Voltage-Gating Mechanism in Potassium Channels
Voltage-gated potassium channels are membrane proteins that regulate the ﬂow of K+ ions across the cell membrane. These channels respond to changes in electrostatic potential across the cell membrane, and allow passage of K+ ions through their conduction pore. In excitable cells, an interplay of voltage-gated K+, Na+, and Ca2+ channels results in generation of electrical signals, known as action potential, that are propagated along the cell membrane. The crystal structure of Kv1.2, a voltage-gated potassium channel from rat brain, provided the ﬁrst atomic-resolution structure of a voltage-gated potassium channel, in which the ion conduction gate is open. The studies presented in this dissertation use molecular dynamics simulations to investigate the ion permeation, as well as the gating mechanism of voltage-gated potassium channels. The atomic- resolution structures of Kv1.2 in the active and resting state conformations are reﬁned in an explicit representation of the membrane environment. The gating charge of the Kv1.2 channel was calculated from all-atom molecular dynamics simulation. The residue-based decomposition of the gating charge revealed that the initial model of the closed state of Kv1.2 represents an intermediate conformation of the channel that precedes the resting state conformation. Electrostatic calculations revealed a highly-focused electric ﬁeld within the protein, inside membrane. The calculations showed how a rather small movement of gating residues within this highly focused ﬁeld is suﬃcient to provide enough energy to open and close the ion conduction pore. In addition, permeation of K+ ions through potassium channels was investigated. The simulations provided the ﬁrst tra jectories of ion conduction through the selectivity ﬁlter of potassium channels, conﬁrming the notion of “knock-on“ mechanism suggested more than 50 years ago by Hodgkin and Katz. The simulations revealed the sequence of multi-ion conﬁgurations involved in permeation and the jump of ions between previously identiﬁed binding sites.
University of Illinois - Urbana-Champaign
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University of Illinois at Urbana-Champaign