SGTx1, a Kv channel gating-modifier toxin, binds to the interfacial region of lipid bilayers

Abstract

SGTx1 is a gating-modifier toxin that has been shown to inhibit the voltage-gated potassium channel Kv2.1. SGTx1 is thought to bind to the S3b-S4a region of the voltage-sensor, and is believed to alter the energetics of gating. Gating-modifier toxins such as SGTx1 are of interest as they can be used to probe the structure and dynamics of their target channels. Although there are experimental data for SGTx1, its interaction with lipid bilayer membranes remains to be characterized. We performed atomistic and coarse-grained molecular dynamics simulations to study the interaction of SGTx1 with a POPC and a 3:1 POPE/POPG lipid bilayer membrane. We reveal the preferential partitioning of SGTx1 into the water/membrane interface of the bilayer. We also show that electrostatic interactions between the charged residues of SGTx1 and the lipid headgroups play an important role in stabilizing SGTx1 in a bilayer environment.

FIGURE 1

Starting depths of the toxin for the atomistic simulations (SGTx1 in POPC shown). The z axis of the simulation box corresponds to the bilayer normal. Distances (in angstroms) are relative to the bilayer center of mass. SGTx1 is shown at a starting depth of 23.5 Å. The hydrophobic, basic, acidic, and polar residues of SGTx1 are shown in green, blue, red, and white, respectively. POPC carbon, oxygen, nitrogen, and phosphorus atoms are shown in cyan, red, blue, and gold, respectively. The water molecules are shown in light blue.

FIGURE 2

Average displacement of the toxin from the different toxin starting depths during the course of the SGTX-PEPG simulation. Bars represent standard deviation. Gray arrows indicate the directionality of movement of the toxin relative to the bilayer.

FIGURE 3

Distance of toxin center of mass from bilayer center of mass measured along the bilayer normal for the coarse-grained simulations; SGTX-PC-CG (dark gray) and SGTX-PEPG-CG (black). The inset is for SGTX-PEPG-CG, shown over a 10 ns duration.

FIGURE 4

Distribution of lipid headgroup and toxin charged groups at the membrane/water interface for simulations (A) SGTX-PC-CG and (B) SGTX-PEPG-CG, both from t = 50 to 200 ns. In A, the black line shows the distribution of the phosphates of POPC. In B, the phosphate of POPE (black) and POPG (gray) are shown separately. The distributions of basic and acidic residues are in blue and red, respectively.