Ion permeation mechanism of the potassium channel

Ion-selective channels enable the specific permeation of ions through cell membranes and provide the basis of several important biological functions; for example, electric signalling in the nervous system(1). Although a large amount of electrophysiological data is available(1,2), the molecular mecha nisms by which these channels can mediate ion transport remain a significan t unsolved problem. With the recently determined crystal structure of the r epresentative K+ channel (KcsA) from Streptomyces lividans(3), it becomes p ossible to examine ion conduction pathways on a microscopic level. K+ chann els utilize multi-ion conduction mechanisms(1,2,4-6), and the three-dimensi onal structure also shows several ions present in the channel. Here we repo rt results from molecular dynamics free energy perturbation calculations th at both establish the nature of the multiple ion conduction mechanism and y ield the correct ion selectivity of the channel. By evaluating the energeti cs of all relevant occupancy states of the selectivity filter, we rnd that the favoured conduction pathway involves transitions only between two main states with a free difference of about 5 kcal mol(-1). Other putative perme ation pathways can be excluded because they would involve states that are t oo high in energy.