Figure 2. There are two modes of protein-lipid interactions each favored either in the activated/open (A/O, top panels) or resting/closed (R/C, bottom panels) states of Kv7.1.

(a) Probabilities of salt bridges formation between PIP₂ and positive residues of Kv7.1 among all subunits. Multiple MD runs are considered. The standards deviations (SDs) are represented as bars. (b) Coordination of PIP₂ by residues composing the intrasubunit binding site: K183, R190 and R195 of the S2–S3 loop, R237 and R243 of S4, R249 of the S4–S5 linker, K354 and K358 of the S6 terminus. K183 and R249, the gain-of-function residues, are highlighted in red. (c) Side (left panel) and top (right panel) views of the representative equilibrium position of PIP₂ at the intrasubunit binding site. Note that PIP₂ anchors the S6 terminus in the A/O state of Kv7.1. When the channel is R/C, the lipid is shifted toward the VSD to interact with the bottom of S4.