Transition between conformational states of the TREK-1 K2P channel promoted by interaction with PIP2

Abstract

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 (PIP2). This study used coarse-grained molecular dynamics (CG-MD) and atomistic MD simulations to model the PIP2 binding site on both the up and down state conformations of TREK-1. We also calculated the free energy of PIP2 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 PIP2 to sites involving the proximal C-terminus and we show that PIP2 promotes a conformational transition from a down state towards an intermediate that resembles the up state. These results are consistent with functional data for PIP2 regulation and together provide evidence for a structural mechanism of TREK-1 channel activation by phosphoinositides.