Using theory and simulation to understand permeation and selectivity in ion channels.

It is clear that the function of ion channels must flow from their structure. With recent advances in computational power and methodology, it appears feasible to correlate structure to ion channel permeation at an atomistically detailed level of description. The overall strategy is to structure the calculations in a hierarchy, ranging from coarse-grained thermodynamic and kinetic descriptions to fine-grained molecular dynamics descriptions with atomic detail. Each level of description is connected to the others by appropriate statistical mechanical theory. The coarse-grained descriptions can be correlated directly with electrophysiological experiment. The fine-grained descriptions are used to parameterize the coarse-grained descriptions and to describe the permeation process at the most detailed level. This strategy has so far had varying degrees of success. It has successfully described water permeation through lipid bilayers and gramicidin channels. It has revealed the essential events of ion permeation through gramicidin channels at an atomistically detailed level. The role of channel protein motions in permeation has been elucidated. However, it appears that force fields used to describe molecular dynamics must be refined further to achieve completely accurate predictions of the permeation of such small ions as sodium. Channels with more complex structure and more multiion occupancy than gramicidin pose major computational challenges with respect to sampling protein conformations and ion distributions involved in the permeation process. Possible approaches to meeting these challenges are discussed.