Coordination Numbers of K+ and Na+ Ions Inside the Selectivity Filter of the KcsA Potassium Channel: Insights from First Principles Molecular Dynamics

Quantum mechanics/molecular mechanics (QM/MM) Car-Parrinello simulations were performed to estimate the coordination numbers of K+ and Na+ ions in the selectivity filter of the KcsA channel, and in water. At the DFT/BLYP level, K+ ions were found to display an average coordination number of 6.6 in the filter, and 6.2 in water. Na+ ions displayed an average coordination number of 5.2 in the filter, and 5.0 in water. A comparison was made with the average coordination numbers obtained from using classical molecular dynamics (6.7 for K+ in the filter, 6.6 for K+ in water, 6.0 for Na+ in the filter, and 5.2 for Na+ in water). The observation that different coordination numbers were displayed by the ions in QM/MM simulations and in classical molecular dynamics is relevant to the discussion of selectivity in K-channels.Potassium channels are membrane proteins that can catalyze K+ ions permeation across cellular membranes while simultaneously discriminating the permeation of Na+ ions by several orders of magnitude. To uncover the mechanism of K-channel selectivity in theoretical studies, the KcsA channel has proved to be a particularly useful system, because it is relatively small, and it contains the essential structural elements that are shared by all potassium channels (1). The selectivity of the KcsA channel is believed to originate from the conserved TVGYG signature sequence, which forms a narrow constriction in the tetrameric pore called the selectivity filter (Fig. 1). The K+/Na+ selectivity in the KcsA channel was initially proposed to arise from the geometrical arrangement of ligands in the filter (1), the so-called snug-fit hypothesis. However, molecular dynamics (MD) simulations have shown that the selectivity filter is relatively flexible and that Na+ ions are able to interact with the carbonyl ligands that pave the interior of the selectivity filter (2). This leads to the idea that other interactions, such as the repulsion between carbonyl groups, play an important role in the selectivity (3). In addition, the selectivity has been discussed as arising from the favorable arrangement of the carbonyl in the filter, which may promote high coordination numbers, compared to the ion coordination numbers in water (4 and 22)