Schematic representation of hERG channel gating. (A) Reaction coordinate diagram for hERG gating, based on the linear gating scheme proposed by Wang et al. (1997). Activation involves transitions through three closed (C) states to a single open (O) state; the inactivated state has been omitted for simplicity. The black line represents the gating reaction for WT channels; the red line highlights possible changes caused by the K525R mutation. These include a more negative value for ΔG₀ consistent with stabilization of the O state and a decrease in the energy barrier (E_(deact)) for the O → C₂ transition to allow for faster deactivation. (B) The same reaction coordinate diagram in A is used to highlight the possible changes to the gating reaction caused by the K538R mutation (green line). These include a positive value for ΔG₀ consistent with stabilization of the closed state and a large increase in the energy barriers for transitions between the C₂ and O states that allows for the increases in the values of τ_act and τ_deact. (C) Schematic showing the proposed functional interactions between the S4 gating charges and F463 and D466 in the S2 segment. Broken lines illustrate the interaction pairs thought to occur in the resting state (left) and the activated state (right).