Evolution of eukaryotic ion channels: principles underlying the conversion of Ca²⁺-selective to Na⁺-selective...

Ion selectivity of four-domain voltage-gated Ca(2+) and Na(+) channels, which is controlled by the selectivity filter (the narrowest region of an open pore), is crucial for electrical signaling. Over billions of years of evolution, mutation of the Glu from domain II/III in the EEEE/DEEA selectivity filters of Ca(2+)-selective channels to Lys made these channels Na(+)-selective. Why Lys is sufficient for Na(+) selectivity and why the DKEA selectivity filter is less Na(+)-selective than the DEKA one are intriguing, fundamental questions. By computing the free energy for replacing Ca(2+) inside model selectivity filters with Na(+), we find that the nonmetal-ligating Lys in the DKEA/DEKA selectivity filter attenuates metal-protein interactions to such an extent that solvation effects become dominant, favoring Na(+). It constricts and rigidifies the DEKA pore to bind Na(+) optimally, highlighting the importance of lysine's nonobvious structural role, in addition to its electrostatic role, in the selectivity of Na(+) over Ca(2+).