Computational Modeling Of Sodium Channel Inactivation

Fast inactivation of the voltage-gated sodium (NaV) channel is crucial in the regulation of the membrane potential in neural and muscle cells. A “hinged lid” mechanism has been proposed to explain the rapid inactivation, in which the inactivation gate (a motif comprised of the intracellular linker between domain III and IV) occludes the channel pore. Interestingly, recent cross-link data suggest a close functional coupling between the inactivation gate and domain IV voltage sensor (DIV VS). However, there is no complete structure available for a eukaryotic NaV channel to support such coupling and reveal the related inactivation mechanism. In the present study, an atomic structure of a eukaryotic NaV channel, including both the transmembrane domain and the inactivation gate, was built by homology modeling and molecular dynamics refinement. The model suggests that the inactivation gate consists of a flexible linker with three short alpha helices. Despite its high flexibility, the inactivation gate mostly interacts with the central pore and DIV VS, a result that agrees with cross-link experimental data. Novel hydrophobic interactions between DIV VS and the inactivation gate have been identified as being key in the stabilization of the inactivated state.