Abstract
Understanding how physiological ion channels simultaneously exhibit the apparently contradictory properties of high throughput and great discrimination is a long-standing theoretical problem. These nanodevices all operate on the same basic principle: ions, solvated by bulk water, lose a significant part of their hydration shell as they pass through a constriction where a chemical selection process occurs (Hille, 2001). High throughput requires that the chosen ion faces no significant energy barrier, which would forbid its entry. On first blush, it seems that falling into a deep well is also forbidden, since that would apparently trap it in the channel and block further passage. While generally true, some channels function in multi-ion mode, so that they are permanently ion-occupied; permeation then occurs with the entry of a second (or third) ion, repelling the prior occupant and leading to conduction. In all instances, high selectivity requires that there is a mechanism by which all other physiologically prevalent ions face significant energetic discrimination.