The bacterial chloride channel EcCLC:
This page will describe some aspects of the biophysics of ion channels. A particular system we are working on is the ClC H+/Cl- transporter found in bacteria. Very similar transporters are important in eukaryotic cells also. We will focus on theory and simulation applied to channels.
Ion channels, transporters, and pumps
Ion channels are large membrane proteins that control the flux of ions into and out of cells. Starting in 1998, crystal structures of bacterial homologs of eukaryotic ion channels began to appear. MacKinnon's group pioneered these structural studies. The beautiful structures of the potassium and chloride channels (and more recently, several others) has opened the door for molecular modeling of these proteins. See the top page of this website for a picture of the bacterial chloride transporter, which is closely related to the chloride channels in humans.
Ion channels control the passive diffusion of ions across membranes. They typically possess gates that open or close based on external stimuli (such as voltage, chemical interactions, pH, etc). Once the gate is open, a gradient in the electrochemical potential drives ions in the downhill direction. Channels can display exquisite sensitivity, a primary example being the potassium channel that can discriminate between K+ and Na+ ions. Understanding this selectivity is a major goal of ongoing computational/theoretical work.
Pumps are membrane proteins that utilize chemical energy in the form of ATP to drive certain ions across membranes. Pumps tend to 'do the job', but are quite slow in their turnover rates. An example is the HKATPase pump that moves protons across membranes, for example into the stomach.
Transporters are situated in between channels and pumps in terms of turnover rates. They can drive one ion across a membrane driven by an electrochemical gradient in another ion.
Our understanding of the chloride channel family has grown immensely in the last decade. In humans, there are about 10 known members of the family. The crystal structure from Dutzler, MacKinnon, et al. is for a bacterial homolog. At the time of the crystal structure determination, it was thought that this ClC homolog was a channel. But Accardi, Miller, Jentsch, Pusch, and others have now shown that not only is the bacterial case an H+/Cl- transporter that moves 2 Cl- ions in one direction and a single proton in the other, but the majority of the human ClC family is in the transporter class too. These findings have created a dramatic alteration of our picture of this family and transporters in general. Thus a great deal of work is now directed at understanding how the amazing bacterial ClC transporter (for which we have the structure) performs its task. Our work is focused on this problem -- what are the key steps in the transport cycle? Can we calculate free energies for each of the steps, and enter those in kinetic models for the long time scale behavior? We are collaborating with Rob Coalson's group in this work.
Some papers from our group on the ClC channels/transporters (more extensive refs. to the recent literature can be found in these papers):
J. Yin, Z. Kuang, U. Mahankali, and T. L. Beck, Ion Transit Pathways and Gating in ClC Chloride Channels, Proteins: Struct., Funct., and Bioinform., 57, 414-421 (2004).
T. L. Beck, J. Yin, Z. Kuang, U. Mahankali, and G. Feng, Comment on Ion Transit Pathways and Gating in ClC Chloride Channels, Proteins: Struct., Funct., and Bioinform., 62, 553-554 (2006).
Z. Kuang, U. Mahankali, and T. L. Beck, Proton Pathways and H+/Cl- Stoichiometry in Bacterial Chloride Transporters,Proteins: Structure, Function, and Bioinformatics 68, 26-33 (2007).
Kuang, Z., A. Liu, and T. Beck. May 2008. TransPath: a computational method for locating ion transit pathways through membrane proteins. Proteins: Struct., Func., Bioinform. 71(3):1349–1359.