Theoretical Studies of Structure-Function Relationships in Kv Channels: Electrostatics of the Voltage Sensor

TL;DR

This paper uses electrostatic models to analyze the structure-function relationships of Kv channel voltage sensors, favoring a sliding helix model with counter-charges over the paddle model, and compares predictions with experimental data.

Contribution

It introduces an electrostatic framework to evaluate voltage sensor models, supporting the sliding helix with counter-charges as a plausible mechanism.

Findings

The paddle model is electrostatically unfavorable.

The sliding helix model with counter-charges aligns well with experimental data.

Counter-charge positioning influences energy barriers and stability.

Abstract

Voltage-gated ion channels mediate electrical excitability of cellular membranes. Reduced models of the voltage sensor (VS) of Kv channels produce insight into the electrostatic physics underlying the response of the highly positively charged S4 transmembrane domain to changes in membrane potential and other electrostatic parameters. By calculating the partition function computed from the electrostatic energy over translational and/or rotational degrees of freedom, I compute expectations of charge displacement, energetics, probability distributions of translation & rotation and Maxwell stress for arrangements of S4 positively charged residues; these computations can then be compared with experimental results to elucidate the role of various putative atomic level features of the VS. A `paddle' model is rejected on electrostatic grounds, owing to unfavorable energetics, insufficient charge displacement and excessive Maxwell stress. On the other hand, a `sliding helix' model with three local counter-charges, a protein dielectric coefficient of 4 and a 2/3 interval of counter-charge positioning relative to the S4-helix period of positive residues is electrostatically reasonable, comparing well with Shaker (Seoh et al., 1996). Lack of counter-charges destabilizes the S4 in the membrane; counter-charge interval helps determine the number and shape of energy barriers and troughs over the range of motion of the S4; and the local dielectric coefficient of the protein constrains the height of energy maxima. These `sliding helix' models compare favorably with experimental results for single & double mutant charge experiments on Shaker. Single S4 positive charge mutants are predicted quite well by this model; single counter-charge mutants are predicted less well; and double mutants for both an S4 charge and a counter-charge are characterized least well.