Skip to main content
NCBI home page
Biophysical Journal logoLink to Biophysical Journal
. 2000 Mar;78(3):1376–1389. doi: 10.1016/S0006-3495(00)76691-4

Cholesterol effects on the phosphatidylcholine bilayer polar region: a molecular simulation study.

M Pasenkiewicz-Gierula 1, T Róg 1, K Kitamura 1, A Kusumi 1
PMCID: PMC1300736  PMID: 10692323

Abstract

A molecular dynamics (MD) simulation of a fully hydrated, liquid-crystalline dimyristoylphosphatidylcholine (DMPC)-Chol bilayer membrane containing approximately 22 mol% Chol was carried out for 4.3 ns. The bilayer reached thermal equilibrium after 2.3 ns of MD simulation. A 2.0-ns trajectory generated during 2.3-4.3 ns of MD simulation was used for analyses to determine the effects of Chol on the membrane/water interfacial region. In this region, 70% of Chol molecules are linked to DMPC molecules via short-distance interactions, where the Chol hydroxyl group (OH-Chol) is 1) charge paired to methyl groups of the DMPC choline moiety ( approximately 34%), via the hydroxyl oxygen atom (Och); 2) water bridged to carbonyl ( approximately 19%) and nonester phosphate ( approximately 14%) oxygen atoms, via both Och and the hydroxyl hydrogen atom (Hch); and 3) directly hydrogen (H) bonded to carbonyl ( approximately 11%) and nonester phosphate ( approximately 5%) oxygen atoms, via Hch ( approximately 17% of DMPC-Chol links are multiple). DMPC's gamma-chain carbonyl oxygen atom is involved in 44% of water bridges and 51% of direct H bonds formed between DMPC and Chol. On average, a Chol molecule forms 0.9 links with DMPC molecules, while a DMPC molecule forms 2.2 and 0.3 links with DMPC and Chol molecules, respectively. OH-Chol makes hydrogen bonds with 1.1 water molecules, preferentially via Hch. The average number of water molecules H bonded to the DMPC headgroup is increased by 7% in the presence of Chol. These results indicate that inclusion of Chol decreases interlipid links and increases hydration in the polar region of the membrane.

Full Text

The Full Text of this article is available as a PDF (1.1 MB).

Selected References

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

  1. Bicknell-Brown E., Brown K. G. Raman studies of lipid interactions at the bilayer interface: phosphatidyl choline--cholesterol. Biochem Biophys Res Commun. 1980 May 30;94(2):638–645. doi: 10.1016/0006-291x(80)91280-2. [DOI] [PubMed] [Google Scholar]
  2. Bittman R., Clejan S., Lund-Katz S., Phillips M. C. Influence of cholesterol on bilayers of ester- and ether-linked phospholipids. Permeability and 13C-nuclear magnetic resonance measurements. Biochim Biophys Acta. 1984 May 16;772(2):117–126. doi: 10.1016/0005-2736(84)90034-8. [DOI] [PubMed] [Google Scholar]
  3. Bloom M., Evans E., Mouritsen O. G. Physical properties of the fluid lipid-bilayer component of cell membranes: a perspective. Q Rev Biophys. 1991 Aug;24(3):293–397. doi: 10.1017/s0033583500003735. [DOI] [PubMed] [Google Scholar]
  4. