An Open State Was Induced by Mimicking Mechanosensitive Piezo1 Channel Clusters in Molecular Dynamic Simulations

Abstract

Piezo ion channels are major mechanotransduction proteins in eukaryotes. Their bowl-like structure creates a local membrane pit, called Piezo dome, whose membrane footprint extends beyond the channel boundary. Several studies have reported the presence of Piezo1 clusters at the cell membrane. Here, using a hyperbolic tangent model, we first propose that the overlap of neighboring footprints in such clusters create membrane topology constraints that spontaneously flatten the Piezo dome. Several all-atom molecular dynamics simulations of Piezo1 show that this spontaneous flattening is accompanied by gating motions that open the pore. This open state recapitulates ionic selectivity, unitary conductance and mutant phenotypes obtained from many experimental studies. Tracking ion permeation through the open pore reveals the presence of intracellular and extracellular fenestrations acting as selectivity filters. In addition, we show the existence of multiple potential binding sites for phosphatidylinositol 4,5-bisphosphates, whose individual disruption by mutagenesis do not abolish mechanically-induced Piezo1 currents. This open state model sheds light on the interplay between Piezo1 and membrane topology, and the mechanisms of ion permeation and selectivity.