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

Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637.
The Journal of General Physiology (Impact Factor: 4.79). 12/2012; 140(6):587-94. DOI: 10.1085/jgp.201210873
Source: PubMed


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.

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    • "A central pore module composed of the pore-forming S5, P, and S6 transmembrane segments from four homologous subunits or domains (Fig. 4A, left, blue) is surrounded by four symmetrically arranged voltage-sensing modules containing the S1–S4 transmembrane segments (Fig. 4A, left, green) connected by the S4–S5 linkers (Fig. 4A, left, red). Current structure-function models indicate that positive gating charges at intervals of three amino acid residues in the S4 transmembrane segment in each voltage-sensing module move outward under the influence of the electric field and initiate opening of the activation gate at the intracellular end of the pore by exerting a torque on the inner end of the pore-lining S6 segments (Catterall, 2010; Vargas et al., 2012; Yarov-Yarovoy et al., 2012). The structure of Na V Ab captures the preopen state—all voltage sensors are activated while the pore remains closed but poised to open (Payandeh et al., 2011). "
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