Flexibility mechanism of claudin-15 strands. (a and b) Claudins monomers assembly in the cell membrane is facilitated by (a) face-to-face cis-interactions and (b) side-by-side cis-interactions between monomers. The tetrameric ion channel pore is formed by head-to-head trans-interactions between claudins in two membranes (not shown here). Three side-by-side cis-interacting regions identified in the simulations are shown in b. The ECH (green) acts as a pivot point as the local curvatures of the strand change in the plane of the membrane. (c–e) Claudin pairs connected through face-to-face interactions slide with respect to each other to respond to local fluctuations in the strand curvature. Lateral flexibility of the strand originates from the robustness of side-by-side cis-interactions via these three interacting regions.