application): The sodium and potassium voltage-gated channels found in nerve and other tissues have been intensively studied for over a half century. Many of their properties have been worked out, but not the mechanism of gating; the structure of these channels is still not determined at the atomic level, although the major structural motifs have become clear recently. There is enough information on their dimensions, amino acid sequence, and the topology of the transmembrane segments that calculations on models of the channels should help elucidate the function of the channels. Over the past several years, the PI has carried out simulation of the water in a model channel, in which the protein was replaced by a dielectric containing charge; the results have shown that the water, and its interaction with charges, may be extremely important in determining the gating mechanism. The gating current is postulated to be protons moving among amino acids upon depolarization of the membrane. The extremely high fields accompanying the charges on some of the basic amino acids both fie up water in the pore of the channel and prevent other basic amino acids from ionizing. The charge shift upon depolarization leaves different amino acids unionized and frees the water. In order to show that the change can indeed move under fields of the correct order of magnitude, ab initio calculations with model compounds (methylamines) and with water, plus an added proton, are being done. Results to date indicate that the shift in proton position from one model compound to another does occur with a field of the current order of magnitude. The electric field has been calculated without assuming a concentration of ions, as the Poisson-Boltzmann (PB) equation is not used; the ionic concentration in the protein, and in much of the pore, is not a quantity defined in a form properly usable in the PB equation. The model will not be made more realistic by including some of the pore lining amino acids and enlarging the diameter to accommodate the more distinct wall protein. This is an extension of the methods the PI has been using. Furthermore, it should be possible to make the charge distribution self- consistent instead of testing guessed at charge distributions. Experimental tests of the model are suggested, and the model itself will make it possible to test additional ideas concerning the nature of gating in the channel; these include calculation of the current-voltage curve and of the outcome of certain physiological experiments. When the mechanism of gating of Na+ and K+ channels is understood, the control of those diseases which are consequences of the malfunction of these channels should be brought closer; these include neurological diseases but, as the channels are found in all cells, are not limited to these.
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