BK Channel Hydrophobic Gating

In addition to the comprehensive model of BK gating, I have worked on advanced sampling methods for the free energy of dewetting in nanoscale pores including the one in BK. BK channels can be activated by both membrane voltage and intracellular calcium binding. Intriguingly, the structures reveal that the inner pore remains wide-open in both activated and deactivated states. Combining atomistic simulations and experiments, we recently showed that BK channels contain a “hydrophobic gate”, where the inner pore desolvates and is impermeable to ions. I proposed a sampling protocol to accelerate simulations of reversible hydrophobic dewetting transitions, and validated its accuracy and efficiency using simulations of model nanopores. My undergraduate mentee and I showed that the protocol could be extended to sample dewetting alongside cosolvents relevant to ion channels like salt and glycerol. I have applied a modified protocol to quantify how key inner pore mutations modulate the open-close equilibrium in the BK channel itself. I am currently working on quantifying the effect channel-activating small molecules have on the free energy of dewetting. The mechanism of action of these channel-activators is yet unknown but may be partially related to desolvation. Sometimes, I even able to see an ion permeation, as in the video...