A kinetic role for ionizable sites in membrane channel proteins.

Electrically charged residues in a membrane channel protein will certainly have a direct effect upon its gating and selectivity if they are near the channel pore. It is customary to regard the charged state of such residues as a fixed feature of the channel. In this paper it is argued that far from being fixed, the charged state of ionizable residues near the pore will very probably change rapidly in response to the channel opening and to ions passing through it. Calculations are presented using simple models which demonstrate that changes in the dielectric environment and changes in the distances to other charged groups resulting from channel opening can shift the effective pK values of the sites by 3 or 4 units leading to switching of its charged state. Examples are given of how this time dependent charge state of ionizable residues may play an important role in the functioning of channels. Also, by considering the influence of the electric field due to the mobile ion upon the charge state of a residue in the channel wall, it is shown that a channel lined with acid residues may very effectively block the passage of cations while allowing the passage of anions.