Figure 5. Chemical mechanism of ion permeation and selectivity of Na_V and Ca_V channels with structural models of their ion selectivity filters with ions bound.

a, Na⁺ selectivity filter (TLESWSM) in Na_VAb. b, Representative conformations of Na⁺ selectivity filter from molecular dynamic simulations of sodium permeation in Na_VAb. Conformational dunking of Glu side chain of the high-field strength site allows direct coordination of Na⁺ ions. c, Ca²⁺ selectivity filter (TLDDWSN) in Ca_VAb. d, Hydrated Ca²⁺ bound in the Ca_VAb selectivity filter. e, Ca²⁺ selectivity filter of Ca_V1.1 from Domains I (TMEGWTD) and III (TFEGWPQ). f, Ca²⁺ selectivity filter of Ca_V1.1 from Domains II (TGEDWNS) and IV (TGEAWQE). Na⁺ (purple) and Ca²⁺ (green) ions are shown with semi-transparent ionic sphere. Dash lines indicate network of interactions among coordinated water molecules with the ions and protein atoms from high-filed strength site (Glu in Na_VAb and Ca_V1.1, and Asp in Ca_VAb, underlined) and backbone carbonyls of Leu and Thr. For clarity, only two opposing subunits in the tetramer are shown. Of note, a distantly related non-voltage-gated Ca²⁺ channel has a different architecture of its outer pore with Asp residues from each subunit directly binding dehydrated Ca2+ in a closed state structure⁵⁶. The significance of this binding mode in ion conductance is unknown.