Computational insight into the peptide-based inhibition of α-cobratoxin

Snakebite envenoming results in the death of thousands of people each year and has been classified as a neglected tropical disease by the World Health Organization (WHO). The toxins released into the bloodstream of the victim bind to the nicotinic acetylcholine receptor and restrict transmission of nerve impulses leading to paralysis and cardiac arrest. Conventional antibody-based treatments often have adverse side effects or are difficult to perform. Hence, efforts are underway to devise alternative forms of treatment that address these therapeutic shortcomings. Peptide-based inhibitors have recently gained attention due to their high specificity and ease of preparation. Here, we explore the mechanism of a peptide inhibitor of α-cobratoxin using all-atom molecular dynamics (MD) simulations. We also quantify the energetics of the toxin-peptide dissociation process using the non-equilibrium steered MD technique. Our study reveals that the inhibitor migrates close to Loop-II of α-cobratoxin and alters its dimerization tendency. From energy studies, we found that the peptide first binds to one unit of α-cobratoxin in a particular orientation, followed by the binding of a second toxin molecule, which effectively masks the residues that interact with the nicotinic acetylcholine receptor. Our work provides atomic-level insight into the inhibition process that can be utilized in the future design of inhibitors with superior binding capabilities.