Mechano-electrical coupling in PIEZO channels revealed from multiscale simulations

The mechanosensitive PIEZO ion channels are implicated in many clinical conditions, including lymphedema, xerocytosis, inflammation, chronic pain, and cancer. However, the molecular mechanisms by which PIEZO senses force remain largely unknown. PIEZO ion channels are thought to open a central pore domain through tension-induced flattening of large peripheral transmembrane domains called arms. Here, we uncover the conformational coupling between arm flattening and pore opening in PIEZO1 and PIEZO2 using hybrid-resolution Molecular Dynamics (MD) simulations. By sampling multiple independent trajectories under physiological activation tension, we reveal an intricate clockwork gating mechanism in which arm flattening correlates with an anticlockwise rotation of the pore relative to the arms and with a clockwise twisting of inner pore helices, enabling dilation and hydration of a transmembrane pore gate. Remarkably, pore dilation is accompanied by the creation of large interhelical gaps filled with lipids, resulting in a fully conducting open walled by lipids and protein. Our work reveals how large-scale rearrangements of mechanosensory domains are precisely funneled into subtle yet complex gating motions in PIEZO channels. The MD-generated open-state model enabled us to discover two new PIEZO1 small-molecule activators through virtual screening.