Transition between conformational states of the TREK-1 K2P channel promoted by interaction with PIP(2)

Members of the TREK family of two-pore domain potassium channels are highly sensitive to regulation by membrane lipids, including phosphatidylinositol-4,5-bisphosphate (PIP(2)). Previous studies have demonstrated that PIP(2) increases TREK-1 channel activity; however, the mechanistic understanding of the conformational transitions induced by PIP(2) remain unclear. Here, we used coarse-grained molecular dynamics and atomistic molecular dynamics simulations to model the PIP(2)-binding site on both the up and down state conformations of TREK-1. We also calculated the free energy of PIP(2) binding relative to other anionic phospholipids in both conformational states using potential of mean force and free-energy-perturbation calculations. Our results identify state-dependent binding of PIP(2) to sites involving the proximal C-terminus, and we show that PIP(2) promotes a conformational transition from a down state toward an intermediate that resembles the up state. These results are consistent with functional data for PIP(2) regulation, and together provide evidence for a structural mechanism of TREK-1 channel activation by phosphoinositides.