Inherent Leakage of Hydrophobic Gating in BK Channels

The big potassium (BK) channels remain open with a small limiting probability of P _o ~ 10^-7 at minimal Ca²⁺ and negative voltages < -100 mV. The molecular origin of such "intrinsic opening" are not understood. Here, free energy analysis of K+ permeation shows that intrinsic opening of BK channels is likely an inherent property of the vapor barrier, generated by hydrophobic dewetting of the inner pore in the Ca²⁺-free state. The vapor barrier only gives rise to a finite free energy barrier, of ~ 8 kcal/mol, and cannot completely shut down K⁺ flow even when the voltage sensor domains are fully deactivated. The resulting "leaking" currents can be measured at negative voltages as intrinsic opening. The shallow limiting slope of P _o at negative voltages arises primarily from the electric field effects on the permeating ion through the vapor barrier. We further demonstrate that the vapor barrier can be perturbed by truncation of the cytosolic domains, inner pore mutations, and ligand binding to the pore, leading to predicable changes in limiting slope measurements highly consistent with existing experimental data. Therefore, the intrinsic opening opens up an opportunity for direct experimental study of hydrophobic gating in BK and many other ion channels.