Long-pore electrostatics in inward-rectifi er potassium channels

Inward-rectifi er potassium (Kir) channels differ from the canonical K + channel structure in that they possess a long extended pore ( - 85 Å ) for ion conduction that reaches deeply into the cytoplasm. This unique structural feature is presumably involved in regulating functional properties specifi c to Kir channels, such as conductance, rectifi cation block, and ligand-dependent gating. To elucidate the underpinnings of these functional roles, we examine the electrostatics of an ion along this extended pore. Homology models are constructed based on the open-state model of KirBac1.1 for four mammalian Kir channels: Kir1.1/ROMK, Kir2.1/IRK, Kir3.1/GIRK, and Kir6.2/KATP. By solving the Poisson-Boltzmann equation, the electrostatic free energy of a K + ion is determined along each pore, revealing that mammalian Kir channels provide a favorable environment for cations and suggesting the existence of high-density regions in the cytoplasmic domain and cavity. The contribution from the reaction fi eld (the selfenergy arising from the dielectric polarization induced by the ion ' s charge in the complex geometry of the pore) is unfavorable inside the long pore. However, this is well compensated by the electrostatic interaction with the static fi eld arising from the protein charges and shielded by the dielectric surrounding. Decomposition of the static fi eld provides a list of residues that display remarkable correspondence with existing mutagenesis data identifying amino acids that affect conduction and rectifi cation. Many of these residues demonstrate interactions with the ion over long distances, up to 40 Å , suggesting that mutations potentially affect ion or blocker energetics over the entire pore. These results provide a foundation for understanding ion interactions in Kir channels and extend to the study of ion permeation, block, and gating in long, cation-specifi c pores.