Simulation setup and Piezo1 structure. Shown is the initial system setup as viewed from (A) the side of the bilayer and (B) from the extracellular side of the membrane. In (A), Piezo1 is shown by the gray surface, whereas each different lipid type is shown in different colors, and water is shown as a green surface. Ions are omitted for clarity. In the top down view, each protein chain colored differently. The box highlights one protein subunit as represented in (C). Only the central part of the simulation system is shown. (C) Shown is the topology of a single subunit of the truncated construct, with each part of the secondary structure labeled. Helices 1–12 are absent in this protein model. ah6 is a computationally predicted amphipathic helix. The location of predicted PIP- and CHOL-binding sites are highlighted by purple and yellow regions, respectively. To see this figure in color, go online.