Skip to main content
PMC home page
Biophysical Journal logoLink to Biophysical Journal
. 2000 Feb;78(2):800–811. doi: 10.1016/S0006-3495(00)76637-9

Distribution of halothane in a dipalmitoylphosphatidylcholine bilayer from molecular dynamics calculations.

L Koubi 1, M Tarek 1, M L Klein 1, D Scharf 1
PMCID: PMC1300682  PMID: 10653792

Abstract

We report a 2-ns constant pressure molecular dynamics simulation of halothane, at a mol fraction of 50%, in the hydrated liquid crystal bilayer phase of dipalmitoylphosphatidylcholine. Halothane molecules are found to preferentially segregate to the upper part of the lipid acyl chains, with a maximum probability near the C(5) methylene groups. However, a finite probability is also observed along the tail region and across the methyl trough. Over 95% of the halothane molecules are located below the lipid carbonyl carbons, in agreement with photolabeling experiments. Halothane induces lateral expansion and a concomitant contraction in the bilayer thickness. A decrease in the acyl chain segment order parameters, S(CD), for the tail portion, and a slight increase for the upper portion compared to neat bilayers, are in agreement with several NMR studies on related systems. The decrease in S(CD) is attributed to a larger accessible volume per lipid in the tail region. Significant changes in the electric properties of the lipid bilayer result from the structural changes, which include a shift and broadening of the choline headgroup dipole (P-N) orientation distribution. Our findings reconcile apparent controversial conclusions from experiments on diverse lipid systems.

Full Text

The Full Text of this article is available as a PDF (1.2 MB).

