Radical Stabilization Energies for Enzyme Engineering: Tackling the Substrate Scope of the Radical Enzyme QueE.
Identifieur interne : 000213 ( Main/Exploration ); précédent : 000212; suivant : 000214Radical Stabilization Energies for Enzyme Engineering: Tackling the Substrate Scope of the Radical Enzyme QueE.
Auteurs : Christian J. Suess [Royaume-Uni] ; Floriane L. Martins [Royaume-Uni] ; Anna K. Croft [Royaume-Uni] ; Christof M. J Ger [Royaume-Uni]Source :
- Journal of chemical information and modeling [ 1549-960X ] ; 2019.
Descripteurs français
- KwdFr :
- MESH :
- composition chimique : Carbon-nitrogen lyases.
- génétique : Carbon-nitrogen lyases.
- métabolisme : Carbon-nitrogen lyases, Métaux.
- Conformation des protéines, Ingénierie des protéines, Simulation de dynamique moléculaire.
English descriptors
- KwdEn :
- MESH :
- chemical , chemistry : Carbon-Nitrogen Lyases.
- chemical , genetics : Carbon-Nitrogen Lyases.
- chemical , metabolism : Carbon-Nitrogen Lyases, Metals.
- Molecular Dynamics Simulation, Protein Conformation, Protein Engineering.
Abstract
Experimental assessment of catalytic reaction mechanisms and profiles of radical enzymes can be severely challenging due to the reactive nature of the intermediates and sensitivity of cofactors such as iron-sulfur clusters. Here, we present an enzyme-directed computational methodology for the assessment of thermodynamic reaction profiles and screening for radical stabilization energies (RSEs) for the assessment of catalytic turnovers in radical enzymes. We have applied this new screening method to the radical S-adenosylmethione enzyme 7-carboxy-7-deazaguanine synthase (QueE), following a detailed molecular dynamics (MD) analysis that clarifies the role of both specific enzyme residues and bound Mg2+, Ca2+, or Na+. The MD simulations provided the basis for a statistical approach to sample different conformational outcomes. RSE calculation at the M06-2X/6-31+G* level of theory provided the most computationally cost-effective assessment of enzyme-based energies, facilitated by an initial triage using semiempirical methods. The impact of intermolecular interactions on RSE was clearly established, and application to the assessment of potential alternative substrates (focusing on radical clock type rearrangements) proposes a selection of carbon-substituted analogues that would react to afford cyclopropylcarbinyl radical intermediates as candidates for catalytic turnover by QueE.
DOI: 10.1021/acs.jcim.9b00017
PubMed: 31730347
Affiliations:
Links toward previous steps (curation, corpus...)
Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Radical Stabilization Energies for Enzyme Engineering: Tackling the Substrate Scope of the Radical Enzyme QueE.</title><author><name sortKey="Suess, Christian J" sort="Suess, Christian J" uniqKey="Suess C" first="Christian J" last="Suess">Christian J. Suess</name><affiliation wicri:level="1"><nlm:affiliation>Department of Chemical and Environmental Engineering , The University of Nottingham , University Park, Nottingham NG7 2RD , United Kingdom.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Chemical and Environmental Engineering , The University of Nottingham , University Park, Nottingham NG7 2RD </wicri:regionArea><wicri:noRegion>Nottingham NG7 2RD </wicri:noRegion></affiliation></author><author><name sortKey="Martins, Floriane L" sort="Martins, Floriane L" uniqKey="Martins F" first="Floriane L" last="Martins">Floriane L. Martins</name><affiliation wicri:level="1"><nlm:affiliation>Department of Chemical and Environmental Engineering , The University of Nottingham , University Park, Nottingham NG7 2RD , United Kingdom.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Chemical and Environmental Engineering , The University of Nottingham , University Park, Nottingham NG7 2RD </wicri:regionArea><wicri:noRegion>Nottingham NG7 2RD </wicri:noRegion></affiliation></author><author><name sortKey="Croft, Anna K" sort="Croft, Anna K" uniqKey="Croft A" first="Anna K" last="Croft">Anna K. Croft</name><affiliation wicri:level="1"><nlm:affiliation>Department of Chemical and Environmental Engineering , The University of Nottingham , University Park, Nottingham NG7 2RD , United Kingdom.