Members of the TREK family of two-pore domain potassium channels are highly sensitive to regulation by membrane lipids, including phosphatidylinositol-4,5-bisphosphate (PIP₂). Previous studies have demonstrated that PIP₂ increases TREK-1 channel activity; however, the mechanistic understanding of the conformational transitions induced by PIP₂ remain unclear. Here, we used coarse-grained molecular dynamics and atomistic molecular dynamics 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 and free-energy-perturbation 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 toward 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.

双孔结构域钾通道 TREK 家族的成员对膜脂的调节高度敏感，包括磷脂酰肌醇-4,5-二磷酸 (PIP ₂ )。先前的研究表明，PIP ₂会增加 TREK-1 通道的活性；_{然而，对 PIP 2}诱导的构象转变的机制理解仍不清楚。在这里，我们使用粗粒度分子动力学和原子分子动力学模拟来模拟TREK-1 上态和下态构象上的PIP _{2结合位点。我们还计算了 PIP 2}的自由能使用平均力势和自由能微扰计算，在两种构象状态下相对于其他阴离子磷脂进行结合。_{我们的结果确定了 PIP 2}与涉及近端 C 末端的位点的状态依赖性结合，并且我们表明 PIP ₂促进从向下状态到类似于向上状态的中间状态的构象转变。_{这些结果与 PIP 2}调节的功能数据一致，并共同为磷酸肌醇激活 TREK-1 通道的结构机制提供了证据。