On the selective ion binding hypothesis for potassium channels

Abstract

The mechanism by which K þ channels select for K þ over Na þ ions has been debated for the better part of a century. The prevailing view is that K þ channels contain highly conserved sites that selectively bind K þ over Na þ 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 þ (cage made from two planes of oxygen atoms) or Na þ ions (a single plane of four oxygen atoms). By combining Bennett free energy perturbation calculations with umbrella sampling, we show that when K þ and Na þ are both permitted to move into their preferred positions, the thermodynamic preference for K þ over Na þ is significantly reduced throughout the entire selectivity filter. We offer a rationale for experimental measures of thermodynamic preference for K þ over Na þ from Ba 2þ blocking data, by demonstrating that the presence of Ba 2þ ions exaggerates K þ over Na þ thermodynamic stability due to the different binding locations of these ions. These studies reveal that K þ channel selectivity may not be associated with the thermodynamics of ions in crystallographic K þ binding sites, but requires consideration of the kinetic barriers associated with the different multi-ion permeation mechanisms.ion selectivity | potassium ion channel | BAR-US method

Filter gate closure inhibits ion but not water transport through potassium channels

“…Another consequence of its smaller radius is that Na + does not enter the cage cornered by eight carbonyl oxygens (as does K + ) but instead binds in the plane of only four carbonyl oxygens (37,38). Those of T75 provide a site of particularly high affinity for both Na + and Li + according to both crystal structures [PDB ID codes 2ITC (27) and 3GB7 (37), respectively] and molecular dynamics simulations (37).…”

“…This requirement is met during osmotic water flow, which explains the capability of Na + to block it (8). Na + does not block the K + current because the 1-Å shift of its binding site closer to the K + binding site creates an energy barrier that Na + has to overcome to enter a K + -containing selectivity filter (38).…”

Equilibrium selectivity alone does not create K+-selective ion conduction in K+ channels

“…A variety of experimental techniques all support the conclusion that different K þ channels have a preference for K þ ions over Na þ ions at equilibrium [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] . The simplest mechanism to explain ion selectivity is that the equilibrium preference of a channel determines its selectivity during ion conduction.…”

Competition for water between protein (from Haloferax mediterranei) and cations $$\hbox {Na}^+$$ Na + and $$\hbox {K}^+$$ K + : a quantum approach to problem

“…These facts can not only explain the prevalence of potassium as an intracellular cation, but also give another reason for the selectivity of the potassium ion channels [5,13], since the energy to compensate for the dehydration of the potassium cation is less than for sodium, independently of the involvement of other processes to compensate for the dehydration, such as polarization [30].…”

“…How these ions move from the aqueous phase into biological systems, such as at the entrance of an ion channel, depends on the interplay between competing intermolecular forces, which first must involve ion-water and water-water interactions, and the cation-protein binding energy [4,5].…”