Molecular Strategies to Achieve Selective Conductance in NaK Channel Variants

A recent crystallization of several ion channels has provided strong impetus for efforts aimed at understanding the different strategies employed by nature for selective ion transport. In this work, we used two variants of the selectivity filter of NaK channel to explore molecular mechanisms that give rise to K⁺-selectivity. We computed one-dimensional (1D) and two-dimensional (2D) potentials of mean force (PMFs) for ion permeation across the channel. The results indicate that the energies for Na⁺ and K⁺ permeation across the selectivity filter display significant differences in positions of the binding sites and barriers. One characteristic signature of a K⁺-selective channel is the apparent preservation of the site analogous to that of S2 in KcsA. The S2-bound ion can be almost ideally dehydrated and coordinated by 6 to 8 carbonyls. In a striking contrast, the PMFs controlling transport of ions in a nonselective variant show almost identical profiles for either K⁺ or Na⁺ and significant involvement of water molecules in ion coordination across the entire selectivity filter. An analysis of differences in 1D PMFs for Na⁺ and K⁺ suggests that coordination number alone is an insufficient predictor of site selectivity, while chemical composition (ratio of carbonyls and water molecules) correlates well with preference for K⁺. Multi-ion effects such as dependence of the barriers and wells for permeant ion on the type of copermeant ion were found to play a significant role in the selectivity signature of the channel as well.