PLA₂-like proteins myotoxic mechanism: a dynamic model description.

Area of Science:

• Biochemistry
• Structural Biology
• Toxicology

Background:

• Phospholipase A2-like (PLA2-like) proteins from Viperidae snakes cause muscle necrosis.
• These toxins are not effectively neutralized by current antivenom therapies.
• The exact toxic mechanisms of catalytically inactive PLA2-like proteins remain unclear, though dimerization and C-terminal residues are implicated in myotoxicity.

Purpose of the Study:

• To characterize the functional mechanism of bothropic PLA2-like proteins.
• To investigate the structural dynamics and allosteric activation of these toxins.
• To provide insights for developing novel antivenom strategies.

Main Methods:

• Utilized Protein Data Bank models and normal mode molecular dynamics (NM-MD).
• Performed geometric analysis of monomer interactions using Euler angles.
• Characterized C-terminal residue conformations, hydrophobic channel accessibility, ligand interactions, and residue clustering at the toxin interface.

Main Results:

• Described novel geometric parameters for PLA2-like protein monomers.
• Identified distinct canonical and non-canonical conformations of C-terminal residues.
• Revealed allosteric activation and hypothesized that natural monomer movement, calculated via NM-MD, drives membrane disruption.

Conclusions:

• The study elucidates the allosteric activation mechanism of PLA2-like proteins.
• Natural monomer dynamics are linked to the membrane disruption process, a key factor in myotoxicity.
• The findings offer a foundation for future research into inhibiting these snake venom toxins.