An emerging consensus on voltage-dependent gating from computational modeling and molecular dynamics simulations

Abstract

Developing an understanding of the mechanism of voltage-gated ion channels in molecular terms requires knowledge of the structure of the active and resting conformations. Although the active-state conformation is known from x-ray structures, an atomic resolution structure of a voltage-dependent ion channel in the resting state is not currently available. This has motivated various efforts at using computational modeling methods and molecular dynamics (MD) simulations to provide the missing information. A comparison of recent computational results reveals an emerging consensus on voltage-dependent gating from computational modeling and MD simulations. This progress is highlighted in the broad context of preexisting work about voltage-gated channels.

Figure 1.

Overall view of the voltage-activated Kv1.2 K⁺ channel (Protein Data Bank accession no. 3LUT). (A) Two of the four subunits of the channel are displayed from a side view. The VSD comprises the transmembrane segments S1–S4, and the pore domain comprises the transmembrane segments S5–S6. (B) The tetramer is displayed from the extracellular side (each subunit is a different color). The two views are related by a 90° rotation.

Figure 2.

Main elements of secondary structure of the VSD in the active and resting state. (A) The VSD in the active conformation (taken from the x-ray structure; PDB accession no. 3LUT). (B) A superposition of different models of the resting-state configuration of the VSD obtained by independent research teams (Delemotte et al., 2010; Schwaiger et al., 2011; Vargas et al., 2011; Jensen et al., 2012) using different constraints and methodologies. The four helices, S1 (gray), S2 (yellow), S3 (red), and S4 (blue), are displayed. The spheres correspond to the Cα atoms of E1 (Glu226) and E2 (Glu236) along S2, and R1 (Arg294) along S4.