Key result
Atomistic molecular dynamics simulations provided insights into the Shaker VSD permeation pathway, protein-ion interactions controlling permeation kinetics, and voltage-dependent activation mechanisms.
Atomistic molecular dynamics simulations provide mechanistic insights into ion conduction through the voltage-sensing domain of the Shaker K+ channel.
No clinical implications for arrhythmia care; leaves open translation of Shaker VSD mechanisms to human cardiac channels.
Voltage-sensing domains (VSDs) sense changes in the membrane electrostatic potential and, through conformational changes, regulate a specific function. The VSDs of wild-type voltage-dependent K +, Na +, and Ca 2+ channels do not conduct ions, but they can become ion-permeable through pathological mutations in the VSD. Relatively little is known about the underlying mechanisms of conduction through VSDs. The most detailed studies have been performed on Shaker K + channel variants in which ion conduction through the VSD is manifested in electrophysiology experiments as a voltage-dependent inward current, the so-called omega current, which appears when the VSDs are in their resting state conformation. Only monovalent cations appear to permeate the Shaker VSD via a pathway that is believed to be, at least in part, the same as that followed by the S4 basic side chains during voltage-dependent activation. We performed μs-time scale atomistic molecular dynamics simulations of a cation-conducting variant of the Shaker VSD under applied electric fields in an experimentally validated resting-state conformation, embedded in a lipid bilayer surrounded by solutions containing guanidinium chloride or potassium chloride. Our simulations provide insights into the Shaker VSD permeation pathway, the protein-ion interactions that control permeation kinetics, and the mechanism of voltage-dependent activation of voltage-gated ion channels.
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Wood et al. (2017) studied this question. Atomistic molecular dynamics simulations was evaluated on Insights into the Shaker VSD permeation pathway, protein-ion interactions, and mechanism of voltage-dependent activation. Atomistic molecular dynamics simulations provided insights into the Shaker VSD permeation pathway, protein-ion interactions controlling permeation kinetics, and voltage-dependent activation mechanisms.
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