Hemolytic mechanism of dioscin proposed by molecular dynamics simulations

Saponins are a class of compounds containing a triterpenoid or steroid core with some attached carbohydrate modules. Many saponins cause hemolysis. However, the hemolytic mechanism of saponins at the molecular level is not yet fully understood. In an attempt to explore this issue, we have studied dioscin-a saponin with high hemolytic activity-through extensive molecular dynamics (MD) simulations. Firstly, all-atom MD simulations of 8 ns duration were conducted to study the stability of the dioscin-cholesterol complex and the cholesterol-cholesterol complex in water and in decane, respectively. MM-GB/SA computations indicate that the dioscin-cholesterol complex is energetically more favorable than the cholesterol-cholesterol complex in a non-polar environment. Next, several coarse-grained MD simulations of 400 ns duration were conducted to directly observe the distribution of multiple dioscin molecules on a DPPC-POPC-PSM-CHOL lipid bilayer. Our results indicate that dioscin can penetrate into the lipid bilayer, accumulate in the lipid raft micro-domain, and then bind cholesterol. This leads to the destabilization of lipid raft and consequent membrane curvature, which may eventually result in the hemolysis of red cells. This possible mechanism of hemolysis can well explain some experimental observations on hemolysis.