Skip to main content
NCBI home page
Biophysical Journal logoLink to Biophysical Journal
. 2000 Mar;78(3):1359–1375. doi: 10.1016/S0006-3495(00)76690-2

Protein-induced membrane disorder: a molecular dynamics study of melittin in a dipalmitoylphosphatidylcholine bilayer.

M Bachar 1, O M Becker 1
PMCID: PMC1300735  PMID: 10692322

Abstract

A molecular dynamics simulation of melittin in a hydrated dipalmitoylphosphatidylcholine (DPPC) bilayer was performed. The 19, 000-atom system included a 72-DPPC phospholipid bilayer, a 26-amino acid peptide, and more than 3000 water molecules. The N-terminus of the peptide was protonated and embedded in the membrane in a transbilayer orientation perpendicular to the surface. The simulation results show that the peptide affects the lower (intracellular) layer of the bilayer more strongly than the upper (extracellular) layer. The simulation results can be interpreted as indicating an increased level of disorder and structural deformation for lower-layer phospholipids in the immediate vicinity of the peptide. This conclusion is supported by the calculated deuterium order parameters, the observed deformation at the intracellular interface, and an increase in fractional free volume. The upper layer was less affected by the embedded peptide, except for an acquired tilt relative to the bilayer normal. The effect of melittin on the surrounding membrane is localized to its immediate vicinity, and its asymmetry with respect to the two layers may result from the fact that it is not fully transmembranal. Melittin's hydrophilic C-terminus anchors it at the extracellular interface, leaving the N-terminus "loose" in the lower layer of the membrane. In general, the simulation supports a role for local deformation and water penetration in melittin-induced lysis. As for the peptide, like other membrane-embedded polypeptides, melittin adopts a significant 25 degree tilt relative to the membrane normal. This tilt is correlated with a comparable tilt of the lipids in the upper membrane layer. The peptide itself retains an overall helical structure throughout the simulation (with the exception of the three N-terminal residues), adopting a 30 degree intrahelical bend angle.

