Multi-scale modeling shows that dielectric differences make NaV channels faster than KV channels

The generation of action potentials in excitable cells requires different activation kinetics of voltage gated Na (Na V ) and K (K V ) channels. Na V channels activate much faster and allow the initial Na + influx that generates the depolarizing phase and propagates the signal. Recent experimental results suggest that the molecular basis for this kinetic difference is an amino acid side chain located in the gating pore of the voltage sensor domain, which is a highly conserved isoleucine in K V channels, but an equally highly conserved threonine in Na V channels. Mutagenesis suggests that the hydrophobicity of this side chain in Shaker K V channels regulates the energetic barrier that gating charges need to overcome to move through the gating pore, and ultimately the rate of channel opening. We use a multi-scale modeling approach to test this hypothesis. We use high resolution molecular dynamics to study the effect of the mutation on polarization charge within the gating pore. We then incorporate these results in a lower resolution model of voltage gating to predict the effect of the mutation on the movement of gating charges. The predictions of our hierarchical model are fully consistent with the tested hypothesis, thus suggesting that the faster activation kinetics of Na V channels comes from a stronger dielectric polarization by threonine (Na V channel) produced as the first gating charge enters the gating pore, compared to isoleucine (K V channel). eTOC Summary Voltage-gated Na + channels activate faster than K + channels in excitable cells. Catacuzzeno et al. develop a model that shows how the dielectric properties of a divergent side-chain produce this difference in speed.