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Chemical and Environmental Engineering , The University of Nottingham , University Park, Nottingham NG7 2RD </wicri:regionArea><wicri:noRegion>Nottingham NG7 2RD </wicri:noRegion></affiliation></author><author><name sortKey="J Ger, Christof M" sort="J Ger, Christof M" uniqKey="J Ger C" first="Christof M" last="J Ger">Christof M. J Ger</name><affiliation wicri:level="1"><nlm:affiliation>Department of Chemical and Environmental Engineering , The University of Nottingham , University Park, Nottingham NG7 2RD , United Kingdom.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Chemical and Environmental Engineering , The University of Nottingham , University Park, Nottingham NG7 2RD </wicri:regionArea><wicri:noRegion>Nottingham NG7 2RD </wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2019">2019</date><idno type="RBID">pubmed:31730347</idno><idno type="pmid">31730347</idno><idno type="doi">10.1021/acs.jcim.9b00017</idno><idno type="wicri:Area/Main/Corpus">000196</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Corpus" wicri:corpus="PubMed">000196</idno><idno type="wicri:Area/Main/Curation">000196</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Curation">000196</idno><idno type="wicri:Area/Main/Exploration">000196</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Radical Stabilization Energies for Enzyme Engineering: Tackling the Substrate Scope of the Radical Enzyme QueE.</title><author><name sortKey="Suess, Christian J" sort="Suess, Christian J" uniqKey="Suess C" first="Christian J" last="Suess">Christian J. Suess</name><affiliation wicri:level="1"><nlm:affiliation>Department of Chemical and Environmental Engineering , The University of Nottingham , University Park, Nottingham NG7 2RD , United Kingdom.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Chemical and Environmental Engineering , The University of Nottingham , University Park, Nottingham NG7 2RD </wicri:regionArea><wicri:noRegion>Nottingham NG7 2RD </wicri:noRegion></affiliation></author><author><name sortKey="Martins, Floriane L" sort="Martins, Floriane L" uniqKey="Martins F" first="Floriane L" last="Martins">Floriane L. Martins</name><affiliation wicri:level="1"><nlm:affiliation>Department of Chemical and Environmental Engineering , The University of Nottingham , University Park, Nottingham NG7 2RD , United Kingdom.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Chemical and Environmental Engineering , The University of Nottingham , University Park, Nottingham NG7 2RD </wicri:regionArea><wicri:noRegion>Nottingham NG7 2RD </wicri:noRegion></affiliation></author><author><name sortKey="Croft, Anna K" sort="Croft, Anna K" uniqKey="Croft A" first="Anna K" last="Croft">Anna K. Croft</name><affiliation wicri:level="1"><nlm:affiliation>Department of Chemical and Environmental Engineering , The University of Nottingham , University Park, Nottingham NG7 2RD , United Kingdom.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Chemical and Environmental Engineering , The University of Nottingham , University Park, Nottingham NG7 2RD </wicri:regionArea><wicri:noRegion>Nottingham NG7 2RD </wicri:noRegion></affiliation></author><author><name sortKey="J Ger, Christof M" sort="J Ger, Christof M" uniqKey="J Ger C" first="Christof M" last="J Ger">Christof M. J Ger</name><affiliation wicri:level="1"><nlm:affiliation>Department of Chemical and Environmental Engineering , The University of Nottingham , University Park, Nottingham NG7 2RD , United Kingdom.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Chemical and Environmental Engineering , The University of Nottingham , University Park, Nottingham NG7 2RD </wicri:regionArea><wicri:noRegion>Nottingham NG7 2RD </wicri:noRegion></affiliation></author></analytic><series><title level="j">Journal of chemical information and modeling</title><idno type="eISSN">1549-960X</idno><imprint><date when="2019" type="published">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Carbon-Nitrogen Lyases (chemistry)</term><term>Carbon-Nitrogen Lyases (genetics)</term><term>Carbon-Nitrogen Lyases (metabolism)</term><term>Metals (metabolism)</term><term>Molecular Dynamics Simulation (MeSH)</term><term>Protein Conformation (MeSH)</term><term>Protein Engineering (MeSH)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Carbon-nitrogen lyases (composition chimique)</term><term>Carbon-nitrogen lyases (génétique)</term><term>Carbon-nitrogen lyases (métabolisme)</term><term>Conformation des protéines (MeSH)</term><term>Ingénierie des protéines (MeSH)</term><term>Métaux (métabolisme)</term><term>Simulation de dynamique moléculaire (MeSH)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Carbon-Nitrogen Lyases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Carbon-Nitrogen Lyases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Carbon-Nitrogen Lyases</term><term>Metals</term></keywords><keywords scheme="MESH" qualifier="composition chimique" xml:lang="fr"><term>Carbon-nitrogen lyases</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Carbon-nitrogen lyases</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Carbon-nitrogen lyases</term><term>Métaux</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Molecular Dynamics Simulation</term><term>Protein Conformation</term><term>Protein Engineering</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Conformation des protéines</term><term>Ingénierie des protéines</term><term>Simulation de dynamique moléculaire</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Experimental assessment of catalytic reaction mechanisms and profiles of radical enzymes can be severely challenging due to the reactive nature of the intermediates and sensitivity of cofactors such as iron-sulfur clusters. Here, we present an enzyme-directed computational methodology for the assessment of thermodynamic reaction profiles and screening for radical stabilization energies (RSEs) for the assessment of catalytic turnovers in radical enzymes. We have applied this new screening method to the radical <i>S</i>-adenosylmethione enzyme 7-carboxy-7-deazaguanine synthase (QueE), following a detailed molecular dynamics (MD) analysis that clarifies the role of both specific enzyme residues and bound Mg<sup>2+</sup>, Ca<sup>2+</sup>, or Na<sup>+</sup>. The MD simulations provided the basis for a statistical approach to sample different conformational outcomes. RSE calculation at the M06-2X/6-31+G* level of theory provided the most computationally cost-effective assessment of enzyme-based energies, facilitated by an initial triage using semiempirical methods. The impact of intermolecular interactions on RSE was clearly established, and application to the assessment of potential alternative substrates (focusing on radical clock type rearrangements) proposes a selection of carbon-substituted analogues that would react to afford cyclopropylcarbinyl radical intermediates as candidates for catalytic turnover by QueE.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">31730347</PMID><DateCompleted><Year>2020</Year><Month>09</Month><Day>28</Day></DateCompleted><DateRevised><Year>2020</Year><Month>09</Month><Day>28</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1549-960X</ISSN><JournalIssue CitedMedium="Internet"><Volume>59</Volume><Issue>12</Issue><PubDate><Year>2019</Year><Month>12</Month><Day>23</Day></PubDate></JournalIssue><Title>Journal of chemical information and modeling</Title><ISOAbbreviation>J Chem Inf Model</ISOAbbreviation></Journal><ArticleTitle>Radical Stabilization Energies for Enzyme Engineering: Tackling the Substrate Scope of the Radical Enzyme QueE.</ArticleTitle><Pagination><MedlinePgn>5111-5125</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1021/acs.jcim.9b00017</ELocationID><Abstract><AbstractText>Experimental assessment of catalytic reaction mechanisms and profiles of radical enzymes can be severely challenging due to the reactive nature of the intermediates and sensitivity of cofactors such as iron-sulfur clusters. Here, we present an enzyme-directed computational methodology for the assessment of thermodynamic reaction profiles and screening for radical stabilization energies (RSEs) for the assessment of catalytic turnovers in radical enzymes. We have applied this new screening method to the radical <i>S</i>-adenosylmethione enzyme 7-carboxy-7-deazaguanine synthase (QueE), following a detailed molecular dynamics (MD) analysis that clarifies the role of both specific enzyme residues and bound Mg<sup>2+</sup>, Ca<sup>2+</sup>, or Na<sup>+</sup>. The MD simulations provided the basis for a statistical approach to sample different conformational outcomes. RSE calculation at the M06-2X/6-31+G* level of theory provided the most computationally cost-effective assessment of enzyme-based energies, facilitated by an initial triage using semiempirical methods. The impact of intermolecular interactions on RSE was clearly established, and application to the assessment of potential alternative substrates (focusing on radical clock type rearrangements) proposes a selection of carbon-substituted analogues that would react to afford cyclopropylcarbinyl radical intermediates as candidates for catalytic turnover by QueE.