Biological membranes are composed of lipid bilayers which contain protein components which are sensitive to the electric field across the membrane. Increased conductance can be triggered by changes in the membrane potential. The molecular mechanisms of such changes in conductance are the core of this proposal. In particular, a model system in which the chemical identity of all components is known will be studied in detail. Alamethicin, a twenty residue peptide, induces voltage-dependent conductance changes when added to lipid bilayers by aggregation. Synthetic analogs of alamethicin in which charge, length, covalent oligomerization, etc are varied will be characterized. A model of the alamethicin channel has been proposed and will be tested by synthesis of analogs with predictable properties. Synthetic oligomers in which aggregation is not necessary will be prepared and studied. A natural protein, triose phosphate isomerase, will be modified to allow incorporation into bilayers as it possesses a molecular architecture similar to the alamethicin pore. A molecular understanding of gateable membrane channels offers a basis for novel therapeutics as well as a test bed for the relation between protein architecture in membranes and imposed electrical fields.