Modeling the concentration-dependent permeation modes of the KcsA potassium ion channel

The potassium channel from Streptomyces lividans (KcsA) is an integral membrane protein with sequence similarity to all known potassium channels, particularly in the selectivity filter region. A recently proposed model for ion channels containing either n or $\left(n-1\right)$ single-file ions in their selectivity filters [P. H. Nelson, J. Chem. Phys. 177, 11396 (2002)] is applied to published KcsA channel ${\mathrm{K}}^{+}$ permeation data that exhibit a high-affinity process at low concentrations and a low-affinity process at high concentrations [M. LeMasurier et al., J. Gen. Physiol. 118, 303 (2001)]. The kinetic model is shown to provide a reasonable first-order explanation for both the high- and low-concentration permeation modes observed experimentally. The low-concentration mode $\left(\right[{\mathrm{K}}^{+}]<200\mathrm{}\mathrm{m}M)$ has a 200-mV dissociation constant of $56\mathrm{m}M$ and a conductance of 88 pS. The high-concentration mode $\left(\right[{\mathrm{K}}^{+}]>200\mathrm{}\mathrm{m}M)$ has a 200-mV dissociation constant of $1100\mathrm{m}M$ and a conductance of 500 pS. Based on the permeation model, and x-ray analysis [J. H. Morais-Cabral et al., Nature (London) 414, 37 (2001)], it is suggested that the experimentally observed ${\mathrm{K}}^{+}$ permeation modes correspond to an $n=3\mathrm{}$ mechanism at high concentrations and an $n=2\mathrm{}$ mechanism at low concentrations. The ratio of the electrical dissociation distances for the high- and low-concentration modes is 3:2, also consistent with the proposed $n=3\mathrm{}$ and $n=2\mathrm{}$ modes. Model predictions for ${\mathrm{K}}^{+}$ channels that exhibit asymmetric current-voltage $\mathrm{}(I-V)\mathrm{}$ curves are presented, and further validation of the kinetic model via molecular simulation and experiment is discussed. The qualitatively distinct $I-V$ characteristics exhibited experimentally by ${\mathrm{Tl}}^{+},$ ${\mathrm{NH}}_4^{+},$ and ${\mathrm{Rb}}^{+}$ ions at $100\mathrm{m}M$ concentration can also be explained using the model, but more extensive experimental tests are required for quantitative validation of the model predictions.