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Suess</LastName><ForeName>Christian J</ForeName><Initials>CJ</Initials><AffiliationInfo><Affiliation>Department of Chemical and Environmental Engineering , The University of Nottingham , University Park, Nottingham NG7 2RD , United Kingdom.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Martins</LastName><ForeName>Floriane L</ForeName><Initials>FL</Initials><AffiliationInfo><Affiliation>Department of Chemical and Environmental Engineering , The University of Nottingham , University Park, Nottingham NG7 2RD , United Kingdom.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Croft</LastName><ForeName>Anna K</ForeName><Initials>AK</Initials><Identifier Source="ORCID">0000-0001-5330-150X</Identifier><AffiliationInfo><Affiliation>Department of Chemical and Environmental Engineering , The University of Nottingham , University Park, Nottingham NG7 2RD , United Kingdom.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Jäger</LastName><ForeName>Christof M</ForeName><Initials>CM</Initials><Identifier Source="ORCID">0000-0002-1802-1892</Identifier><AffiliationInfo><Affiliation>Department of Chemical and Environmental Engineering , The University of Nottingham , University Park, Nottingham NG7 2RD , United Kingdom.</Affiliation></AffiliationInfo></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>2019</Year><Month>12</Month><Day>03</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>J Chem Inf Model</MedlineTA><NlmUniqueID>101230060</NlmUniqueID><ISSNLinking>1549-9596</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D008670">Metals</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 4.3.-</RegistryNumber><NameOfSubstance UI="D019759">Carbon-Nitrogen Lyases</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D019759" MajorTopicYN="N">Carbon-Nitrogen Lyases</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008670" MajorTopicYN="N">Metals</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D056004" MajorTopicYN="Y">Molecular Dynamics Simulation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D011487" MajorTopicYN="N">Protein Conformation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D015202" MajorTopicYN="Y">Protein Engineering</DescriptorName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2019</Year><Month>11</Month><Day>16</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2020</Year><Month>9</Month><Day>29</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2019</Year><Month>11</Month><Day>16</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">31730347</ArticleId><ArticleId IdType="doi">10.1021/acs.jcim.9b00017</ArticleId></ArticleIdList></PubmedData></pubmed><affiliations><list><country><li>Royaume-Uni</li></country></list><tree><country name="Royaume-Uni"><noRegion><name sortKey="Suess, Christian J" sort="Suess, Christian J" uniqKey="Suess C" first="Christian J" last="Suess">Christian J. Suess</name></noRegion><name sortKey="Croft, Anna K" sort="Croft, Anna K" uniqKey="Croft A" first="Anna K" last="Croft">Anna K. Croft</name><name sortKey="J Ger, Christof M" sort="J Ger, Christof M" uniqKey="J Ger C" first="Christof M" last="J Ger">Christof M. J Ger</name><name sortKey="Martins, Floriane L" sort="Martins, Floriane L" uniqKey="Martins F" first="Floriane L" last="Martins">Floriane L. Martins</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Bois/explor/IronSulferCluV1/Data/Main/Exploration
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000213 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd -nk 000213 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Bois
|area= IronSulferCluV1
|flux= Main
|étape= Exploration
|type= RBID
|clé= pubmed:31730347
|texte= Radical Stabilization Energies for Enzyme Engineering: Tackling the Substrate Scope of the Radical Enzyme QueE.
}}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Main/Exploration/RBID.i -Sk "pubmed:31730347" \
| HfdSelect -Kh $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd \
| NlmPubMed2Wicri -a IronSulferCluV1
| This area was generated with Dilib version V0.6.38. |  |