Towards voltage-gated ion channels, molecular diodes

Date

2018-07-31

Authors

Zhou, Xin

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Abstract

The goals of this project were to synthesize voltage-gated ion channels based upon previously studied pore-formers and to further explore the mechanism of ion transport with this type of pore-former. The syntheses of bis-macrocyclic bola-amphiphiles started with two different macrocycles prepared via a two-step cyclization from maleic anhydride by reaction with 1,8-octanediol alone or with triethyleneglycol. The macrocycles were then modified to a set of mono-adducts and bis-adducts by Michael addition of thiols (3-mercaptopropanol, 2-mercaptoacetic acid, or 3-mercaptopropionic acid). The mercaptopropanol adduct was converted to a mesylate and coupled with a carboxylate derivative to form a bis-macrocycle. Repetitious gel permeation chromatography gave a bis-macrocycle bearing only one head group, a carboxylate. The second head group was added via Michael addition to give a bis-macrocyclic bola-amphiphile which could have either the same head groups or different head groups. Two symmetrical transporters were synthesized via another route: two macrocycles reacted with 2-mercaptoethyl sulfide to generate a bis-macrocycle, and the same head group was then simultaneously added to both ends to give a symmetrical bola-amphiphile. Transporters with different combinations of head groups were synthesized to compare head group effects on cation transport properties, while different macrocycles were used in the backbone of transporter candidates to give two series of compounds for comparison of their behaviors. The second phase of this project investigated the transport properties of candidates using pH-stat titration. The pH-stat titration of bilayer vesicles allowed determination of dynamic transport properties: transport rate, apparent kinetic order and cation selectivity. Combined with information from planar bilayer experiments (done by D. Loock), it was found that an asymmetrical bis-macrocyclic bola-amphiphile with an acetate and a succinate head group behaves as voltage-gated ion channel in planar bilayers. An ion transport mechanism of the present system was proposed which involves the formation of active aggregates (probably dimers or oligomers).

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Keywords

Ion channels, Diodes

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