The proposed research is directed toward a detailed understanding of the structure and function of ion channels in biological membranes at the molecular level, and of the role of such channels in cell communication. Ion channels are important for the transmission of signals that allow a cell or tissue to communicate with its environment or with other parts of a multicomponent organism. This project takes a """"""""bottom-up"""""""" approach to the design and mechanism of action of ion channels, starting with a chemically defined """"""""baseline"""""""" system and then introducing a series of subtle chemical changes, some of which will significantly influence important channel properties, such as the ion selectivity, the voltage dependence, and the assembly of channels in membranes. For these types of experiments, the gramicidin family of membrane channels offers several advantages: (i) a known tertiary structure; (ii) a well defined and well characterized channel function; (iii) an amenability to amino acid sequence substitutions and other chemical modifications; and (iv) an amenability to biophysical methods that have been well established for characterizing both the structures and the functional properties of modified channels in relation to the parent channels. The proposed investigations of the gramicidin family of channels are aimed at further understanding of general principles that govern structure-function relationships for ion-selective membrane channels.
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