Structural Basis for Differences in Dynamics Induced by Leu Versus Ile Residues in the CD Loop of Kir Channels

The effect of the conserved Leu/Ile site in the CD loop on the gating dynamics of Kir channels and corresponding micro-structural mechanism remains unclear. Molecular dynamics simulations were performed to investigate the structural mechanism of chicken Kir2.2. Compared to WT, the I223L mutant channel bound to PIP(2) more strongly, was activated more rapidly, and maintained the activation state more stably after PIP(2) dissociation. Cellular electrophysiology assays of mouse Kir2.1 and human Kir2.2 indicated that, consistent with simulations, the Leu residue increased the channel responses to PIP(2) through increased binding affinity and faster activation kinetics, and the deactivation kinetics decreased upon PIP(2) inhibition. The Ile residue induced the opposite responses. This difference was attributed to the distinct hydrophobic side chain symmetries of Leu and Ile; switching between these residues caused the interaction network to redistribute and offered effective conformation transduction in the Leu systems, which had more rigid and independent subunits. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12035-015-9466-x) contains supplementary material, which is available to authorized users.