Flipping mechanism of R253 between D400 and E402 in the WT model.

Interaction interface between the linker (blue backbone) and the TI loop (beige backbone) in the WT model. Membrane lipids are represented as cyan-colored sticks. A typical snapshot of the most frequently occurring state is shown in (A). Here, salt bridges between R253 and D400 strongly stabilize the contact between linker and TI loop. In this state, K252 is able to interact with E402. (B) The stable configuration between R253 and D400 breaks several times during the 50 ns long MD simulation whereby R253 gets in contact with E402. In this constellation of salt bridges, the interaction between K252 and the TI loop is interrupted.