On the selective ion binding hypothesis for potassium channels.
The mechanism by which K(+) channels select for K(+) over Na(+) ions has been debated for the better part of a century. The prevailing view is that K(+) channels contain highly conserved sites that selectively bind K(+) over Na(+) ions through optimal coordination. We demonstrate that a series of alternating sites within the KcsA channel selectivity filter exists, which are thermodynamically selective for either K(+) (cage made from two planes of oxygen atoms) or Na(+) ions (a single plane of four oxygen atoms). By combining Bennett free energy perturbation calculations with umbrella sampling, we show that when K(+) and Na(+) are both permitted to move into their preferred positions, the thermodynamic preference for K(+) over Na(+) is significantly reduced throughout the entire selectivity filter. We offer a rationale for experimental measures of thermodynamic preference for K(+) over Na(+) from Ba(2+) blocking data, by demonstrating that the presence of Ba(2+) ions exaggerates K(+) over Na(+) thermodynamic stability due to the different binding locations of these ions. These studies reveal that K(+) channel selectivity may not be associated with the thermodynamics of ions in crystallographic K(+) binding sites, but requires consideration of the kinetic barriers associated with the different multi-ion permeation mechanisms.
Department of Chemistry, University of California, One Shields Avenue, Davis, CA 95616, USA.
Ilsoo
I
Kim
Toby W
TW
Allen
D018360:Crystallography, X-Ray; D008958:Models, Molecular; D011188:Potassium / Q000378:metabolism*; D015221:Potassium Channels / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D012964:Sodium / Q000378:metabolism*; D013816:Thermodynamics
D015221:Potassium Channels; D012964:Sodium; D011188:Potassium