Abstract
Tarantula toxins compose an important class of spider toxins that target ion channels, and some are known to interact with lipid membranes. In this study, we focus on a tarantula toxin, Jingzhaotoxin-III (JZTx-III) that specifically targets the cardiac voltage-gated sodium channel Na[Formula: see text]1.5 and is suspected to be able to interact with lipid membranes. Here, we use an all-atom model and long-term molecular dynamics simulations to investigate the interactions between JZTx-III and lipid membranes of different compositions. Trajectory analyses show that JZTx-III has no substantial interaction with the neutral 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipids, but binds to membranes containing negatively charged 1-palmitoyl-2-oleoyl-sn-glycero-3-[phospho-rac-(1-glycerol)] (POPG). The most intriguing observations in our simulation are the different interactions between the toxin and the membrane in the mixed and pure POPG membrane systems. The POPC/POPG mixed membrane undergoes a phase transition to a rippled phase upon binding of the toxin, while the pure POPG membrane has no apparent change. Moreover, the binding of JZTx-III to both of the mixture and the pure POPG membrane systems induce small conformational changes. The sequence alignment shows that JZTx-III may not partition into the lipid bilayer due to the mutations of a C-terminal hydrophobic residue and some charged residues that affect toxin orientation. Taken together, JZTx-III and lipid membranes have unique effects on each other that may facilitate the specific binding of JZTx-III to Na[Formula: see text]1.5. This computational study also enriches our understanding of the potential complex interactions between spider toxins and lipid membranes.
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