Ions in Channels

Professor Bob Eisenberg
Department of Molecular Biophysics
Rush University


Ion channels are irresistible objects for biological study because they are 'nanovalves of life' controlling most biological functions, much as transistors control computers. Direct simulation of channel behavior in atomic detail is difficult if not impossible. Gaps in scales of time, volume, and concentration between atoms and biological systems are each ~10^12. All the gaps must be dealt with at once, because biology occurs on all the scales at once.

Simple models are surprisingly successful in dealing with ion binding in three very different (and important) channels: the sodium channel that produces the signals of nerve and muscle and two cardiac calcium channels that control contraction. Amazingly, one model with the same three parameters accounts quantitatively for qualitatively different binding in a wide range conditions for two very different calcium and sodium channels. Binding free energy is an output of the calculation, produced by crowding charged spheres into a very small space. The model does not involve any traditional chemical 'quantum' binding energies at all.

How can such a simple model give selectivity when crystallographic wisdom and chemical intuition says that selectivity depends on the precise structural relation of ions and side chains? The answer is that structure is a computed consequence of forces in these correlated crowded systems. Binding sites are self-organized and at their free energy minimum. Different structures form in different conditions. Binding is a consequence of the 'induced fit' of side chains to ions and ions to side chains.

Equilibrium is death to biology. A variational approach is obviously needed to replace our equilibrium analysis and is well under way, applying the energy variational methods of Chun Liu, used to deal with highly correlated systems like liquid crystals.