Modelling and simulations of the inward-rectifying potassium channel Kir2.1

Abstract

The Kir2.x family of inward-rectifying potassium channels is responsible for the IK1 current in the human heart. This current stabilizes the resting membrane potential and shapes the final repolarization the ventricular action potential in the late phase. We built homology models for human Kir2.1, starting with the crystallographic structures of a chimera of mouse Kir3.1 and KirBac1.3 as templates. We performed full-atomistic molecular dynamics simulations starting with one of these models. Five production trajectories, totalling 100 ns, were obtained using different equilibrating conditions and initial numbers of potassium ions in the cavity. Analyses of these trajectories included diagonally-opposite carbonyl carbon measurements for the filter region and pore radius profiles. Results from these analyses gave insight to the gating and permeation processes of Kir2.1. For example, the 4 residues of Met180, located next to the cavity away from the filter region, were the major determinant of gating in the transmembrane domain. A cross-product indicator showed the opening extent of this gate. Further, to investigate the role of magnesium binding in the mechanism of inward-rectification, we calculated the Poisson-Boltzmann energy profiles for a magnesium ion in the pores of the models. This suggested possible magnesium binding sites.