jp709675e_si_005.mpg (6.37 MB)
Gating Motions in Voltage-Gated Potassium Channels Revealed by Coarse-Grained Molecular Dynamics Simulations
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posted on 2008-03-20, 00:00 authored by Werner Treptow, Siewert-J Marrink, Mounir TarekVoltage-gated potassium (Kv) channels are ubiquitous transmembrane proteins involved in electric signaling
of excitable tissues. A fundamental property of these channels is the ability to open or close in response to
changes in the membrane potential. To date, their structure-based activation mechanism remains unclear, and
there is a large controversy on how these gates function at the molecular level, in particular, how movements
of the voltage sensor domain are coupled to channel gating. So far, all mechanisms proposed for this coupling
are based on the crystal structure of the open voltage-gated Kv1.2 channel and structural models of the closed
form based on electrophysiology experiments. Here, we use coarse-grain (CG) molecular dynamics simulations
that allow conformational changes from the open to the closed form of the channel (embedded in its membrane
environment) to be followed. Despite the low specificity of the CG force field, the obtained closed structure
satisfies several experimental constraints. The overall results suggest a gating mechanism in which a lateral
displacement the S4−S5 linker leads to a closing of the gate. Only a small up−down movement of the S4
helices is noticed. Additionally, the study suggests a peculiar upward motion of the intracellular tetramerization
domain of the channel, hence providing a molecular view on how this domain may further regulate conduction
in Kv channels.