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1.D.29 The Macrocyclic Oligocholate (Oligocholate) Family

Hydrophobic interactions normally are not considered a major driving force for self-assembly in a hydrophobic environment. When macrocyclic oligocholates were placed within lipid membranes, however, the macrocycles pulled water molecules from the aqueous phase into their hydrophilic internal cavities (Cho et al., 2011). These water molecules had strong tendencies to aggregate in a hydrophobic environment and templated the macrocycles to self-assemble into transmembrane nanopores. This effect resulted in some highly unusual transport behavior. Cholesterol normally increases the hydrophobicity of lipid membranes and makes them less permeable to hydrophilic molecules. The permeability of glucose across the oligocholate-containing membranes, however, increased significantly upon the inclusion of cholesterol. Large hydrophilic molecules tend to have difficulty traversing a hydrophobic barrier, but the cyclic cholate tetramer was more effective at permeating maltotriose than glucose (Cho et al., 2011).

Macrocyclic oligocholates stack on top of one another in lipid membranes to form nanopores. Cholate oligomers terminated with guanidinium and carboxylate groups were found to cause efflux of hydrophilic molecules such as glucose, maltotriose, and carboxyfluorescein (CF) from POPC/POPG liposomes (Cho and Zhao, 2011). The cholate trimer outperformed other oligomers in transport. A dependence on chain length argued against random intermolecular aggregates as the active transporters. Efflux of glucose increased significantly when the bilayers contained 30 mol% cholesterol. Hill analysis suggested that the active transporter consisted of four molecules. The oligocholates were proposed to fold into 'noncovalent macrocycles' by the guanidinium-carboxylate salt bridge and stack on top of one another to form similar transmembrane pores as their covalent counterparts (Cho and Zhao, 2011).

The aggregation of macrocyclic oligocholates with introverted hydrophilic groups and aromatic side chains allows stacking in membranes to form transmembrane nanopores. Smaller, more rigid macrocycles stacked better than larger, more flexible ones because the cholate building blocks in the latter could rotate outward and diminish the conformation needed for the water-templated hydrophobic stacking. The acceptor-acceptor interactions among naphthalenediimide (NDI) groups were more effective than the pyrene-NDI donor-acceptor interactions in promoting the transmembrane pore formation of the oligocholate macrocycles (Widanapathirana and Zhao, 2012 a, b).

References associated with 1.D.29 family:

Cho, H. and Y. Zhao. (2011). Translocation of hydrophilic molecules across lipid bilayers by salt-bridged oligocholates. Langmuir 27: 4936-4944. 21446684
Cho, H., L. Widanapathirana, and Y. Zhao. (2011). Water-templated transmembrane nanopores from shape-persistent oligocholate macrocycles. J. Am. Chem. Soc. 133: 141-147. 21142045
Widanapathirana L. and Zhao Y. (2012). Effects of amphiphile topology on the aggregation of oligocholates in lipid membranes: macrocyclic versus linear amphiphiles. Langmuir. 28(21):8165-73. 22563986
Widanapathirana, L. and Y. Zhao. (2012). Aromatically functionalized cyclic tricholate macrocycles: aggregation, transmembrane pore formation, flexibility, and cooperativity. J Org Chem 77: 4679-4687. 22524459