The mechanosensitive ion channels Piezo 1 and 2 induce a curved protein-membrane nanodome that flattens with increasing membrane tension γ. The tension-induced flattening of the nanodome is associated with Piezo activation and driven by the energy γΔA where ΔA is the excess area of the curved nanodome relative to its planar projected area. Based on extensive coarse-grained and atomistic simulations of membrane-embedded Piezo 1 and 2 proteins, we report here an excess area ΔA for the Piezo protein-membrane nanodome of about 40 nm2 in tensionless membranes, and a half-maximal reduction of ΔA at tension values of about 3–4 mN/m, which is within the range of experimentally determined values for the half-maximal activation of Piezo 1. In line with recent experimental investigations of Piezo proteins in cell membranes and membrane vesicles, the membrane-embedded Piezo proteins adopt conformations in our simulations that are significantly less curved than the protein conformation in the detergent micelles of cryo-EM structures. An elasticity analysis of the nanodome shapes and protein conformations obtained from our simulations leads to an elastic model for Piezo activation that distinguishes the different energy components of the protein and the membrane in the tension-induced flattening of the nanodome. According to this model, the Piezo proteins resist flattening with a force constant of about 60 pN/nm.
