Mechanosensitive Piezo ion channels are implicated in a wide range of physiological processes in multicellular organisms, through sensing the mechanical stimuli experienced by various cell types. Up to now, it is still unclear how Piezo channels sense mechanical stimuli through membrane to activate and open the pore formed by the assembly of three identical subunits. In this work, we employed multiscale simulations to explore the lipid-protein interactions for Piezo channels. We first probed the lipid binding to Piezo1 with different symmetric and asymmetric lipid bilayers, including 1-palmitoyl-2-oleoy phosphatidylcholine (POPC), 1-palmitoyl-2-oleoyl phosphatidylserine (POPS), Phosphatidylinositol-(4,5)-bisphosphate (PIP2), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE), and also a model plasma membrane. Each system was first simulated for 30-40 µs using molecular dynamics (MD) simulations at the coarse-grained (CG) level with MARTINI force field, and then reverse-mapped to all-atom representation (around 670,000 atoms) for 1µs simulation on Anton2 supercomputer. To identify statistically significant lipid-protein interactions, we calculated lipid residence time, diffusion, lipid interaction site-coupling statistical analysis. To investigate the impacts of the intrinsic property lipid bilayers on Piezo1 channel, we also simulated the pure bilayer with different composition of lipids and measured membrane thickness, curvature, area compressibility, and bending rigidity. The membrane footprint calculated from Piezo1 embedded in a 50 × 50 nm dimension plasma membrane CG simulation was also quantitatively compared with a mathematical footprint model. Our results show that most of the PIP2s in the lower leaflet bind to Piezo1 intracellular part, while POPS lipids are evenly distributed through the whole lower leaflet. The difference between PIP2 and POPS binding affinity can attribute to the strong electrostatic interaction between Piezo1 intracellular surface and negative charged PIP2. Lipid density maps in POPS bilayer membrane through 30µs show several stable binding sites around Piezo 1, one of which is located in the pore, which left upon mechanical stimulation by membrane tension. Thus our results suggest a polymodal modulation of lipid on Piezo1 channel, ranging from pore blocking, curvature modulation, to force-from-lipid enhancer.

Investigating the mechanical perturbations of asymmetric lipid bilayers on mechanosensitive Piezo ion channels through multiscale approach

2019 Fall National Meeting

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