  The large-conductance, calcium-activated potassium (BK) channel lacks the
typical intracellular bundle-crossing gate present in most ion channels of the
6TM family. This observation, initially inferred from Ca$^{2+}$-free-pore
accessibility experiments and recently corroborated by a CryoEM structure of
the non-conductive state, raises a puzzling question: how can gating occur in
absence of steric hindrance? To answer this question, we carried out molecular
simulations and accurate free energy calculations to obtain a microscopic
picture of the sequence of events that, starting from a Ca$^{2+}$-free state
leads to ion conduction upon Ca$^{2+}$ binding. Our results highlight an
unexpected role for annular lipids, which turn out to be an integral part of
the gating machinery. Due to the presence of fenestrations, the "closed"
Ca$^{2+}$-free pore can be occupied by the methyl groups from the lipid alkyl
chains. This dynamic occupancy triggers and stabilizes the nucleation of a
vapor bubble into the inner pore cavity, thus hindering ion conduction. By
contrast, Ca$^{2+}$ binding results into a displacement of these lipids outside
the inner cavity, lowering the hydrophobicity of this region and thus allowing
for pore hydration and conduction. This lipid-mediated hydrophobic gating
rationalizes several seemingly problematic experimental observations, including
the state-dependent pore accessibility of blockers.
