Elucidating on the quaternary structure of viper venom phospholipase A enzymes in aqueous solution.

This study focuses on the quaternary structure of the viper-secreted phospholipase A (PLA), a central toxin in viper envenomation. PLA enzymes catalyze the hydrolysis of the sn-2 ester bond of membrane phospholipids. Small-molecule inhibitors that act as snakebite antidotes, such as varespladib, are currently in clinical trials. These inhibitors likely bind to the enzyme in the aqueous cytosol prior to membrane-binding. Thus, understanding its controversial solution structure is key for drug design. Crystal structures of PLA in the PDB show at least four different dimeric conformations, the most well-known being "extended" and "compact". This variability among enzymes with >50 % sequence identity raises questions about their transferability to aqueous solution. Therefore, we performed extensive molecular dynamics (MD) simulations of several PLA enzymes in water to determine their quaternary structure under physiological conditions. The MD simulations strongly indicate that PLA enzymes adopt a "semi-compact" conformation in cytosol, a hybrid between extended and compact conformations. To our knowledge, this is the first study that determines the most favorable dimeric conformation of PLA enzymes in solution, providing a basis for advancements in snakebite envenoming treatment. Recognizing snakebite envenoming as a neglected tropical disease has driven the search for efficient, affordable alternatives to the current antivenoms. Therefore, understanding the main drug targets within snake venom is crucial to this achievement.