Hydrophobic cholate scaffolds anchor these synthetic channels-formers in phospholipid bilayers.
Controlled communication between cells is vital for a host of biological processes, and two key methods used by cells to communicate are the transport of ions across the membrane or conformational/positional changes in membrane proteins. The first method requires fine control of the influx and efflux of ions and small molecules into and out of cells. Our interests lie in developing synthetic ion channels which can be opened and closed by external stimuli. For example, we have described novel pyridyl-functionalised cholic acid-based ion channels that could be opened by palladium(II), which allowed transport of ions into phospholipid vesicles. We are now looking to develop new ion channels that contain different gating motifs and/or link vesicles together, which will copy gap junctions.
(a) A fluorescent Aib oligomer that is able to insert into phospholipid bilayers. (b) Non-covalent conformational control of helical Aib peptide secondary structures.
The second method requires an external ligand to bind to and induce a conformation change in a membrane-spanning protein, which is transmitted to the interior of the cell and initiates a cascade of enzymatic transformations. In conjunction with Prof. Jonathan Clayden (University of Bristol), we have been designing and synthesising a series of conformationally-responsive helical peptides, which will mimic the signal transduction mechanisms of G-protein coupled receptors upon receipt of an external signal. To date we have been able to acheive the transmission of a photochemical signal deep into a phospholpid bilayer, and more recently the binding of an externally-added chemical messenger (enkephalin) and the relay of this binding information over a multi-nanometre distance into a bilayer.
Ligand-modulated conformational switching in a fully synthetic membrane-bound receptor.
Nature Chem. 2017, 9, 420–425
Conformational photoswitching of a synthetic peptide foldamer bound within a phospholipid bilayer.
Science 2016, 352, 575-580.
Length-dependent formation of transmembrane pores by 310 helical Aib foldamers.
J. Am. Chem Soc. 2016, 138, 688–695.
Pd(II)-mediated assembly of porphyrin channels in bilayer membranes.
Langmuir 2011, 27, 1448-1456.
Palladium(II)-mediated assembly of biotinylated ion channels.
Chem. Eur. J. 2011, 17, 3465-3473.
Palladium(II)-gated ion channels.
Chem. Commun. 2008, 4007-4009.