Planar-bilayer activities of linear oligoester bolaamphiphiles

Abstract

SummaryVoltage-clamp experiments of eight oligoester bolaamphiphiles in two subclasses are described. Syntheses of three new terephthalate-based compounds were achieved in three linear steps. Together with five previously described, related compounds, the ion transport activity was assessed by means of the voltage-clamp technique. All of the compounds show multiple types of conductance behavior in planar bilayers, a subset of which was exponentially voltage-dependent. The varied and irregular activities were summarized with the aid of a recently developed “activity-grid” method.

A membrane-spanning macrocyclic bolaamphiphile lipid mimic of archaeal lipids

“…The design is driven by a combination of practical considerations and experience derived from linear oligoester ion channels 19,20,[28][29][30][31] . Good phospholipid miscibility is associated with extended alkyl esters 32,33 and the use of glutarate diesters in place of glycerol diesters is both a reliable and simplifying synthetic strategy 28,34 . The 1,2,3-triazole produced via copper-catalyzed alkyneazide coupling (CuAAC) 35 also has good lipid miscibility in conjunction with esters elsewhere in D r a f t the structure 33 and has previously featured in single-chain archaeal lipid mimics designed to enhance membrane permeability via flip-flop which necessarily requires a U-shaped insertion 36,37 .…”

“…Good phospholipid miscibility is associated with extended alkyl esters 32,33 and the use of glutarate diesters in place of glycerol diesters is both a reliable and simplifying synthetic strategy 28,34 . The 1,2,3-triazole produced via copper-catalyzed alkyneazide coupling (CuAAC) 35 also has good lipid miscibility in conjunction with esters elsewhere in D r a f t the structure 33 and has previously featured in single-chain archaeal lipid mimics designed to enhance membrane permeability via flip-flop which necessarily requires a U-shaped insertion 36,37 . Membrane-inactive per-substituted cyclodextrins bearing triazoles and esters 38 suggest that there is no inherent membrane destabilizing character to triazoles or esters provided U-shaped insertions can be avoided.…”

Dissipative assembly of a membrane transport system

“…17 Similar non-linear conductance changes do occur in aromaticcore oligoester channels terminated in amines. 42,43 A mechanistic analysis is deferred, but the practical implications are important for the dissipative assembly experiment. Firstly the appearance of the activity grid will be voltage-dependent.…”

Cyclodextrin ion channels

“…These considerations prompted our development of activity grids and their exploration with literature data 16 and a limited set of experimental data. 43 Activity grids summarize experimental observations by the type, the duration, and the conductance of events observed on a coarse-grained scale (Fig. 3).…”

“…Our experience with simple compounds revealed the advantages of a modular approach with a limited number of optimized reactions to produce a suite of closely related compounds in a few steps from starting materials. 43 We therefore sought a design which was amenable to rapid modular assembly based on a macrocyclic portal element to provide the structural integrity absent in simpler transporters. Although transmembrane spanning structures are appealing, a "halfchannel" motif involving end-to-end dimerization of components in the opposing leaflets of a bilayer membrane, as seen in the gramicidin channel, [44][45][46] offers a clear on-off mechanism which could be modulated.…”