Ion channels, permeation, and electrostatics:: Insight into the function of KcsA

There is no doubt that MD simulations in which water and lipid molecules are treated explicitly represent the most detailed method for studying ion channels. Nevertheless, this computationally intensive methodology often suffers from statistical uncertainties due to finite sampling. From this perspective, a continuum model can be very useful for examining various energetic factors arising from long-range electrostatic effects involved in the function of an ion channel. This review shows that relatively simple numerical calculations based on continuum electrostatic models can be used to characterize ion - channel interactions, ion - ion repulsion, and the transmembrane potential profile, thus, providing very valuable insight into the function of the KcsA channel. Nonetheless, it is also important to recognize the limitations of the continuum approximation and use it only within its range of validity. Those were illustrated with MD/FES calculations applied to the GA channel. The results indicate that a continuum approximation cannot realistically account for ion - channel and ion - ion interaction in the confined environment of a narrow selectivity filter. Atomic models are and will remain necessary for addressing such detailed questions. Our focus in the current review has been exclusively on equilibrium energetics. Ion fluxes are, of course, observed under nonequilibrium conditions. In the future, it will be important to take thoses aspects of the problem into consideration. It is likely that a combination of approaches, including continuum electrostatics based on the PB equation, MD and MD/FES calculations (see refs 8-23, 87, 88), and Brownian dynamics simulations (89-92), as well as continuum theories of electrodiffusion (93, 94) will contribute to refining our understanding of ion permeation in the future.