Inwardly rectifying potassium (Kir) channel activity is important in the control of membrane potentials in both excitable and non-excitable cells and is regulated through various ligands, including specific membrane lipids. Phosphatidyl-4,5-bisphosphate (PIP2) is required for activity of all Kir channels, binding to the cytoplasmic domain in a compact conformation tightly tethered to the transmembrane domain. Most Kir2 channel structures determined in complex with PIP2 molecules are nevertheless in a closed state, requiring additional conformational changes for channel opening. We have carried out full atomistic MD simulations, which indicate PIP2-dependent conformational changes that are coupled to opening and closing of the channel. In the presence of bound PIP2, the cytoplasmic domain performs clockwise twisting motions, with a pivot residing near the C-linker in each subunit. These motions are reduced when PIP2 is removed, leading to narrowing of the critical gate at the M2 helix bundle crossing (HBC), but expansion at the region G-loop, as well as reduced overall fourfold symmetry, in turn coupled to cessation of ion permeation.
