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Article

Specific refolding pathway of viscumin A chain in membrane-like medium reveals a possible mechanism of toxin entry into cell.

Scientific Reports. 2019. Vol. 9. No. 413. P. 1-12.
Efremov R., Нольде Д. Е., Волынский П. Е., Захарова Г. С., Palmer R. A., Tonevitsky A.

How is a water-soluble globular protein able to spontaneously cross a cellular membrane? It is commonly accepted that it undergoes significant structural rearrangements on the lipid-water interface, thus acquiring membrane binding and penetration ability. In this study molecular dynamics (MD) simulations have been used to explore large-scale conformational changes of the globular viscumin A chain in a complex environment – comprising urea and chloroform/methanol (CHCl3/MeOH) mixture. Being well-packed in aqueous solution, viscumin A undergoes global structural rearrangements in both organic media. In urea, the protein is “swelling” and gradually loses its long-distance contacts, thus resembling the “molten globule” state. In CHCl3/MeOH, viscumin A is in effect turned “inside out”. This is accompanied with strengthening of the secondary structure and surface exposure of hydrophobic epitopes originally buried inside the globule. Resulting solvent-adapted models were further subjected to Monte Carlo simulations with an implicit hydrophobic slab membrane. In contrast to only a few point surface contacts in water and two short regions with weak protein-lipid interactions in urea, MD-derived structures in CHCl3/MeOH reveal multiple determinants of membrane interaction. Consequently it is now possible to  propose a specific pathway for the structural adaptation of viscumin A with respect to the cell membrane – a probable first step of its translocation into cytoplasmic targets.