Force field sensitivity of ion occupancy in potassium channels.

Potassium ion channels are responsible for the rapid selective conduction of K+ ions through the cellular membrane. In 1955, Hodgkin and Keynes showed that K+ channel conduction occurs via a multi-ion process in which two to three ions diffuse in single file along a narrow pore. This process is now commonly referred to as the "knock-on" mechanism. The availability of the crystallographic structure of the KcsA channel at atomic resolution nearly 50 years later made it possible to examine the ion conduction mechanism at the atomic level, prompting multiple molecular dynamics simulation studies. Two multi-ion conduction mechanisms have emerged from the initial knock-on proposal, whereby ion conduction occurs via the translocation of a single file of alternating K+ ions and water molecules ("soft-knock"), or via the translocation of a single file comprising only K+ ions with no water molecules ("hard-knock"). Relying on molecular dynamics simulations of the MthK channel with a total aggregate sampling of 78 μs, the occupancy of the selectivity filter is examined for several force field models-including CHARMM C36, AMBER ff14sb, Drude2023, and a set of 26 custom models derived from CHARMM C36 with modified ion-water, ion-backbone, and water-backbone interactions. The results indicate that small variations on the order of kBT in these interactions can lead to pore occupancy states consistent with either the hard- or soft-knock model.