The hydraphile class of synthetic ion channels: Insights into channel-stabilizing interactions

Nearly 40 years have passed since the fluid mosaic bilayer model provided the first illuminating insight into the structure of a biological membrane comprised of protein and lipid molecules. Despite tremendous effort worldwide, a detailed picture of membrane structure remains elusive. A phospholipid cell membrane can be comprised of more than 50% by weight proteins, many of which function as channels that span the bilayer and maintain finite control of the delicate osmotic balance required for life. The synthetic ion channels we have termed the hydraphiles are smaller, simpler models of these large protein channels, yet they exhibit ion translocation much like their natural counterparts. We have developed a methodology for studying Na + transport by the hydraphiles based on an ion selective electrode (ISE). Once optimized, this methodology was used to study the mechanism and efficiency of ion transport of the hydraphiles in reconstituted membranes, and hence better understand how interactions between the hydraphile and the bilayer could affect transport. Specifically, we have examined bilayer thickness, and reported that the hydrophobic length of the channel must match the hydrophobic width of the bilayer for the most effective ion transport. A second study examined interactions between the cations provided by the lipid headgroups and the pi-electrons of the hydraphiles sidearms, and how these interactions may be utilized to maximize Na+ transport. We determined that hydraphiles containing arene-based sidearms can form cation-pi interactions with the lipid headgroups and serve to stabilize an active channel conformation in the bilayer. A study of amide bond positioning found that an amide in the channel sidearm resulted in enhanced transport, presumably by stabilizing the sidearm in the bilayer. Finally, we have examined the effect of conformational flexibility on hydraphile activity using a library of hydraphiles containing rigid spacer chains. We found that rigidification of the backbone has mixed results on Na+ transport, and that some rigidity is beneficial. Taken together, a better understanding has emerged of how hydraphiles interact with the bilayer for optimal ion transport. Our results, although conducted with simple channel model systems, have provided significant insights into channel transport which are likely to be applicable to their biological counterparts.