Seven-state gating polarity model describes bipolar gating phenotype of HHHE-X chimeras. (A) Gating scheme of the seven-state gating polarity model. Voltage-dependent steps, K1 and K2, are bolded to indicate they are constrained, where K1 and K2 values from HHHEH fitting are applied to all HHHE-X chimeras. K3, K4, K5, and K6 are voltage-independent transition steps and vary for each chimera. C, OH, and OD are the closed and opened states of the pore, where OH is for hyperpolarization and OD is for depolarization. V is the state of the voltage sensor such that VR is at rest, VH is upon membrane hyperpolarization, and VD is upon membrane depolarization. N is the interaction due to the cytosolic C terminus upon hyperpolarization, NH, and depolarization, ND. Equations for open probability calculations are in Materials and methods, and parameter values used for fitting are reported in Table S3. (B–J)PO−V plots of fitting the gating scheme in A to the PO−V scatter plot data are shown as a solid black line in each figure panel. PO−V scatter plot data from hERG mutants, i.e., B–D, are adapted from Tristani-Firouzi et al. (2002). These data have been normalized again such that the maximum PO value across all test potentials is normalized to 1 (i.e., relative current/maximum relative current). PO−V scatter plot data from HHHE-X, i.e., E–J, are adapted from Lin et al. (2024). PO−V scatter plot data of D540K hERG (circle ●), D540K-Q664A hERG (upward-pointing triangle ▲), D540K-L666A hERG (square ■), HHHEH (diamond ♦), HHHEH2 (downward-pointing triangle ▼), HHHES (asterisk *), HHHER (right-pointing triangle ►), HHHEK (pentagram ★), and HHHEA (left-pointing triangle ◄).