Molecular Dynamics Simulations of Voltage-Gated Cation Channels: Insights on Voltage-Sensor Domain Function and Modulation

Abstract

Since their discovery in the 1950s, the structure and function of voltage-gated cation channels (VGCC) has been largely understood thanks to results stemming from electrophysiology, pharmacology, spectroscopy, and structural biology. Over the past decade, computational methods such as molecular dynamics (MD) simulations have also contributed, providing molecular level information that can be tested against experimental results, thereby allowing the validation of the models and protocols. Importantly, MD can shed light on elements of VGCC function that cannot be easily accessed through “classical” experiments. Here, we review the results of recent MD simulations addressing key questions that pertain to the function and modulation of the VGCC’s voltage-sensor domain (VSD) highlighting: (1) the movement of the S4-helix basic residues during channel activation, articulating how the electrical driving force acts upon them; (2) the nature of the VSD intermediate states on transitioning between open and closed states of the VGCC; and (3) the molecular level effects on the VSD arising from mutations of specific S4 positively charged residues involved in certain genetic diseases.

The Voltage Sensor Module in Sodium Channels

“…X-ray diffraction data of the S1-S4 region from the crystal structure of the bacterial cyclic nucleotide channel MIotiK1 resolved in the closed state (Clayton et al 2008) has also proven useful in generating models of voltage-gated channels in the resting conformation. In general, these investigations support a model of voltage gating in which the S4 helix translocates a short distance across a focused electric field, with limited movement of the S1, S2, and S3 helices (studies reviewed in Delemotte et al 2012;Vargas et al 2012).…”

“…Structural or homology modeling of open and closed states of ion channels has been exploited in computer simulations of voltage sensor movement in molecular dynamics trajectory calculations (reviewed by Sigworth 2007;Dror et al 2010;Roux 2010;Delemotte et al 2012;Vargas et al 2012). An example of a voltage sensor module embedded in a POPC membrane after equilibration and prior to simulation of an applied membrane potential is shown in Fig.…”

Membrane Protein Structure, Function, and Dynamics: a Perspective from Experiments and Theory

“…Using an MD based protocol to trigger deactivation (closing) of the channel in a model POPC membrane the details of the S4 sensor downwards movement were revealed (Delemotte, Klein & Tarek, 2012; Delemotte et al, 2011; Tarek & Delemotte, 2013). Interestingly, several of the S4 positive charges are stabilized by their interaction with the lipid head groups, not only in the activated state, where the two top charges are bound to top leaflet phosphate groups, but also in the intermediate and resting states: in the middle intermediate state, the outermost charge is in contact with the top PO 4 -group and the innermost charge in contact with the inner leaflet PO 4 -groups and in the resting state, the innermost three charges interact with the inner leaflet phosphate group.…”

Molecular biology and biophysical properties of ion channel gating pores

“…The identification of the GCTC as the interaction partner of the S4 segment led to the observation that this interaction creates a hydrophobic septum in the center of the VSD (Fig. 4) (Delemotte et al 2012) that is maintained during the movement of S4 since the positively charged residues of S4 interact sequentially with the GCTC, resulting in metastable intermediate states (Amaral et al 2012;Delemotte et al 2011).…”