Full Text

The Full Text of this article is available as a PDF (958.6 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bazzo R., Tappin M. J., Pastore A., Harvey T. S., Carver J. A., Campbell I. D. The structure of melittin. A 1H-NMR study in methanol. Eur J Biochem. 1988 Apr 5;173(1):139–146. doi: 10.1111/j.1432-1033.1988.tb13977.x. [DOI] [PubMed] [Google Scholar]
  2. Belohorcová K., Davis J. H., Woolf T. B., Roux B. Structure and dynamics of an amphiphilic peptide in a lipid bilayer: a molecular dynamics study. Biophys J. 1997 Dec;73(6):3039–3055. doi: 10.1016/S0006-3495(97)78332-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Berger O., Edholm O., Jähnig F. Molecular dynamics simulations of a fluid bilayer of dipalmitoylphosphatidylcholine at full hydration, constant pressure, and constant temperature. Biophys J. 1997 May;72(5):2002–2013. doi: 10.1016/S0006-3495(97)78845-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. 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]
  5. Bradrick T. D., Philippetis A., Georghiou S. Stopped-flow fluorometric study of the interaction of melittin with phospholipid bilayers: importance of the physical state of the bilayer and the acyl chain length. Biophys J. 1995 Nov;69(5):1999–2010. doi: 10.1016/S0006-3495(95)80070-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bradshaw J. P., Dempsey C. E., Watts A. A combined X-ray and neutron diffraction study of selectively deuterated melittin in phospholipid bilayers: effect of pH. Mol Membr Biol. 1994 Apr-Jun;11(2):79–86. doi: 10.3109/09687689409162224. [DOI] [PubMed] [Google Scholar]
  7. Chiu S. W., Clark M., Balaji V., Subramaniam S., Scott H. L., Jakobsson E. Incorporation of surface tension into molecular dynamics simulation of an interface: a fluid phase lipid bilayer membrane. Biophys J. 1995 Oct;69(4):1230–1245. doi: 10.1016/S0006-3495(95)80005-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Damodaran K. V., Merz K. M., Jr, Gaber B. P. Interaction of small peptides with lipid bilayers. Biophys J. 1995 Oct;69(4):1299–1308. doi: 10.1016/S0006-3495(95)79997-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. DeGrado W. F., Musso G. F., Lieber M., Kaiser E. T., Kézdy F. J. Kinetics and mechanism of hemolysis induced by melittin and by a synthetic melittin analogue. Biophys J. 1982 Jan;37(1):329–338. doi: 10.1016/S0006-3495(82)84681-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Dempsey C. E. The actions of melittin on membranes. Biochim Biophys Acta. 1990 May 7;1031(2):143–161. doi: 10.1016/0304-4157(90)90006-x. [DOI] [PubMed] [Google Scholar]
  11. Devaux P. F., Seigneuret M. Specificity of lipid-protein interactions as determined by spectroscopic techniques. Biochim Biophys Acta. 1985 Jun 12;822(1):63–125. doi: 10.1016/0304-4157(85)90004-8. [DOI] [PubMed] [Google Scholar]
  12. Douliez J. P., Léonard A., Dufourc E. J. Restatement of order parameters in biomembranes: calculation of C-C bond order parameters from C-D quadrupolar splittings. Biophys J. 1995 May;68(5):1727–1739. doi: 10.1016/S0006-3495(95)80350-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Ducarme P., Rahman M., Brasseur R. IMPALA: a simple restraint field to simulate the biological membrane in molecular structure studies. Proteins. 1998 Mar 1;30(4):357–371. [PubMed] [Google Scholar]
  14. Dufourc E. J., Smith I. C., Dufourcq J. Molecular details of melittin-induced lysis of phospholipid membranes as revealed by deuterium and phosphorus NMR. Biochemistry. 1986 Oct 21;25(21):6448–6455. doi: 10.1021/bi00369a016. [DOI] [PubMed] [Google Scholar]
  15. Feller S. E., Pastor R. W. On simulating lipid bilayers with an applied surface tension: periodic boundary conditions and undulations. Biophys J. 1996 Sep;71(3):1350–1355. doi: 10.1016/S0006-3495(96)79337-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Gevod V. S., Birdi K. S. Melittin and the 8-26 fragment. Differences in ionophoric properties as measured by monolayer method. Biophys J. 1984 Jun;45(6):1079–1083. doi: 10.1016/S0006-3495(84)84255-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Habermann E., Kowallek H. Modifikationen der Aminogruppen und des Tryptophans im Melittin als Mittel zur Erkennung von Struktur-Wirkungs-Beziehungen. Hoppe Seylers Z Physiol Chem. 1970 Jul;351(7):884–890. [PubMed] [Google Scholar]
  18. Jost P. C., Griffith O. H., Capaldi R. A., Vanderkooi G. Evidence for boundary lipid in membranes. Proc Natl Acad Sci U S A. 1973 Feb;70(2):480–484. doi: 10.1073/pnas.70.2.480. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kini R. M., Evans H. J. A common cytolytic region in myotoxins, hemolysins, cardiotoxins and antibacterial peptides. Int J Pept Protein Res. 1989 Oct;34(4):277–286. doi: 10.1111/j.1399-3011.1989.tb01575.x. [DOI] [PubMed] [Google Scholar]
  20. Koynova R., Caffrey M. Phases and phase transitions of the phosphatidylcholines. Biochim Biophys Acta. 1998 Jun 29;1376(1):91–145. doi: 10.1016/s0304-4157(98)00006-9. [DOI] [PubMed] [Google Scholar]
  21. Marrink S. J., Berger O., Tieleman P., Jähnig F. Adhesion forces of lipids in a phospholipid membrane studied by molecular dynamics simulations. Biophys J. 1998 Feb;74(2 Pt 1):931–943. doi: 10.1016/S0006-3495(98)74016-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Milik M., Skolnick J. Insertion of peptide chains into lipid membranes: an off-lattice Monte Carlo dynamics model. Proteins. 1993 Jan;15(1):10–25. doi: 10.1002/prot.340150104. [DOI] [PubMed] [Google Scholar]
