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Computational predictions of volatile anesthetic interactions with the microtubule cytoskeleton: implications for side effects of general anesthesia

2012-06Journal article Open access
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dc.contributor.authorCraddock, Travis J. A.
dc.contributor.authorGeorge, Marc St.
dc.contributor.authorFreedman, Holly
dc.contributor.authorBarakat, Khaled H.
dc.contributor.authorDamaraju, Sambasivarao
dc.contributor.authorHameroff, Stuart
dc.contributor.authorTuszynski, Jack A.
dc.date.accessioned2018-12-07T14:57:58Z
dc.date.available2018-12-07T14:57:58Z
dc.date.issued2012-06
dc.description.abstractThe cytoskeleton is essential to cell morphology, cargo trafficking, and cell division. As the neuronal cytoskeleton is extremely complex, it is no wonder that a startling number of neurodegenerative disorders (including but not limited to Alzheimer's disease, Parkinson's disease and Huntington's disease) share the common feature of a dysfunctional neuronal cytoskeleton. Recently, concern has been raised about a possible link between anesthesia, post-operative cognitive dysfunction, and the exacerbation of neurodegenerative disorders. Experimental investigations suggest that anesthetics bind to and affect cytoskeletal microtubules, and that anesthesia-related cognitive dysfunction involves microtubule instability, hyper-phosphorylation of the microtubule-associated protein tau, and tau separation from microtubules. However, exact mechanisms are yet to be identified. In this paper the interaction of anesthetics with the microtubule subunit protein tubulin is investigated using computer-modeling methods. Homology modeling, molecular dynamics simulations and surface geometry techniques were used to determine putative binding sites for volatile anesthetics on tubulin. This was followed by free energy based docking calculations for halothane (2-bromo-2-chloro-1,1,1-trifluoroethane) on the tubulin body, and C-terminal regions for specific tubulin isotypes. Locations of the putative binding sites, halothane binding energies and the relation to cytoskeleton function are reported in this paper.
dc.description.sponsorshipNSERC (Natural Sciences and Engineering Research Council); Alberta Cancer Foundation [23783]; Alberta Advanced Education and Technology [TC-LSI-08-09]; Allard Foundation [23676]; Portuguese Foundation for Science and Technology (FCT)
dc.description.versioninfo:eu-repo/semantics/publishedVersion
dc.identifier.doi10.1371/journal.pone.0037251
dc.identifier.issn1932-6203
dc.identifier.urihttp://hdl.handle.net/10400.1/11794
dc.language.isoeng
dc.peerreviewedyes
dc.publisherPublic Library of Science
dc.relationStrategic Clean Technology Policies for Climate Change
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectCentral-nervous-system
dc.subjectAlpha-Beta-Tubulin
dc.subjectRat-Brain Proteins
dc.subjectMolecular-dynamics
dc.subjectInhaled anesthetics
dc.subjectBinding-sites
dc.subjectSevoflurane anesthesia
dc.subjectHippocampal-neurons
dc.subjectCognitive decline
dc.subjectHalothane binding
dc.titleComputational predictions of volatile anesthetic interactions with the microtubule cytoskeleton: implications for side effects of general anesthesia
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleStrategic Clean Technology Policies for Climate Change
oaire.awardURIinfo:eu-repo/grantAgreement/EC/FP7/623783/EU
oaire.citation.endPage10
oaire.citation.issue6
oaire.citation.startPage1
oaire.citation.titlePLoS ONE
oaire.citation.volume7
oaire.fundingStreamFP7
project.funder.identifierhttp://doi.org/10.13039/501100008530
project.funder.nameEuropean Commission
rcaap.rightsopenAccess
rcaap.typearticle
relation.isProjectOfPublicationc4e65272-fbae-452c-b932-985db4301b45
relation.isProjectOfPublication.latestForDiscoveryc4e65272-fbae-452c-b932-985db4301b45

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