How an Inhibitor Bound to Subunit Interface Alters Triosephosphate Isomerase Dynamics

dc.contributor.authorAkdoğan, Ebru Demet
dc.contributor.authorFındık, Doğa
dc.contributor.authorAkdoğan, Ebru Demet
dc.contributor.authorDoruker, Pemra
dc.date.accessioned2019-06-27T08:02:13Z
dc.date.available2019-06-27T08:02:13Z
dc.date.issued2015
dc.departmentFakülteler, Mühendislik ve Doğa Bilimleri Fakültesi, Biyoinformatik ve Genetik Bölümüen_US
dc.description.abstractThe tunnel region at triosephosphate isomerase (TIM)'s dimer interface distant from its catalytic site is a target site for certain benzothiazole derivatives that inhibit TIM's catalytic activity in Trypanosoma cruzi the parasite that causes Chagas disease. We performed multiple 100-ns molecular-dynamics (MD) simulations and elastic network modeling (ENM) on both apo and complex structures to shed light on the still unclear inhibitory mechanism of one such inhibitor named bt10. Within the time frame of our MD simulations we observed stabilization of aromatic clusters at the dimer interface and enhancement of intersubunit hydrogen bonds in the presence of bt10 which point to an allosteric effect rather than destabilization of the dimeric structure. The collective dynamics dictated by the topology of TIM is known to facilitate the closure of its catalytic loop over the active site that is critical for substrate entrance and product release. We incorporated the ligand's effect on vibrational dynamics by applying mixed coarse-grained ENM to each one of 54000 MD snapshots. Using this computationally efficient technique we observed altered collective modes and positive shifts in eigenvalues due to the constraining effect of bt10 binding. Accordingly we observed allosteric changes in the catalytic loop's dynamics flexibility and correlations as well as the solvent exposure of catalytic residues. A newly (to our knowledge) introduced technique that performs residue-based ENM scanning of TIM revealed the tunnel region as a key binding site that can alter global dynamics of the enzyme.en_US]
dc.identifier.citation24
dc.identifier.doi10.1016/j.bpj.2015.06.031en_US
dc.identifier.endpage1178
dc.identifier.issn0006-3495en_US
dc.identifier.issn1542-0086en_US
dc.identifier.issn0006-3495
dc.identifier.issn1542-0086
dc.identifier.issue6
dc.identifier.pmid26190635en_US
dc.identifier.scopus2-s2.0-84941807856en_US
dc.identifier.scopusqualityQ1
dc.identifier.startpage1169en_US
dc.identifier.urihttps://hdl.handle.net/20.500.12469/573
dc.identifier.urihttps://doi.org/10.1016/j.bpj.2015.06.031
dc.identifier.volume109en_US
dc.identifier.wosWOS:000361565400013en_US
dc.identifier.wosqualityQ2
dc.institutionauthorAkdoğan, Ebru Demeten_US
dc.language.isoenen_US
dc.publisherCell Pressen_US
dc.relation.journalBiophysical Journalen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.titleHow an Inhibitor Bound to Subunit Interface Alters Triosephosphate Isomerase Dynamicsen_US
dc.typeArticleen_US
dspace.entity.typePublication
relation.isAuthorOfPublication558d2b8e-c713-49e0-9350-d354abb5cd69
relation.isAuthorOfPublication.latestForDiscovery558d2b8e-c713-49e0-9350-d354abb5cd69

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