabolism), Protein Binding, Thermodynamics, Water (chemistry).
- MESH :
- chemical , chemistry : Neuraminidase, Water.
- chemical , genetics : Neuraminidase.
- chemical , metabolism : Antiviral Agents, Neuraminidase, Oseltamivir.
- enzymology : Influenza A Virus, H1N1 Subtype, Influenza A Virus, H2N2 Subtype, Influenza A Virus, H5N1 Subtype, Influenza A virus.
- Catalytic Domain, Enzyme Stability, Molecular Dynamics Simulation, Mutation, Protein Binding, Thermodynamics.
Abstract
Tamiflu, also known as oseltamivir (OTV), binds to influenza A neuraminidase (H5N1) with very high affinity (0.32 nM). However, this inhibitor binds to other neuraminidases as well. In the present work, a systematic computational study is performed to investigate the mechanism underlying the binding of oseltamivir to N8 neuraminidase (NA) in "open" and "closed" conformations of the 150-loop through molecular dynamics simulations and the popular and well established molecular mechanics Poisson-Boltzmann (MM-PBSA) free energy calculation method. Whereas the closed conformation is stable for wild type N8, it transforms into the open conformation for the mutants Y252H, H274Y, and R292K, indicating that bound to oseltamivir these mutants are preferentially in the open conformation. Our calculations show that the binding of wild type oseltamivir to the closed conformation of N8 neuraminidase is energetically favored compared to the binding to the open conformation. We observe water mediated binding of oseltamivir to the N8 neuraminidase in both conformations which is not seen in the case of binding of the same drug to the H5N1 neuraminidase. The decomposition of the binding free energy reveals the mechanisms underlying the binding and changes in affinity due to mutations. Considering the mutant N8 variants in the open conformation adopted during the simulations, we observe a significant loss in the size of the total binding free energy for the N8(Y252H)-OTV, N8(H274Y)-OTV, and N8(R292K)-OTV complexes compared to N8(WT)-OTV, mainly due to the decrease in the size of the intermolecular electrostatic energy. For R292K, an unfavorable shift in the van der Waals interactions also contributes to the drug resistance. The mutations cause a significant expansion in the active site cavity, increasing its solvent accessible surface compared to the crystal structures of both the open and closed conformations. Our study underscores the need to consider dynamics in rationalizing the structure-function relationships of various antiviral inhibitor-NA complexes.
DOI: 10.1021/jp3022612
PubMed: 22553951
Links to Exploration step
pubmed:22553951Le document en format XML
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B</title><idno type="eISSN">1520-5207</idno><imprint><date when="2012" type="published">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antiviral Agents (metabolism)</term><term>Catalytic Domain</term><term>Enzyme Stability</term><term>Influenza A Virus, H1N1 Subtype (enzymology)</term><term>Influenza A Virus, H2N2 Subtype (enzymology)</term><term>Influenza A Virus, H5N1 Subtype (enzymology)</term><term>Influenza A virus (enzymology)</term><term>Molecular Dynamics Simulation</term><term>Mutation</term><term>Neuraminidase (chemistry)</term><term>Neuraminidase (genetics)</term><term>Neuraminidase (metabolism)</term><term>Oseltamivir (metabolism)</term><term>Protein Binding</term><term>Thermodynamics</term><term>Water (chemistry)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Neuraminidase</term><term>Water</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Neuraminidase</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Antiviral Agents</term><term>Neuraminidase</term><term>Oseltamivir</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Influenza A Virus, H1N1 Subtype</term><term>Influenza A Virus, H2N2 Subtype</term><term>Influenza A Virus, H5N1 Subtype</term><term>Influenza A virus</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Catalytic Domain</term><term>Enzyme Stability</term><term>Molecular Dynamics Simulation</term><term>Mutation</term><term>Protein Binding</term><term>Thermodynamics</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Tamiflu, also known as oseltamivir (OTV), binds to influenza A neuraminidase (H5N1) with very high affinity (0.32 nM). However, this inhibitor binds to other neuraminidases as well. In the present work, a systematic computational study is performed to investigate the mechanism underlying the binding of oseltamivir to N8 neuraminidase (NA) in "open" and "closed" conformations of the 150-loop through molecular dynamics simulations and the popular and well established molecular mechanics Poisson-Boltzmann (MM-PBSA) free energy calculation method. Whereas the closed conformation is stable for wild type N8, it transforms into the open conformation for the mutants Y252H, H274Y, and R292K, indicating that bound to oseltamivir these mutants are preferentially in the open conformation. Our calculations show that the binding of wild type oseltamivir to the closed conformation of N8 neuraminidase is energetically favored compared to the binding to the open conformation. We observe water mediated binding of oseltamivir to the N8 neuraminidase in both conformations which is not seen in the case of binding of the same drug to the H5N1 neuraminidase. The decomposition of the binding free energy reveals the mechanisms underlying the binding and changes in affinity due to mutations. Considering the mutant N8 variants in the open conformation adopted during the simulations, we observe a significant loss in the size of the total binding free energy for the N8(Y252H)-OTV, N8(H274Y)-OTV, and N8(R292K)-OTV complexes compared to N8(WT)-OTV, mainly due to the decrease in the size of the intermolecular electrostatic energy. For R292K, an unfavorable shift in the van der Waals interactions also contributes to the drug resistance. The mutations cause a significant expansion in the active site cavity, increasing its solvent accessible surface compared to the crystal structures of both the open and closed conformations. Our study underscores the need to consider dynamics in rationalizing the structure-function relationships of various antiviral inhibitor-NA complexes.