The Electric Fingerprint of Membrane Voltage Sensor Domains

Abstract

Voltage-sensor domains (VSDs) are electrically-charged constructs controlling the voltage-dependent activity of ion channels in excitable cells. Four packed transmembrane (TM) helices, S1 through S4, form the domain in which S4 contains 4 to 7 positively charged basic amino acids, mostly arginines. VSDs operate essentially by transferring the S4 charges across the transmembrane electric field (E), giving rise to the observable Q, the so-called “gating charge”. Mostly supported by structure-function studies on voltage-gated potassium (Kv) channels, a focused E has been identified as one key electric property of the VSD machinery. The recent increasing availability of other VSD-containing ion channel structures, including the x-ray structures for the NavAb and NavRh voltage-gated Na+ channels, provides us with the opportunity to extend the structure-based investigation of the domain electrostatic properties over a larger set of distinct conformations and isoforms. Using all-atom MD simulations in combination with electrostatic calculations, founded on an energetic formalism, we show that, over the entire set of available VSD structures, a specific hydration of the voltage sensor focuses E over a narrow TM region across the domain, at the vicinity of the so-called catalytic center. Furthermore, its focalization and shape is largely preserved over distinct conformations of the construct. Our results support that a focused and conformation-independent TM field is a robust electric feature of the VSD machinery, despite sequence variations or local structural modifications of the domain. This electric fingerprint seems to favor a highly conserved sensing mechanism for VSDs over the large family of voltage-gated cation channels.