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. 2002 Jul;83(1):144–153. doi: 10.1016/S0006-3495(02)75156-4

Interaction of cardiotoxins with membranes: a molecular modeling study.

Roman G Efremov 1, Pavel E Volynsky 1, Dmitry E Nolde 1, Peter V Dubovskii 1, Alexander S Arseniev 1
PMCID: PMC1302134  PMID: 12080107

Abstract

Incorporation of beta-sheet proteins into membrane is studied theoretically for the first time, and the results are validated by the direct experimental data. Using Monte Carlo simulations with implicit membrane, we explore spatial structure, energetics, polarity, and mode of insertion of two cardiotoxins with different membrane-destabilizing activity. Both proteins, classified as P- and S-type cardiotoxins, are found to retain the overall "three-finger" fold interacting with membrane core and lipid/water interface by the tips of the "fingers" (loops). The insertion critically depends upon the structure, hydrophobicity, and electrostatics of certain regions. The simulations reveal apparently distinct binding modes for S- and P-type cardiotoxins via the first loop or through all three loops, respectively. This rationalizes an earlier empirical classification of cardiotoxins into S- and P-type, and provides a basis for the analysis of experimental data on their membrane affinities. Accomplished with our previous simulations of membrane alpha-helices, the computational method may be used to study partitioning of proteins with diverse folds into lipid bilayers.

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Selected References

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  1. Batenburg A. M., Bougis P. E., Rochat H., Verkleij A. J., de Kruijff B. Penetration of a cardiotoxin into cardiolipin model membranes and its implications on lipid organization. Biochemistry. 1985 Dec 3;24(25):7101–7110. doi: 10.1021/bi00346a013. [DOI] [PubMed] [Google Scholar]
  2. Berman H. M., Westbrook J., Feng Z., Gilliland G., Bhat T. N., Weissig H., Shindyalov I. N., Bourne P. E. The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235–242. doi: 10.1093/nar/28.1.235. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bernèche S., Nina M., Roux B. Molecular dynamics simulation of melittin in a dimyristoylphosphatidylcholine bilayer membrane. Biophys J. 1998 Oct;75(4):1603–1618. doi: 10.1016/S0006-3495(98)77604-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bougis P., Tessier M., Van Rietschoten J., Rochat H., Faucon J. F., Dufourcq J. Are interactions with phospholipids responsible for pharmacological activities of cardiotoxins? Mol Cell Biochem. 1983;55(1):49–64. doi: 10.1007/BF00229242. [DOI] [PubMed] [Google Scholar]
  5. Bowie J. U., Lüthy R., Eisenberg D. A method to identify protein sequences that fold into a known three-dimensional structure. Science. 1991 Jul 12;253(5016):164–170. doi: 10.1126/science.1853201. [DOI] [PubMed] [Google Scholar]
  6. Carbone M. A., Macdonald P. M. Cardiotoxin II segregates phosphatidylglycerol from mixtures with phosphatidylcholine: (31)P and (2)H NMR spectroscopic evidence. Biochemistry. 1996 Mar 19;35(11):3368–3378. doi: 10.1021/bi952349i. [DOI] [PubMed] [Google Scholar]
  7. Chien K. Y., Chiang C. M., Hseu Y. C., Vyas A. A., Rule G. S., Wu W. Two distinct types of cardiotoxin as revealed by the structure and activity relationship of their interaction with zwitterionic phospholipid dispersions. J Biol Chem. 1994 May 20;269(20):14473–14483. [PubMed] [Google Scholar]
  8. Dauplais M., Neumann J. M., Pinkasfeld S., Ménez A., Roumestand C. An NMR study of the interaction of cardiotoxin gamma from Naja nigricollis with perdeuterated dodecylphosphocholine micelles. Eur J Biochem. 1995 May 15;230(1):213–220. [PubMed] [Google Scholar]
  9. Dementieva D. V., Bocharov E. V., Arseniev A. S. Two forms of cytotoxin II (cardiotoxin) from Naja naja oxiana in aqueous solution: spatial structures with tightly bound water molecules. Eur J Biochem. 1999 Jul;263(1):152–162. doi: 10.1046/j.1432-1327.1999.00478.x. [DOI] [PubMed] [Google Scholar]
  10. Dubovskii P. V., Dementieva D. V., Bocharov E. V., Utkin Y. N., Arseniev A. S. Membrane binding motif of the P-type cardiotoxin. J Mol Biol. 2001 Jan 5;305(1):137–149. doi: 10.1006/jmbi.2000.4283. [DOI] [PubMed] [Google Scholar]
  11. Dubovskii P. V., Li H., Takahashi S., Arseniev A. S., Akasaka K. Structure of an analog of fusion peptide from hemagglutinin. Protein Sci. 2000 Apr;9(4):786–798. doi: 10.1110/ps.9.4.786. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Désormeaux A., Laroche G., Bougis P. E., Pézolet M. Characterization by infrared spectroscopy of the interaction of a cardiotoxin with phosphatidic acid and with binary mixtures of phosphatidic acid and phosphatidylcholine. Biochemistry. 1992 Dec 8;31(48):12173–12182. doi: 10.1021/bi00163a029. [DOI] [PubMed] [Google Scholar]
  13. Efremov R. G., Nolde D. E., Vergoten G., Arseniev A. S. A solvent model for simulations of peptides in bilayers. I. Membrane-promoting alpha-helix formation. Biophys J. 1999 May;76(5):2448–2459. doi: 10.1016/S0006-3495(99)77400-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Efremov R. G., Nolde D. E., Vergoten G., Arseniev A. S. A solvent model for simulations of peptides in bilayers. II. Membrane-spanning alpha-helices. Biophys J. 1999 May;76(5):2460–2471. doi: 10.1016/S0006-3495(99)77401-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Efremov R. G., Nolde D. E., Volynsky P. E., Chernyavsky A. A., Dubovskii P. V., Arseniev A. S. Factors important for fusogenic activity of peptides: molecular modeling study of analogs of fusion peptide of influenza virus hemagglutinin. FEBS Lett. 1999 Nov 26;462(1-2):205–210. doi: 10.1016/s0014-5793(99)01505-7. [DOI] [PubMed] [Google Scholar]
  16. Forrest L. R., Sansom M. S. Membrane simulations: bigger and better? Curr Opin Struct Biol. 2000 Apr;10(2):174–181. doi: 10.1016/s0959-440x(00)00066-x. [DOI] [PubMed] [Google Scholar]
  17. Gatineau E., Takechi M., Bouet F., Mansuelle P., Rochat H., Harvey A. L., Montenay-Garestier T., Ménez A. Delineation of the functional site of a snake venom cardiotoxin: preparation, structure, and function of monoacetylated derivatives. Biochemistry. 1990 Jul 10;29(27):6480–6489. doi: 10.1021/bi00479a021. [DOI] [PubMed] [Google Scholar]
