Lipid Bilayer Deformation and the Free Energy of Interaction of a Kv Channel Gating-Modifier Toxin

Abstract

A number of membrane proteins act via binding at the water/lipid bilayer interface. An important example of such proteins is provided by the gating-modifier toxins that act on voltage-gated potassium (Kv) channels. They are thought to partition to the headgroup region of lipid bilayers, and so provide a good system for probing the nature of interactions of a protein with the water/bilayer interface. We used coarse-grained molecular dynamics simulations to compute the one-dimensional potential of mean force (i.e., free energy) profile that governs the interaction between a Kv channel gating-modifier toxin (VSTx1) and model phospholipid bilayers. The reaction coordinate sampled corresponds to the position of the toxin along the bilayer normal. The course-grained representation of the protein and lipids enabled us to explore extended time periods, revealing aspects of toxin/bilayer dynamics and energetics that would be difficult to observe on the timescales currently afforded by atomistic molecular dynamics simulations. In particular, we show for this model system that the bilayer deforms as it interacts with the toxin, and that such deformations perturb the free energy profile. Bilayer deformation therefore adds an additional layer of complexity to be addressed in investigations of membrane/protein systems. In particular, one should allow for local deformations that may arise due to the spatial array of charged and hydrophobic elements of an interfacially located membrane protein.

Effect of Gating Modifier Toxins on Membrane Thickness: Implications for Toxin Effect on Gramicidin and Mechanosensitive Channels

“…However, our simulations suggest that the shallow mode is more favorable than the deep mode, as the deep mode evolves spontaneously to the shallow mode over a simulation period of 50 ns (Figure 3B,C). The interfacial binding by GsMTx4 observed here is consistent with the binding modes of SGTx1 [34] and VSTx1 [35] to POPC bilayers observed in previous computational studies.…”

“…For example, SGTx1 also binds most favorably to this interfacial region [34]. The position of the PMF minima observed here is similar to that for the binding of VSTx1 to several different types of lipid bilayers, including POPC determined by Wee et al [35,36]. Moreover, HaTx1 binds to the interfacial region of lipid bilayers according to the experimental measurements of Phillips et al [29].…”

“…Several molecular dynamics (MD) simulation studies have been carried out to understand the binding mechanism of gating modifier toxins in model membranes [33,34,35,36,37,38]. In these studies, the toxins are frequently embedded into the lipid bilayer at different depths at the start of the simulations to probe the most preferred position of toxin binding.…”

Structural interactions of a voltage sensor toxin with lipid membranes

“…The results of neutron diffraction experiments also demonstrate that the toxin produces a thinning of the membrane (Fig. 3 A and B), in quantitative agreement with the solid-state NMR results and with earlier moleculardynamics simulations (65). Partitioning of the VSTx1 into the membrane also broadens the water distribution determined using neutron diffraction (Fig.…”

Systematic multiscale simulation of membrane protein systems

“…A variant of the MARTINI force field developed by Sansom and coworkers [29,30•] has been used to examine the one-dimensional PMF (free energy profile) governing a gated potassium channel and gating modifier toxin (VSTx1) [44]. The binding constants were significantly larger than those reported experimentally for VSTx1, and the source of this discrepancy has not been resolved.…”