Electro-chemical modeling challenges of biological ion pumps

There are two major classes of proteins that control the movement of ions across biological membranes: channels and transporters. Ion channels allow the passive movement of ions down their electrochemical gradients whereas transporters power uphill movements. Two major questions have challenged channel biophysicist for nearly a half-century: permeation (selective passage of ions through an open channel) and gating (channel opening and closing). A major advance in the understanding of permeation and gating of K/sup +/-selective channels has been made by the publication of atomic resolution structures of a bacterial K/sup +/ channel by the laboratory of Roderick MacKinnon who received the Noble prize in Chemistry in 2003 for this body of work. The availability of detailed atomic structure allows the classical problems of permeation and gating to be addressed by interdisciplinary teams and techniques. Examples of the application of transport modeling to permeation through biological channels include both the Poisson-Nernst-Planck electrodiffusion approach and structurally based Brownian dynamic simulations. Channel gating, however, involves changes in the structure of the protein. A detailed understanding of channel gating is hindered by the computational limitations of molecular dynamic simulations and the lack of structural information about intermediate conformations between the closed and fully open states. The class of transporters known as ion-motive ATPases have a number of features similar to ion channels, but they are more complex proteins since they require coupling of the free energy change associated with ATP hydrolysis with the uphill movement of the actively transported substance. We will review the current state of knowledge concerning ion pumps and discuss various modeling opportunities and challenges presented by this important class of biological molecules. The Na/sup +/-K/sup +/ ATPase will be the principal focus of our discussion.