Ion-blocking sites of the Kir2.1 channel revealed by multiscale modeling

The Kir2.1 potassium channel owes its inward-rectifying behavior to blocking by multivalent ions, e.g., magnesium and spermine, which access the channel from the cytoplasm and are thought to bind within the pore. To investigate the pathway followed by these ions from the cytoplasm through the pore, we have used multiscale modeling (via continuum electrostatics calculations, docking, and molecular dynamics simulations) to identify possible binding sites en route. On its way to eventually binding in the cavity, magnesium interacts extensively with Glu299, which lines the pore in the center of the intracellular domain. Interaction sites for spermine are formed by Asp255, Glu299, and Glu224. Entropic factors seem to favor interactions of spermine within the center of the cytoplasmic domain.