Differences in medium-induced conformational plasticity presumably underlie different cytotoxic activity of ricin and viscumin

Biomolecules. 2022. Vol. 12. No. 2. Article 295.

Volynsky P., Maltseva D., Tabakmakher V., Bocharov E., Raygorodskaya M., Zakharova G., Britikova E., Tonevitsky A., Efremov R.

Structurally similar catalytic subunits A of ricin (RTA) and viscumin (MLA) exhibit cytotoxic activity through ribosome inactivation. Ricin is more cytotoxic than viscumin, although the molecular cause of this is still poorly understood. To shed more light on this problem, we used a combined biochemical / molecular modeling approach to assess the possible relationship between the activity of toxins and their structural/dynamic properties. Based on bioassay measurements, it was suggested that the differences in activity are associated with the ability of RTA and MLA to undergo structural/hydrophobic rearrangements when trafficking through the endoplasmic reticulum (ER) membrane. Molecular dynamics simulations and surface hydrophobicity mapping of both proteins in different media showed that RTA rearranges its structure in a membrane-like environment much more efficiently than MLA. The hydrophobic organization of their refolded states is also drastically different. We assume that the higher conformational plasticity of RTA is favorable for the ER-mediated translocation pathway, which leads to a higher rate of the toxin penetration into the cytoplasm.

Keywords: молекулярная динамика, protein-membrane interactions, molecular dynamics, взаимодействия белок-мембрана, Membrane trafficking of proteins, medium effects on protein structure, type II ribosome inactivating proteins, мембранный транспорт белков, влияние среды на структуру белков, рибосом-инактивирующие белки 2-го типа

Publication based on the results of: Supercomputer technologies, theory and atomistic multiscale modeling in materials physics and life sciences (2022)