Energetics of ion conduction through the K+ channel

K+ channels are transmembrane proteins that are essential for the transmission of nerve impulses. The ability of these proteins to conduct K+ ions at levels near the limit of diffusion is traditionally described in terms of concerted mechanisms in which ion-channel attraction and ion–ion repulsion have compensating effects, as several ions are moving simultaneously in single file through the narrow pore1,2,3,4. The efficiency of such a mechanism, however, relies on a delicate energy balance—the strong ion-channel attraction must be perfectly counterbalanced by the electrostatic ion–ion repulsion. To elucidate the mechanism of ion conduction at the atomic level, we performed molecular dynamics free energy simulations on the basis of the X-ray structure of the KcsA K+ channel4. Here we find that ion conduction involves transitions between two main states, with two and three K+ ions occupying the selectivity filter, respectively; this process is reminiscent of the ‘knock-on’ mechanism proposed by Hodgkin and Keynes in 19551. The largest free energy barrier is on the order of 2–3 kcal mol-1, implying that the process of ion conduction is limited by diffusion. Ion–ion repulsion, although essential for rapid conduction, is shown to act only at very short distances. The calculations show also that the rapidly conducting pore is selective.