Selected References

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

  1. Baber J., Ellena J. F., Cafiso D. S. Distribution of general anesthetics in phospholipid bilayers determined using 2H NMR and 1H-1H NOE spectroscopy. Biochemistry. 1995 May 16;34(19):6533–6539. doi: 10.1021/bi00019a035. [DOI] [PubMed] [Google Scholar]
  2. Boden N., Jones S. A., Sixl F. On the use of deuterium nuclear magnetic resonance as a probe of chain packing in lipid bilayers. Biochemistry. 1991 Feb 26;30(8):2146–2155. doi: 10.1021/bi00222a019. [DOI] [PubMed] [Google Scholar]
  3. Büldt G., Gally H. U., Seelig J., Zaccai G. Neutron diffraction studies on phosphatidylcholine model membranes. I. Head group conformation. J Mol Biol. 1979 Nov 15;134(4):673–691. doi: 10.1016/0022-2836(79)90479-0. [DOI] [PubMed] [Google Scholar]
  4. Cantor R. S. Lipid composition and the lateral pressure profile in bilayers. Biophys J. 1999 May;76(5):2625–2639. doi: 10.1016/S0006-3495(99)77415-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cantor R. S. The lateral pressure profile in membranes: a physical mechanism of general anesthesia. Biochemistry. 1997 Mar 4;36(9):2339–2344. doi: 10.1021/bi9627323. [DOI] [PubMed] [Google Scholar]
  6. Craig N. C., Bryant G. J., Levin I. W. Effects of halothane on dipalmitoylphosphatidylcholine liposomes: a Raman spectroscopic study. Biochemistry. 1987 May 5;26(9):2449–2458. doi: 10.1021/bi00383a008. [DOI] [PubMed] [Google Scholar]
  7. Eckenhoff R. G. An inhalational anesthetic binding domain in the nicotinic acetylcholine receptor. Proc Natl Acad Sci U S A. 1996 Apr 2;93(7):2807–2810. doi: 10.1073/pnas.93.7.2807. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Eckenhoff R. G., Johansson J. S. Molecular interactions between inhaled anesthetics and proteins. Pharmacol Rev. 1997 Dec;49(4):343–367. [PubMed] [Google Scholar]
  9. Essmann U., Berkowitz M. L. Dynamical properties of phospholipid bilayers from computer simulation. Biophys J. 1999 Apr;76(4):2081–2089. doi: 10.1016/S0006-3495(99)77364-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Feller S. E., Pastor R. W. Length scales of lipid dynamics and molecular dynamics. Pac Symp Biocomput. 1997:142–150. [PubMed] [Google Scholar]
  11. Franks N. P., Lieb W. R. Do general anaesthetics act by competitive binding to specific receptors? Nature. 1984 Aug 16;310(5978):599–601. doi: 10.1038/310599a0. [DOI] [PubMed] [Google Scholar]
  12. Franks N. P., Lieb W. R. Is membrane expansion relevant to anaesthesia? Nature. 1981 Jul 16;292(5820):248–251. doi: 10.1038/292248a0. [DOI] [PubMed] [Google Scholar]
  13. Franks N. P., Lieb W. R. Mechanisms of general anesthesia. Environ Health Perspect. 1990 Jul;87:199–205. doi: 10.1289/ehp.9087199. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Franks N. P., Lieb W. R. Molecular and cellular mechanisms of general anaesthesia. Nature. 1994 Feb 17;367(6464):607–614. doi: 10.1038/367607a0. [DOI] [PubMed] [Google Scholar]
  15. Franks N. P., Lieb W. R. Molecular mechanisms of general anaesthesia. Nature. 1982 Dec 9;300(5892):487–493. doi: 10.1038/300487a0. [DOI] [PubMed] [Google Scholar]
  16. Franks N. P., Lieb W. R. The structure of lipid bilayers and the effects of general anaesthetics. An x-ray and neutron diffraction study. J Mol Biol. 1979 Oct 9;133(4):469–500. doi: 10.1016/0022-2836(79)90403-0. [DOI] [PubMed] [Google Scholar]
  17. Gaillard S., Renou J. P., Bonnet M., Vignon X., Dufourc E. J. Halothane-induced membrane reorganization monitored by DSC, freeze fracture electron microscopy and 31P-NMR techniques. Eur Biophys J. 1991;19(5):265–274. doi: 10.1007/BF00183535. [DOI] [PubMed] [Google Scholar]
  18. Kita Y., Bennett L. J., Miller K. W. The partial molar volumes of anesthetics in lipid bilayers. Biochim Biophys Acta. 1981 Sep 21;647(1):130–139. doi: 10.1016/0005-2736(81)90301-1. [DOI] [PubMed] [Google Scholar]
  19. Lieb W. R., Kovalycsik M., Mendelsohn R. Do clinical levels of general anaesthetics affect lipid bilayers? Evidence from Raman scattering. Biochim Biophys Acta. 1982 Jun 14;688(2):388–398. doi: 10.1016/0005-2736(82)90350-9. [DOI] [PubMed] [Google Scholar]
  20. Mihic S. J., Ye Q., Wick M. J., Koltchine V. V., Krasowski M. D., Finn S. E., Mascia M. P., Valenzuela C. F., Hanson K. K., Greenblatt E. P. Sites of alcohol and volatile anaesthetic action on GABA(A) and glycine receptors. Nature. 1997 Sep 25;389(6649):385–389. doi: 10.1038/38738. [DOI] [PubMed] [Google Scholar]
  21. Miller K. W. The nature of the site of general anesthesia. Int Rev Neurobiol. 1985;27:1–61. doi: 10.1016/s0074-7742(08)60555-3. [DOI] [PubMed] [Google Scholar]
  22. North C., Cafiso D. S. Contrasting membrane localization and behavior of halogenated cyclobutanes that follow or violate the Meyer-Overton hypothesis of general anesthetic potency. Biophys J. 1997 Apr;72(4):1754–1761. doi: 10.1016/S0006-3495(97)78821-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Pohorille A., Cieplak P., Wilson M. A. Interactions of anesthetics with the membrane-water interface. Chem Phys. 1996 Apr 1;204(2-3):337–345. doi: 10.1016/0301-0104(95)00292-8. [DOI] [PubMed] [Google Scholar]
  24. Pohorille A., Wilson M. A. Excess chemical potential of small solutes across water--membrane and water--hexane interfaces. J Chem Phys. 1996 Mar 8;104(10):3760–3773. doi: 10.1063/1.471030. [DOI] [PubMed] [Google Scholar]
  25. Qin Z., Szabo G., Cafiso D. S. Anesthetics reduce the magnitude of the membrane dipole potential. Measurements in lipid vesicles using voltage-sensitive spin probes. Biochemistry. 1995 Apr 25;34(16):5536–5543. doi: 10.1021/bi00016a027. [DOI] [PubMed] [Google Scholar]
  26. 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]
  27. Tang P., Yan B., Xu Y. Different distribution of fluorinated anesthetics and nonanesthetics in model membrane: a 19F NMR study. Biophys J. 1997 Apr;72(4):1676–1682. doi: 10.1016/S0006-3495(97)78813-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Trudell J. R., Hubbell W. L. Localization of molecular halothane in phospholipid bilayer model nerve membranes. Anesthesiology. 1976 Mar;44(3):202–205. doi: 10.1097/00000542-197603000-00005. [DOI] [PubMed] [Google Scholar]
  29. Trudell J. R. The membrane volume occupied by anesthetic molecules: a reinterpretation of the erythrocyte expansion data. Biochim Biophys Acta. 1977 Nov 1;470(3):509–510. doi: 10.1016/0005-2736(77)90143-2. [DOI] [PubMed] [Google Scholar]
  30. Tsai Y. S., Ma S. M., Nishimura S., Ueda I. Infrared spectra of phospholipid membranes: interfacial dehydration by volatile anesthetics and phase transition. Biochim Biophys Acta. 1990 Feb 28;1022(2):245–250. doi: 10.1016/0005-2736(90)90120-d. [DOI] [PubMed] [Google Scholar]
  31. Tu K., Tarek M., Klein M. L., Scharf D. Effects of anesthetics on the structure of a phospholipid bilayer: molecular dynamics investigation of halothane in the hydrated liquid crystal phase of dipalmitoylphosphatidylcholine. Biophys J. 1998 Nov;75(5):2123–2134. doi: 10.1016/S0006-3495(98)77655-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Tu K., Tobias D. J., Klein M. L. Constant pressure and temperature molecular dynamics simulation of a fully hydrated liquid crystal phase dipalmitoylphosphatidylcholine bilayer. Biophys J. 1995 Dec;69(6):2558–2562. doi: 10.1016/S0006-3495(95)80126-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Xu Y., Tang P. Amphiphilic sites for general anesthetic action? Evidence from 129Xe-[1H] intermolecular nuclear Overhauser effects. Biochim Biophys Acta. 1997 Jan 14;1323(1):154–162. doi: 10.1016/s0005-2736(96)00184-8. [DOI] [PubMed] [Google Scholar]
  34. Yokono S., Ogli K., Miura S., Ueda I. 400 MHz two-dimensional nuclear Overhauser spectroscopy on anesthetic interaction with lipid bilayer. Biochim Biophys Acta. 1989 Jul 10;982(2):300–302. doi: 10.1016/0005-2736(89)90068-0. [DOI] [PubMed] [Google Scholar]

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

RESOURCES