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">22553951</PMID><DateCompleted><Year>2012</Year><Month>09</Month><Day>21</Day></DateCompleted><DateRevised><Year>2013</Year><Month>11</Month><Day>21</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1520-5207</ISSN><JournalIssue CitedMedium="Internet"><Volume>116</Volume><Issue>21</Issue><PubDate><Year>2012</Year><Month>May</Month><Day>31</Day></PubDate></JournalIssue><Title>The journal of physical chemistry. B</Title><ISOAbbreviation>J Phys Chem B</ISOAbbreviation></Journal><ArticleTitle>Mutation-induced loop opening and energetics for binding of tamiflu to influenza N8 neuraminidase.</ArticleTitle><Pagination><MedlinePgn>6137-49</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1021/jp3022612</ELocationID><Abstract><AbstractText>Tamiflu, also known as oseltamivir (OTV), binds to influenza A neuraminidase (H5N1) with very high affinity (0.32 nM). However, this inhibitor binds to other neuraminidases as well. In the present work, a systematic computational study is performed to investigate the mechanism underlying the binding of oseltamivir to N8 neuraminidase (NA) in "open" and "closed" conformations of the 150-loop through molecular dynamics simulations and the popular and well established molecular mechanics Poisson-Boltzmann (MM-PBSA) free energy calculation method. Whereas the closed conformation is stable for wild type N8, it transforms into the open conformation for the mutants Y252H, H274Y, and R292K, indicating that bound to oseltamivir these mutants are preferentially in the open conformation. Our calculations show that the binding of wild type oseltamivir to the closed conformation of N8 neuraminidase is energetically favored compared to the binding to the open conformation. We observe water mediated binding of oseltamivir to the N8 neuraminidase in both conformations which is not seen in the case of binding of the same drug to the H5N1 neuraminidase. The decomposition of the binding free energy reveals the mechanisms underlying the binding and changes in affinity due to mutations. Considering the mutant N8 variants in the open conformation adopted during the simulations, we observe a significant loss in the size of the total binding free energy for the N8(Y252H)-OTV, N8(H274Y)-OTV, and N8(R292K)-OTV complexes compared to N8(WT)-OTV, mainly due to the decrease in the size of the intermolecular electrostatic energy. For R292K, an unfavorable shift in the van der Waals interactions also contributes to the drug resistance. The mutations cause a significant expansion in the active site cavity, increasing its solvent accessible surface compared to the crystal structures of both the open and closed conformations. Our study underscores the need to consider dynamics in rationalizing the structure-function relationships of various antiviral inhibitor-NA complexes.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Kar</LastName><ForeName>Parimal</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Department of Theory and Bio-Systems, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Knecht</LastName><ForeName>Volker</ForeName><Initials>V</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2012</Year><Month>05</Month><Day>17</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>J Phys Chem B</MedlineTA><NlmUniqueID>101157530</NlmUniqueID><ISSNLinking>1520-5207</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000998">Antiviral Agents</NameOfSubstance></Chemical><Chemical><RegistryNumber>059QF0KO0R</RegistryNumber><NameOfSubstance UI="D014867">Water</NameOfSubstance></Chemical><Chemical><RegistryNumber>20O93L6F9H</RegistryNumber><NameOfSubstance UI="D053139">Oseltamivir</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 3.2.1.18</RegistryNumber><NameOfSubstance UI="D009439">Neuraminidase</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000998" MajorTopicYN="N">Antiviral Agents</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D020134" MajorTopicYN="N">Catalytic Domain</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004795" MajorTopicYN="N">Enzyme Stability</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D053118" MajorTopicYN="N">Influenza A Virus, H1N1 Subtype</DescriptorName><QualifierName UI="Q000201" MajorTopicYN="N">enzymology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D053121" MajorTopicYN="N">Influenza A Virus, H2N2 Subtype</DescriptorName><QualifierName UI="Q000201" MajorTopicYN="N">enzymology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D053124" MajorTopicYN="N">Influenza A Virus, H5N1 Subtype</DescriptorName><QualifierName UI="Q000201" MajorTopicYN="N">enzymology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D009980" MajorTopicYN="N">Influenza A virus</DescriptorName><QualifierName UI="Q000201" MajorTopicYN="Y">enzymology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D056004" MajorTopicYN="Y">Molecular Dynamics Simulation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D009154" MajorTopicYN="Y">Mutation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D009439" MajorTopicYN="N">Neuraminidase</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="Y">chemistry</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D053139" MajorTopicYN="N">Oseltamivir</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D011485" MajorTopicYN="N">Protein Binding</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D013816" MajorTopicYN="N">Thermodynamics</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D014867" MajorTopicYN="N">Water</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="entrez"><Year>2012</Year><Month>5</Month><Day>5</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2012</Year><Month>5</Month><Day>5</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2012</Year><Month>9</Month><Day>22</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">22553951</ArticleId><ArticleId IdType="doi">10.1021/jp3022612</ArticleId></ArticleIdList></PubmedData></pubmed></record>Pour manipuler ce document sous Unix (Dilib)
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