Inward-rectifier K+ (Kir) channels are ion channels that transport potassium into the cell. They are essential to maintain the resting membrane potential and to regulate the action potential duration in excitable cells [1]. As a consequence, Kir mutations result in several diseases, such as periodic paralysis or cardiac arrhythmia [1, 2].The activity of Kir channels is regulated by phosphatidylinositol-(4,5)-bisphosphate (PIP2), a negatively charged phospholipid that has been recognized as one of the major regulators of membrane excitability [2]. Moreover, it has been suggested that Kir activation is not only regulated by PIP2, but it has a secondary, non-specific requirement for other anionic phospholipids [3].Here we have investigated the interaction of phosphatidylserine (PS) with Kir 2.2 by means of all-atom molecular dynamics (MD). Simulations have been performed on both the apo and PIP2-bound states of the channel [4], embedded in a POPS membrane in the presence of KCl. These trajectories reveal the key protein residues interacting with POPS, complementing previous docking [3] and coarse-grain [5] studies. Furthermore, they suggest that the Kir 2.2-POPS interactions drive the cytoplasmic domain closer to the membrane and help to pre-assemble the PIP2 binding site. In other words, our simulations provide a molecular picture of the sensitized state proposed by Nichols and coworkers to explain the synergistic effect of anionic phospholipids [3].[1] Physiol. Rev. 90:291-366 (2010).[2] Pflugers Arch. 460:321-341 (2010).[3] (a) Biophys. J. 100:620-628 (2011). (b) J. Biol. Chem. 288:16726-16737 (2013). (c) Biophys. J., 104:433a (2013).[4] (a) Science, 326:1668-1674 (2009). (b) Nature (Letter), 477:495-499 (2011)[5] Biochemistry, 52:279-281 (2013).