Exploring Structural Interactions of Tarantula Toxins with Lipid Membranes using Rosetta and Molecular Dynamics Simulation

Abstract

Tarantula venom toxins belong to a class of cystine knot peptide toxins that have three disulfide bridges stabilizing the inner core of the toxin structure. These toxins target a wide range of ion channels and modulate physiological activities of channels upon binding. Experimental data indicates that tarantula toxins which target voltage sensors of ion channels interact with cell membrane bilayers and potentially form interactions with channels at the membrane-protein interface. However, how these peptide toxins partition and orient in the membrane are not fully understood. We used Rosetta structural modeling and molecular dynamics simulation, to embed three tarantula toxins, VsTx1, GxTx-1E and SgTx1, into lipid membrane environments. Our results suggest that the three tarantula toxins prefer a similar orientation and depth in the membrane bilayer. We observe that hydrophobic residues on the toxins embed deeper in the hydrophobic lipid core region, basic residues prefer interactions with lipid head groups, and acidic residues are exposed to water environment. This unique orientation of peptide toxins exposes residues critical for interaction with the voltage sensors within the lipid environment, suggesting that toxins may utilize this embedding and orientation to interact favorably with voltage sensors of ion channels.