The cell membrane is the barrier that permits life to maintain its non-equilibrium state. Channels and transporters stud the cell membrane, allowing exchange with the outside environment or the larger organism. Our work focuses on voltage-gated potassium channels, which play a key role in many cellular and organismal functions, including signal transmission in our nervous system. These channels achieve the remarkable feat of fast, efficient transport of potassium ions, while rejecting sodium ions with high fidelity. This feat is even more amazing considering that both are monovalent cations with similar sizes. In fact, sodium is actually smaller than potassium, so selection by simple size exclusion is not possible.

The cover image for the January 7 issue of Biophysical Journal is an artistic rendering of the KcsA protein (blue), a bacterial potassium channel, embedded in a cell membrane (cyan) and surrounded by water (red/white). The image was constructed using a narrow depth of field to bring the potassium ions (purple) and water molecules in the central part of the channel into focus. This central part of the channel, which is small enough to force potassium ions and water molecules into single file, is thought to be responsible for its selectivity and efficiency. Yet, researchers still debate on how the movement of water molecules and potassium ions through the channel creates this selectivity. Even the question of whether water can move through the channel at all is disputed. The yellow beams in the cover art depict one approach to solving this problem: infrared spectroscopy. The incoming laser pulses of a two-dimensional infrared experiment generate spectra like those in the lower right corner. The "silver bullet" of this approach is the ability to compute infrared spectra via computer simulation with atomistic detail, allowing one to assign atomistic detail to experimental spectra. Our work turns this paradigm on its head: instead of using computer simulation to interpret experiments, we use computer simulation to narrow the field of possible infrared experiments and propose a specific set of experiments that will be able to nail down the mechanism of ion transport. These experiments are currently in progress in the Zanni Group. Please visit https://zanni.chem.wisc.edu for more details.

We hope that our work will not only lead to a consensus on the mechanism of ion transport in potassium channels, but also contribute to solving the mystery of fast and selective transport. Further, our work serves as a proof of principal for the general approach of using computer simulation to propose infrared experiments. This approach is applicable to a wide variety of biophysical problems and will hopefully see fruitful use in the future.

- Steven E. Strong, Nicholas J. Hestand, Alexei A. Kananenka, Martin T. Zanni, and J. L. Skinner