Simulation of gating currents of the Shaker K channel using a Brownian model of the voltage sensor

TL;DR

This paper introduces a Brownian dynamics model of the voltage sensor in the Shaker K channel, successfully simulating gating currents and elucidating the physical mechanism of voltage-dependent gating.

Contribution

It presents a novel stochastic model treating the S4 segment as a Brownian particle, enabling efficient simulation of gating currents and detailed analysis of gating charge transfer.

Findings

Model reproduces experimental gating current properties.

S4 segment exhibits five stable positions during gating.

Gating charge transfer occurs through movement among these positions.

Abstract

The physical mechanism underlying the voltage-dependent gating of K channels is usually addressed theoretically using molecular dynamics simulations.However, besides being computationally very expensive, this approach is presently unable to fully predict the behavior of fundamental variables of channel gating, such as the macroscopic gating current.To fill this gap here we propose a voltage gating model that treats the S4 segment as a Brownian particle moving through a gating channel pore and adjacent internal and external vestibules.In our model charges on the S4 segment are screened by charged residues localized on the other segments of the channel protein, and by ions present in the vestibules, whose dynamics is assessed using a flux conservation equation. The electrostatic voltage spatial profile is consistently assessed by applying the Poisson equation to all the charges present in the system. The treatment of the S4 segment as a Brownian particle allows to alternatively describe the dynamics of a single S4 segment, using the Langevin stochastic differential equation, or the behavior of a population of S4 segments, useful to assess the macroscopic gating current, using the Fokker-Planck equation. The proposed model confirms the gating charge transfer hypothesis, with the movement of the S4 segment among 5 different stable positions where the gating charges differently interact with the negatively charged residues on the channel protein. This behavior results in macroscopic gating currents displaying properties quite similar to those experimentally found, including a very fast component followed by a slower one with an evident rising phase at high depolarizing voltages.