A new paradigm for voltage-clamp studies of synthetic ion channels

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dc.contributor.authorChui, Jonathan Ka Wang
dc.contributor.supervisorFyles, Thomas M.
dc.date.accessioned2011-08-24T22:55:58Z
dc.date.available2011-08-24T22:55:58Z
dc.date.copyright2011en_US
dc.date.issued2011-08-24
dc.degree.departmentDepartment of Chemistry
dc.degree.levelDoctor of Philosophy Ph.D.en_US
dc.description.abstractTwo classes of ion-channels comprising 22 members were prepared. Three members were linear oligo-esters with terephthalate core designed to span both leaflets of the bilayer; these were prepared in a modular synthesis in three linear steps. 19 half-channels based on cyclodextrins with functionalized primary-rims were prepared by the Huisgen Cu+-catalyzed [3+2]-cyclization; three distinct synthetic protocols were established to be applicable to these substrates. The voltage-clamp experiment was used to characterize the ion transport properties of these 22 compounds as well as 5 oligo-esters previously prepared by solid-phase synthesis. All but two were active in bilayers, with the majority of these compounds showing highly complex conductance activities. Exponentially voltage-dependent currents were observed for two compounds (both terephthalate-derived); exclusive “square-top” activities were observed for one solid-phase–derived compound and one cyclodextrin-based channels; fractal openings were observed for at least two cyclodextrin-based channels. An “activity grid” notation was proposed as an empirical, coarse, but model-free method of treating the complex data. Through an exhaustive analysis of previously published synthetic ion channels, disparate compounds were found to share modes of activity. Supporting software were developed to facilitate the preparation of activity grids from current traces acquired for the aforementioned 27 compounds. Resulting activity grids for individual experiments were collated to generate an activity profile for each compound, from which a structure–activity map was established and could be compared to the literature data. Four core findings emerged. First, the activity grid notation is sufficiently expressive to denote highly complex mixture of activities. Second, systematic application of the notation reduces selection bias in data analysis. Third, many synthetic ion channels share highly sim- ilar activities and suggests the participation of the lipids, water, and ions in pore-formation. Lastly, the cyclodextrin half-channels are generally membrane active, and their activities are clearly modulated by structural variations.en_US
dc.description.scholarlevelGraduateen_US
dc.identifier.urihttp://hdl.handle.net/1828/3494
dc.languageEnglisheng
dc.language.isoenen_US
dc.rights.tempAvailable to the World Wide Weben_US
dc.subjectVoltage-clamp studiesen_US
dc.subjectsynthetic ion channelsen_US
dc.subjectsupramolecular chemistryen_US
dc.subjectcyclodextrin conjugatesen_US
dc.subjectclick chemistryen_US
dc.subjectmembrane transporten_US
dc.subjectactivity grid notationen_US
dc.titleA new paradigm for voltage-clamp studies of synthetic ion channelsen_US
dc.typeThesisen_US

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