A Molecular Mechanics Model of a Closed Voltage-Gated Potassium Channel Generated from S4-S5 Linker LRET Measurements

Abstract

Voltage-gated potassium ion (Kv) channels regulate action potentials of the nervous system by responding to changes in transmembrane voltage, enabling K+ transport across the membrane to restore cells to their resting potential. While several crystal structures of Kv channels have been presented in the open conformation, the closed structure remains unsolved, leaving the Kv channel gating mechanism unclear. Using lanthanide-based resonance energy transfer (LRET) measurements of the S4-S5 linker, which connects the voltage sensor to the pore domain, we modeled the Kv 1.2/2.1 chimera in the open and closed conformations. Through fully atomistic molecular dynamics simulations of the models, we find that a small 4 A displacement of the linker is sufficient to gate the channel. Additionally, we find a 9 A vertical translation of S4, and a 37° change in tilt of S4 with respect to the S4-S5 linker between the open and closed states, in agreement with previously published studies. Here, we present the first model of the closed channel derived from measurements on the cytosolic side of the channel.