Hemolytic mechanism of dioscin proposed by molecular dynamics simulations

Abstract

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.

Top- and side-view of the last snapshot after coarse-grained molecular dynamics (CGMD) simulation of three dioscin molecules on the DPPC-POPC-PSM-CHOL membrane

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Acknowledgments

The authors are grateful for the financial support of the Chinese National Natural Science Foundation (Grants No.20772149 & No. 90813006), the Chinese Ministry of Science and Technology (the 863 high-tech project, Grant No. 2006AA02Z337), and the Science and Technology Commission of Shanghai Municipality (Grant No. 074319113). The crystal structure of cholesterol isobutyl carbonate was provided by Prof. Ja P. Young at Sookmyung Women’s University. The MARTINI force field was provided by Prof. Siewert J. Marrink at University of Groningen. The authors are also grateful to Prof. Biao Yu and his student Yibing Wang at the Shanghai Institute of Organic Chemistry for their helpful discussions.

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Correspondence to Renxiao Wang.

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ESM 1

Details of some computational tasks, Table S1-S6, and Figures S1-S7 described in this manuscript. This material is available upon request to the authors. (DOC 5327 kb)

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Lin, F., Wang, R. Hemolytic mechanism of dioscin proposed by molecular dynamics simulations. J Mol Model 16, 107–118 (2010). https://doi.org/10.1007/s00894-009-0523-0

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Keywords

  • Hemolysis
  • Saponin
  • Molecular dynamics
  • Coarse-grained model