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 (K2P) potassium channels are highly sensitive to regulation by membrane lipids, including phosphatidylinositol-4,5-bisphosphate (PIP ₂ ). This study used coarse-grained molecular dynamics (CG-MD) and atomistic MD 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 (PMF) and free energy perturbation (FEP) 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 towards 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.