Selective Recognition of Phosphatidylcholine Lipids by a Biomimetic Calix[6]tube Receptor

Phosphatidylcholines (PCs) and phosphatidylethanolamines (PEs) are usually the most abundant phospholipids in membranes. Only a few examples of artificial macrocyclic receptors capable of binding these zwitterionic lipids were reported, and in most cases, their mode of action differs from that of natural receptors. NMR studies show that calix[6]arenes 4-6 behave as heteroditopic receptors that can efficiently bind 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) in nonpolar solvents. Similarly to natural systems, the recognition proceeds through the establishment of specific interactions with the zwitterionic head of the lipid. In a protic environment, calix[6]tube 4 binds DOPC much more strongly than 5 and 6, thanks to the higher acidity of its H-bonding thiourea groups and the better preorganization of its binding site. Moreover, 4 is reluctant to the corresponding PE, highlighting a unique selectivity for PCs over PEs. A high selectivity for DOPC over dodecylphosphocholine (DPC) was also observed, and computer modeling studies showed that it may likely originate from the curved shape of the tubular recognition system of 4, which is well-adapted to the native conformation of DOPC. From a biomimetic point of view, the complex 4⊃DOPC shows remarkable similarities with a natural complex formed between a PC and the human phosphatidylcholine transfer protein.