CONFORMATIONAL DYNAMICS OF THE LIGAND-BINDING DOMAIN OF INWARD RECTIFIER K CHANNELS AS REVEALED BY MD SIMULATIONS: TOWARDS AN UNDERSTANDING OF KIR CHANNEL GATING

¹ Univ of Oxford
² University of Oxford
³ Univ. Lab of Physiology

^* To whom correspondence should be addressed. E-mail: mark{at}biop.ox.ac.uk.

Submitted on August 29, 2004
Revised on October 20, 2004
Accepted on 4 February 2005

	Abstract

Inward rectifier (Kir) potassium channels are characterized by two transmembrane helices per subunit, plus an intracellular C-terminal domain that controls channel gating in response to changes in concentration of various ligands. Based on the crystal structure of the tetrameric C-terminal domain of Kir3.1, it is possible to build a homology model of the ATP-binding C-terminal domain of Kir6.2. Molecular dynamics (MD) simulations have been used to probe the dynamics of Kir C-terminal domains, and to explore the relationship between their dynamics and possible mechanisms of channel gating. Multiple simulations, each of 10 ns duration, have been performed for Kir3.1 (crystal structure) and Kir6.2 (homology model), in both their monomeric and tetrameric forms. The Kir6.2 simulations were performed with and without bound ATP. The results of the simulations reveal comparable conformational stability for the crystal structure and the homology model. There is some decrease in conformational flexibility when comparing the monomers with the tetramers, corresponding mainly to the subunit interfaces in the tetramer. The â-phosphate of ATP interacts with the sidechain of K185 in the Kir6.2 model and simulations. The flexibility of the Kir6.2 tetramer is not changed greatly by the presence of bound ATP, other than in two loop regions. Principal components analysis of the simulated dynamics suggests loss of symmetry in both the Kir3.1 and Kir6.2 tetramers, consistent with 'dimer-of-dimers' motion of subunits in C-terminal domains of the corresponding Kir channels. This is suggestive of a gating model in which a transition between exact tetrameric symmetry and dimer-of-dimers symmetry is associated with a change in transmembrane helix packing coupled to gating of the channel. It is of interest that loss of exact rotational symmetry has also been suggested to play a role in gating in the bacterial Kir homologue, KirBac1.1, and in the nicotinic acetylcholine receptor channel.

Key Words: K channel, gating, homology model, inward rectifier, molecular dynamics, simulation

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