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Investigating the Structure and Function of Ion Conducting Voltage Sensing Domains


Voltage-gated ion channels (VGICs) open and close in response to changes in electric potential across the cell membrane to control the flow of ions into and out of the cell. Typical VGICs contain four subunits, each subunit contains 6 helices (termed S1-S6). Helices S1, S2, S3 and S4 compose a voltage sensing domain, while helices S5 and S6 from each subunit contribute to a single pore domain. The pore domain conducts ions selectively, however mutations in the VSD can lead to aberrant ionic currents through the voltage-sensor. These currents, termed omega currents, are studied in atomistic detail using molecular dynamics simulations. Additionally, I performed simulations of the Hv1 voltage gated proton channel, which is homologous to the VSD of typical VGICs but lacks the typical pore domain. The structural similarities between Hv1 and typical VGIC VSDs were exploited to construct a homology model of the channel, which was used as a starting point for probing the mechanism of proton conduction prior to the discovery of a crystal structure for the channel. I found spontaneous formation of hydrogen bonded water wires in the homology model of Hv1 which do not form in simulations of the non-conducting VSDs, supporting a Grotthuss style hopping mechanism for proton conduction through Hv1. The crystal structure for a mouse voltage-gated proton channel chimera was solved in 2014. The improved template provided inspiration for a new model of the human proton channel, which proved stable on the microsecond timescale. A depolarizing, or opening, applied transmembrane voltage revealed motions of the S4 helix consistent with experimental measurements of gating charge transfer during voltage-activation. The final configuration from these microsecond simulations is presented as a likely open-state model of the channel.

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