1. Selectivity of the Calcium and Chloride Channels Crowded Charge Mechanism Bob Eisenberg Rush Medical Center, Chicago Wolfgang Nonner Dirk Gillespie University of Miami School of Medicine

2. Ion Channels Ion channels are conduits for ions to move from one side of a membrane to the other side. Many types of ion channels preferentially pick one kind of ion over another.

3. Selectivity of Ion Channels Calcium channel selects Ca 2+ over Na + even when there is 10,000 times more Na + than Ca 2+ selects small ions over large ions Chloride channel selects large ions over small ions

4. Crowded Charge Model of Selectivity Inside a channel, ions are in a small, confining space. The channel is an environment of crowded charges. It is the interaction of these crowded charges that make channels selective.

5. Crowded Charge Model of Selectivity The physics we include to model selectivity is: ions interact through the electric fields they create two particles cannot occupy the same space ions are modeled as charged, hard spheres water molecules are modeled as hard spheres each channel type has unique kinds of amino acid residues that interact with ions these determine what ions the channel selects and to what degree

7. Crowded Charge Model of Selectivity Density Functional Theory (DFT) best available to compute flux current implementation only for simple geometries bulk liquid approximation cannot compute current (equilibrium only) simple way to demonstrate underlying principles Different computational methods are available.

8. L-Type Calcium Channel Involved in regulating the rhythm of the heart. The selectivity experiment cell interiorcell exterior 0.1 M NaCl add CaCl 2 (10 -9 to 10 -1 M)

11. Chloride Channel Key to making kidneys work. Also involved in the function of certain muscles and nerves. The selectivity experiment cell interiorcell exterior 0.1 M NaA change size of anion A - repeat at 1 M

12. Chloride Channel Selectivity

13. Conclusions  Crowded Charge is important  Crowded Charge can account for Selectivity for all Protein Function. Future Work