Fig. 7: Schematic of the mechanism of the down-up transition in Ci-VSD.

Sensing arginines and countercharges are depicted as sticks; hydrophobic plug residues are depicted as shaded yellow circles. a In the down state (q₊ = 0), R223 forms a salt bridge with D129 above the hydrophobic plug. R226 is hydrated, while R229 interacts mainly with E183 and D186, and R232 coordinates to POPC headgroups. b First (q₊ ≈ 0.25), R226 rotates upwards as the S4 helix rotates, which allows it to cross the hydrophobic plug and begin forming a salt bridge with D129. c Near the transition state (q₊ ≈ 0.5), R226 interacts with D129, while R229 interacts with both E183 and D186. d Beyond the transition state (q₊ ≈ 0.75), R229 detaches from E183, and R232 interacts with both E183 and D186. e The S4 helix translocates to its final up state position (q₊ = 1).