? The proposed work is based on the fact that we now have in hand a family of completely synthetic, cation-conducting channels that were designed de novo, synthesized, characterized in the chemical and biophysical senses, and studied in phospholipid bilayers. The initial effort was to develop a model for channel mediated ion function. The compounds developed during this program are, in fact, functioning channel molecules. They insert in phospholipid bilayers and they transport ions rapidly and (in many cases) selectively. They exhibit the open-close behavior known for protein channels. The class of molecules can be prepared with a variety of substituents and in various lengths. Because they are modular, we propose to vary their structures in an effort to enhance and understand ion and molecule selectivity. These synthetic channels have exhibited biological activity. We propose to explore toxicity in bacteria, yeast, and mammalian cells and to correlate it with the structural changes made within the channels. Finally, we propose to use the family of synthetic channels to probe membrane properties. The latter goal is particularly timely because the importance of membrane microdomains has only recently been studied extensively. Microdomains are thought to influence protein structure and function and may play a role in signaling. It is hoped that controlled structural changes in the hydraphile synthetic channels will permit us to probe membrane and microdomain organization. ? ?
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