Results of MD simulations in which the cage domain in the resting and inactivated states was subjected to a compressive force applied to the lower half of the cage normally toward the plane of the membrane. (A and B) Closed and inactivate conformations at the start and at 8 ns (marked with black arrows). (C) The applied force causes similar displacement of the bottom and center of mass (COM) of the cage in both closed and inactivated states; however, the gate region displaces more toward the center of the membrane in the inactivated state (blue line), apparently because of the detached state of TM1–TM2 pairs from the TM3 barrel. (D) Cage volume decreases similarly under compression in both conformations; however, cage pressing on the TM barrel causes twice as large of an increase of the in-plane area of the inactivated conformation as it has lipid-facing helices detached from the pore-lining TM3 barrel, thus favoring the transition from the closed to inactivated state under tension. (E and F) Cage compression and the barrel expansion are illustrated by the contours of cross section radii (E), whereas overlay of the closed state with no compression and inactivated state under force (F) explains the geometry change with inactivation and the reason for the synergy between tension and crowding pressure in driving inactivation.