DC FieldValueLanguage
dc.contributor.authorHezaveh, Samira-
dc.contributor.authorZeng, An-Ping-
dc.contributor.authorJandt, Uwe-
dc.date.accessioned2019-05-02T13:31:40Z-
dc.date.available2019-05-02T13:31:40Z-
dc.date.issued2018-02-
dc.identifier.citationJournal of chemical information and modeling 2 (58): 362-369 (2018)de_DE
dc.identifier.issn1549-9596de_DE
dc.identifier.urihttp://hdl.handle.net/11420/2591-
dc.description.abstractThe pyruvate dehydrogenase complex (PDC) is a large macromolecular machine consisting of dozens of interacting enzymes that are connected and regulated by highly flexible domains, also called swinging arms. The overall structure and function of these domains and how they organize the complex function have not been elucidated in detail to date. This lack of structural and dynamic understanding is frequently observed in multidomain enzymatic complexes. Here we present the first full and dynamic structural model of full human PDC (hPDC), including binding of the linking arms to the surrounding E1 and E3 enzymes via their binding domains with variable stoichiometries. All of the linking domains were modeled at atomistic and coarse-grained levels, and the latter was parametrized to reproduce the same properties of those from the atomistic model. The radii of gyration of the wild-type full complex and functional trimeric subunits were in agreement with available experimental data. Furthermore, the E1 and E3 population effect on the overall structure of the full complex was studied. The results indicated that decreasing the number of E1s increases the flexibility of the now nonoccupied arms. Furthermore, their flexibility depends on the presence of other E1s and E3s in the vicinity, even if they are associated with other arms. As one consequence, the radius of gyration decreases with decreasing number of E1s. This effect also provides an indication of the optimal configuration of E1 and E3 on the basis of the assumption that a certain stability of the enymatic cloud is necessary to avoid free metabolic diffusion of intermediates (metabolic channeling). Our approach and results open a window for future enzyme engineering in a more effective way by evaluating the effect of different linker arm lengths, flexibilities, and combinations of mutations on the activity of other complex enzymes that involve flexible domains, including for example processive enzymes.en
dc.language.isoende_DE
dc.relation.ispartofJournal of chemical information and modelingde_DE
dc.subjectBiopolymersde_DE
dc.subjectCatalytic Domainde_DE
dc.subjectHumansde_DE
dc.subjectMultienzyme Complexesde_DE
dc.subjectProtein Bindingde_DE
dc.subjectPyruvate Dehydrogenase Complexde_DE
dc.subjectMolecular Dynamics Simulationde_DE
dc.titleFull enzyme complex simulation: interactions in human pyruvate dehydrogenase complexde_DE
dc.typeArticlede_DE
dc.type.diniarticle-
dcterms.DCMITypeText-
tuhh.abstract.englishThe pyruvate dehydrogenase complex (PDC) is a large macromolecular machine consisting of dozens of interacting enzymes that are connected and regulated by highly flexible domains, also called swinging arms. The overall structure and function of these domains and how they organize the complex function have not been elucidated in detail to date. This lack of structural and dynamic understanding is frequently observed in multidomain enzymatic complexes. Here we present the first full and dynamic structural model of full human PDC (hPDC), including binding of the linking arms to the surrounding E1 and E3 enzymes via their binding domains with variable stoichiometries. All of the linking domains were modeled at atomistic and coarse-grained levels, and the latter was parametrized to reproduce the same properties of those from the atomistic model. The radii of gyration of the wild-type full complex and functional trimeric subunits were in agreement with available experimental data. Furthermore, the E1 and E3 population effect on the overall structure of the full complex was studied. The results indicated that decreasing the number of E1s increases the flexibility of the now nonoccupied arms. Furthermore, their flexibility depends on the presence of other E1s and E3s in the vicinity, even if they are associated with other arms. As one consequence, the radius of gyration decreases with decreasing number of E1s. This effect also provides an indication of the optimal configuration of E1 and E3 on the basis of the assumption that a certain stability of the enymatic cloud is necessary to avoid free metabolic diffusion of intermediates (metabolic channeling). Our approach and results open a window for future enzyme engineering in a more effective way by evaluating the effect of different linker arm lengths, flexibilities, and combinations of mutations on the activity of other complex enzymes that involve flexible domains, including for example processive enzymes.de_DE
tuhh.publisher.doi10.1021/acs.jcim.7b00557-
tuhh.publication.instituteBioprozess- und Biosystemtechnik V-1de_DE
tuhh.type.opus(wissenschaftlicher) Artikel-
tuhh.institute.germanBioprozess- und Biosystemtechnik V-1de
tuhh.institute.englishBioprozess- und Biosystemtechnik V-1de_DE
tuhh.gvk.hasppnfalse-
dc.type.driverarticle-
dc.type.casraiJournal Article-
tuhh.container.issue2de_DE
tuhh.container.volume58de_DE
tuhh.container.startpage362de_DE
tuhh.container.endpage369de_DE
dc.relation.projectEnzymAgglo - Multiskalige modellgestützte Untersuchungen der Formation von katalytisch aktiven Clustern und Agglomeraten großer Multienzymkomplexe-
item.languageiso639-1en-
item.fulltextNo Fulltext-
item.openairetypeArticle-
item.grantfulltextnone-
item.creatorOrcidHezaveh, Samira-
item.creatorOrcidZeng, An-Ping-
item.creatorOrcidJandt, Uwe-
item.openairecristypehttp://purl.org/coar/resource_type/c_6501-
item.creatorGNDHezaveh, Samira-
item.creatorGNDZeng, An-Ping-
item.creatorGNDJandt, Uwe-
item.cerifentitytypePublications-
crisitem.project.funderDeutsche Forschungsgemeinschaft (DFG)-
crisitem.project.funderid501100001659-
crisitem.project.funderrorid018mejw64-
crisitem.project.grantnoDFG-
crisitem.author.deptBioprozess- und Biosystemtechnik V-1-
crisitem.author.deptBioprozess- und Biosystemtechnik V-1-
crisitem.author.deptBioprozess- und Biosystemtechnik V-1-
crisitem.author.orcid0000-0003-2910-2230-
crisitem.author.orcid0000-0001-9768-7096-
crisitem.author.orcid0000-0001-8221-5176-
crisitem.author.parentorgStudiendekanat Verfahrenstechnik-
crisitem.author.parentorgStudiendekanat Verfahrenstechnik-
crisitem.author.parentorgStudiendekanat Verfahrenstechnik-
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