  23. Monette M., Lafleur M. Modulation of melittin-induced lysis by surface charge density of membranes. Biophys J. 1995 Jan;68(1):187–195. doi: 10.1016/S0006-3495(95)80174-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Mouritsen O. G. Theoretical models of phospholipid phase transitions. Chem Phys Lipids. 1991 Mar;57(2-3):179–194. doi: 10.1016/0009-3084(91)90075-m. [DOI] [PubMed] [Google Scholar]
  25. Nagle J. F., Zhang R., Tristram-Nagle S., Sun W., Petrache H. I., Suter R. M. X-ray structure determination of fully hydrated L alpha phase dipalmitoylphosphatidylcholine bilayers. Biophys J. 1996 Mar;70(3):1419–1431. doi: 10.1016/S0006-3495(96)79701-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Pastore A., Harvey T. S., Dempsey C. E., Campbell I. D. The dynamic properties of melittin in solution. Investigations by NMR and molecular dynamics. Eur Biophys J. 1989;16(6):363–367. doi: 10.1007/BF00257885. [DOI] [PubMed] [Google Scholar]
  27. Ruggiero A., Hudson B. Critical density fluctuations in lipid bilayers detected by fluorescence lifetime heterogeneity. Biophys J. 1989 Jun;55(6):1111–1124. doi: 10.1016/S0006-3495(89)82908-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Scott H. L., Kalaskar S. Lipid chains and cholesterol in model membranes: a Monte Carlo Study. Biochemistry. 1989 May 2;28(9):3687–3691. doi: 10.1021/bi00435a010. [DOI] [PubMed] [Google Scholar]
  29. Scott H. L. Monte Carlo calculations of order parameter profiles in models of lipid-protein interactions in bilayers. Biochemistry. 1986 Oct 7;25(20):6122–6126. doi: 10.1021/bi00368a043. [DOI] [PubMed] [Google Scholar]
  30. Seelig A., Seelig J. The dynamic structure of fatty acyl chains in a phospholipid bilayer measured by deuterium magnetic resonance. Biochemistry. 1974 Nov 5;13(23):4839–4845. doi: 10.1021/bi00720a024. [DOI] [PubMed] [Google Scholar]
  31. Shen L., Bassolino D., Stouch T. Transmembrane helix structure, dynamics, and interactions: multi-nanosecond molecular dynamics simulations. Biophys J. 1997 Jul;73(1):3–20. doi: 10.1016/S0006-3495(97)78042-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Terwilliger T. C., Eisenberg D. The structure of melittin. II. Interpretation of the structure. J Biol Chem. 1982 Jun 10;257(11):6016–6022. [PubMed] [Google Scholar]
  33. Tieleman D. P., Berendsen H. J. A molecular dynamics study of the pores formed by Escherichia coli OmpF porin in a fully hydrated palmitoyloleoylphosphatidylcholine bilayer. Biophys J. 1998 Jun;74(6):2786–2801. doi: 10.1016/S0006-3495(98)77986-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Tieleman D. P., Forrest L. R., Sansom M. S., Berendsen H. J. Lipid properties and the orientation of aromatic residues in OmpF, influenza M2, and alamethicin systems: molecular dynamics simulations. Biochemistry. 1998 Dec 15;37(50):17554–17561. doi: 10.1021/bi981802y. [DOI] [PubMed] [Google Scholar]
  35. Tieleman D. P., Marrink S. J., Berendsen H. J. A computer perspective of membranes: molecular dynamics studies of lipid bilayer systems. Biochim Biophys Acta. 1997 Nov 21;1331(3):235–270. doi: 10.1016/s0304-4157(97)00008-7. [DOI] [PubMed] [Google Scholar]
  36. Tieleman D. P., Sansom M. S., Berendsen H. J. Alamethicin helices in a bilayer and in solution: molecular dynamics simulations. Biophys J. 1999 Jan;76(1 Pt 1):40–49. doi: 10.1016/S0006-3495(99)77176-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Tosteson M. T., Holmes S. J., Razin M., Tosteson D. C. Melittin lysis of red cells. J Membr Biol. 1985;87(1):35–44. doi: 10.1007/BF01870697. [DOI] [PubMed] [Google Scholar]
  38. Vogel H. Comparison of the conformation and orientation of alamethicin and melittin in lipid membranes. Biochemistry. 1987 Jul 14;26(14):4562–4572. doi: 10.1021/bi00388a060. [DOI] [PubMed] [Google Scholar]
  39. Vogel H., Jähnig F. The structure of melittin in membranes. Biophys J. 1986 Oct;50(4):573–582. doi: 10.1016/S0006-3495(86)83497-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Weaver A. J., Kemple M. D., Brauner J. W., Mendelsohn R., Prendergast F. G. Fluorescence, CD, attenuated total reflectance (ATR) FTIR, and 13C NMR characterization of the structure and dynamics of synthetic melittin and melittin analogues in lipid environments. Biochemistry. 1992 Feb 11;31(5):1301–1313. doi: 10.1021/bi00120a005. [DOI] [PubMed] [Google Scholar]
  41. Woolf T. B. Molecular dynamics of individual alpha-helices of bacteriorhodopsin in dimyristol phosphatidylocholine. I. Structure and dynamics. Biophys J. 1997 Nov;73(5):2376–2392. doi: 10.1016/S0006-3495(97)78267-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Woolf T. B. Molecular dynamics simulations of individual alpha-helices of bacteriorhodopsin in dimyristoylphosphatidylcholine. II. Interaction energy analysis. Biophys J. 1998 Jan;74(1):115–131. doi: 10.1016/S0006-3495(98)77773-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Woolf T. B., Roux B. Structure, energetics, and dynamics of lipid-protein interactions: A molecular dynamics study of the gramicidin A channel in a DMPC bilayer. Proteins. 1996 Jan;24(1):92–114. doi: 10.1002/(SICI)1097-0134(199601)24:1<92::AID-PROT7>3.0.CO;2-Q. [DOI] [PubMed] [Google Scholar]
  44. de Planque M. R., Greathouse D. V., Koeppe R. E., 2nd, Schäfer H., Marsh D., Killian J. A. Influence of lipid/peptide hydrophobic mismatch on the thickness of diacylphosphatidylcholine bilayers. A 2H NMR and ESR study using designed transmembrane alpha-helical peptides and gramicidin A. Biochemistry. 1998 Jun 30;37(26):9333–9345. doi: 10.1021/bi980233r. [DOI] [PubMed] [Google Scholar]

Articles from Biophysical Journal are provided here courtesy of The Biophysical Society

RESOURCES