  18. Golovanov A. P., Efremov R. G., Jaravine V. A., Vergoten G., Arseniev A. S. Amino acid residue: is it structural or functional? FEBS Lett. 1995 Nov 13;375(1-2):162–166. doi: 10.1016/0014-5793(95)01212-w. [DOI] [PubMed] [Google Scholar]
  19. Jahnke W., Mierke D. F., Béress L., Kessler H. Structure of cobra cardiotoxin CTX I as derived from nuclear magnetic resonance spectroscopy and distance geometry calculations. J Mol Biol. 1994 Jul 29;240(5):445–458. doi: 10.1006/jmbi.1994.1460. [DOI] [PubMed] [Google Scholar]
  20. Kabsch W., Sander C. Dictionary of protein secondary structure: pattern recognition of hydrogen-bonded and geometrical features. Biopolymers. 1983 Dec;22(12):2577–2637. doi: 10.1002/bip.360221211. [DOI] [PubMed] [Google Scholar]
  21. Koradi R., Billeter M., Wüthrich K. MOLMOL: a program for display and analysis of macromolecular structures. J Mol Graph. 1996 Feb;14(1):51-5, 29-32. doi: 10.1016/0263-7855(96)00009-4. [DOI] [PubMed] [Google Scholar]
  22. Kumar T. K., Jayaraman G., Lee C. S., Arunkumar A. I., Sivaraman T., Samuel D., Yu C. Snake venom cardiotoxins-structure, dynamics, function and folding. J Biomol Struct Dyn. 1997 Dec;15(3):431–463. doi: 10.1080/07391102.1997.10508957. [DOI] [PubMed] [Google Scholar]
  23. La Rocca P., Biggin P. C., Tieleman D. P., Sansom M. S. Simulation studies of the interaction of antimicrobial peptides and lipid bilayers. Biochim Biophys Acta. 1999 Dec 15;1462(1-2):185–200. doi: 10.1016/s0005-2736(99)00206-0. [DOI] [PubMed] [Google Scholar]
  24. Lee C. S., Kumar T. K., Lian L. Y., Cheng J. W., Yu C. Main-chain dynamics of cardiotoxin II from Taiwan cobra (Naja naja atra) as studied by carbon-13 NMR at natural abundance: delineation of the role of functionally important residues. Biochemistry. 1998 Jan 6;37(1):155–164. doi: 10.1021/bi971979c. [DOI] [PubMed] [Google Scholar]
  25. Roumestand C., Gilquin B., Trémeau O., Gatineau E., Mouawad L., Ménez A., Toma F. Proton NMR studies of the structural and dynamical effect of chemical modification of a single aromatic side-chain in a snake cardiotoxin. Relation to the structure of the putative binding site and the cytolytic activity of the toxin. J Mol Biol. 1994 Nov 4;243(4):719–735. doi: 10.1016/0022-2836(94)90043-4. [DOI] [PubMed] [Google Scholar]
  26. Shai Y. Mechanism of the binding, insertion and destabilization of phospholipid bilayer membranes by alpha-helical antimicrobial and cell non-selective membrane-lytic peptides. Biochim Biophys Acta. 1999 Dec 15;1462(1-2):55–70. doi: 10.1016/s0005-2736(99)00200-x. [DOI] [PubMed] [Google Scholar]
  27. Sivaraman T., Kumar T. K., Hung K. W., Yu C. Comparison of the structural stability of two homologous toxins isolated from the Taiwan cobra (Naja naja atra) venom. Biochemistry. 2000 Aug 1;39(30):8705–8710. doi: 10.1021/bi992867j. [DOI] [PubMed] [Google Scholar]
  28. Sivaraman T., Kumar T. K., Yu C. Investigation of the structural stability of cardiotoxin analogue III from the Taiwan cobra by hydrogen-deuterium exchange kinetics. Biochemistry. 1999 Aug 3;38(31):9899–9905. doi: 10.1021/bi9901230. [DOI] [PubMed] [Google Scholar]
  29. Sue S. C., Rajan P. K., Chen T. S., Hsieh C. H., Wu W. Action of Taiwan cobra cardiotoxin on membranes: binding modes of a beta-sheet polypeptide with phosphatidylcholine bilayers. Biochemistry. 1997 Aug 12;36(32):9826–9836. doi: 10.1021/bi970413l. [DOI] [PubMed] [Google Scholar]
  30. Sun Y. J., Wu W. G., Chiang C. M., Hsin A. Y., Hsiao C. D. Crystal structure of cardiotoxin V from Taiwan cobra venom: pH-dependent conformational change and a novel membrane-binding motif identified in the three-finger loops of P-type cardiotoxin. Biochemistry. 1997 Mar 4;36(9):2403–2413. doi: 10.1021/bi962594h. [DOI] [PubMed] [Google Scholar]
  31. Tieleman D. P., Berendsen H. J., Sansom M. S. Voltage-dependent insertion of alamethicin at phospholipid/water and octane/water interfaces. Biophys J. 2001 Jan;80(1):331–346. doi: 10.1016/S0006-3495(01)76018-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Vincent J. P., Balerna M., Lazdunski M. Properties of association of cardiotoxin with lipid vesicles and natural membranes. A fluorescence study. FEBS Lett. 1978 Jan 1;85(1):103–108. doi: 10.1016/0014-5793(78)81258-7. [DOI] [PubMed] [Google Scholar]
  33. White S. H., Wimley W. C. Membrane protein folding and stability: physical principles. Annu Rev Biophys Biomol Struct. 1999;28:319–365. doi: 10.1146/annurev.biophys.28.1.319. [DOI] [PubMed] [Google Scholar]

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