Supramolecular Approaches to Combining Membrane Transport with Adhesion

Abstract

Cells carefully control the transit of compounds through their membranes using “gated” protein channels that respond to chemical stimuli. Connexin gap junctions, which are high conductance cell-to-cell channels, are a remarkable class of “gated” channel with multiple levels of assembly. A gap junction between adhering cells comprises two half-channels in each cell membrane that adhere to each other to form a continuous cell-to-cell channel. Each half-channel is a hexameric assembly of six protein transmembrane subunits. These gap junctions display both intramembrane assembly and intermembrane assembly, making them an attractive target for biomimetic studies. Although many examples of self-assembled channels have been developed, few can also mediate intermembrane adhesion. Developing systems that combine membrane adhesion with controlled transit across the membrane would not only provide a better understanding of self-assembly in and around the membrane, but would also provide a route towards smart biomaterials, targeted drug delivery and an interface with nanotechnology.This Account describes our biomimetic approaches to combining membrane adhesion with membrane transport, using both self-assembled “sticky” pores and “sticky” nanoparticles to trigger transit across membranes. This combination links both fundamental and applied research, acting as a bridge between molecular level assembly and the formation of functional biomaterials. The ultimate goal is to create complex self-assembled systems in biological or biomimetic environments that can both interface with cells and transport compounds across bilayers in response to remote chemical or electromagnetic signals. Our research in this area started with fundamental studies of intramembrane and intermembrane self-assembly, building upon previously known channel-forming compounds to create self-assembled channels that were switchable or able to mediate vesicle–vesicle adhesion. Subsequently, nanoparticles with a “sticky” coating were used to mediate adhesion between vesicles. Combining these adhesive properties with the unique characteristics of nanosized magnetite allowed a noninvasive magnetic signal to trigger transport of compounds out of magnetic nanoparticle-vesicle assemblies. Adding an extravesicular matrix produced new responsive biomaterials for use in tissue engineering. These biomaterials can be magnetically patterned and can deliver drugs upon receipt of a magnetic signal, allowing spatiotemporal control over cellular responses.

Artificial transmembrane signal transduction mediated by dynamic covalent chemistry

“…Signalling processes across lipid bilayers can be activated through mechanisms involving either transduction of chemical signals [6][7][8][9][10] or exchange of active components between the two sides of a membrane. [11][12][13][14][15][16][17][18][19] Synthetic systems inspired by transmembrane protein receptors have been developed to control the generation of a compartmentalized signal in response to a specic molecular recognition event. [20][21][22][23][24][25][26][27] In addition, dynamic covalent chemistry based on boronate esters, 28,29 hemiaminals, 30 and disulphides, [31][32][33] has been used to mediate the transport of specic molecules across lipid bilayers.…”

How the biomimetic assembly of membrane receptors into multivalent domains is regulated by a small ligand

“…[4][5][6] Simple models of a cell membrane, in the form of lipid vesicles equipped with minimal synthetic membrane receptors and ligands, have shown that the lateral assembly of receptors enhances both binding to ligands in solution 7,8 and membrane adhesion. 9,10 These studies have shown that large increases in avidity are largely due to a multivalent effect. The corollary is that ON/OFF regulation of membrane receptor function can be achieved by means of a bimodal control of the receptor assembly, i.e.…”

Steroid-Based Supramolecular Systems and their Biomedical Applications: Biomolecular Recognition and Transportation

“…by interacting (host) molecules with certain (guest) molecular species [5]. Molecular transportation is the use of supramolecules to translocate bounded/ loaded molecular species (such as anions [6]) through membranes (especially cell membranes [7]), which could be coupled with chemical potentials [8]. Biomolecular recognition (detecting/sensing of certain biomolecules) and biomolecular transportation (administration/delivery of bioactive molecules into the cells/organs) have been regarded as two important fields in biomedical-orientated supramolecular (medicinal) chemistry [9].…”