Big potassium conductance (BK) channels exist in every cell in the body and are important for regulating neuronal firing, vascular smooth muscle tone, circadian rhythms and neurotransmitter release. Here we have used atomistic molecular dynamics simulations based on high-resolution cryo-EM structures to describe the activation cycle of the BK homologue channel, MthK, from <i>Methanobacterium thermoautotrophicum</i>. These structures have resolved previous uncertainty in the closed state of MthK and BK channels, now seen with a narrow intracellular gate that is expected to sterically block ions and other molecules. Our simulations reveal extensive membrane interactions involving the calcium-binding domain and C-linkers that communicate change to the pore domain, as well as lipid-facing fenestrations that connect the pore to the membrane interface, offering a potential pathway for drugs into the closed channel. Our free energy calculations show that these fenestrations provide a preferred pathway for channel blockers, including hydrophobic ions such as tetrapentylammonium, with high calculated on-rates to explain experimental measurements. Our simulations have also described high-affinity N-terminal pore block, known as ball-and-chain N-type inactivation. We show that the N-termini are dynamic in the open state and can bind strongly to lipids, potentially helping explain lipid-composition dependent inactivation. Overall these simulations shed light on the activity and modulation of potassium channels by membrane-active molecules.

Simulations of calcium-activated potassium channel activity and modulation from the membrane

ACS Fall 2021

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