Venomous Peptides: Molecular Origin of the Toxicity of Snake Venom PLA₂-like Peptides

Snakebite envenoming claims 81-138 thousand lives annually, with vipers responsible for many of those. Phospholipase A₂ (PLA₂) enzymes and PLA₂-like proteins are among the most important viper venom toxins. The latter are particularly intriguing, as three decades after their discovery, their molecular mechanism of toxicity is still poorly understood at best. PLA₂-like proteins destabilize eukaryotic cell membranes through an unknown mechanism, causing an uncontrolled influx of Ca²⁺ ions and ultimately triggering cell death. It is now clear that the C-terminal segment is fundamental to the toxicity, as 13-mer peptides with the same sequence exhibit most or all of the activities of the complete PLA₂-like proteins. To finally clarify the mechanism of toxicity of these venom peptides, we have simulated their interaction with model cell membranes. Molecular dynamics simulations showed that peptides initially dispersed across the cell membrane quickly and spontaneously migrated, aggregated, induced membrane thinning, and formed clear and transient membrane pores. We calculated the potentials of the mean force for Ca²⁺ transfer across the cell membranes through the transient pores. The pores significantly lower the free energy barrier for Ca²⁺ translocation, an effect that grows with the size of the peptide aggregates and, thus, with the pore radius. Ca²⁺ flowed across the membrane through the largest pores with almost no barrier. The permeability of Ca²⁺ through the largest pores exceeded the permeability of pharmaceutical drugs by 4 orders of magnitude, revealing the easiness by which Ca²⁺ overflows the intracellular medium. These results elucidate the illusive molecular origin of the toxicity of this famous class of snake venom-derived peptides.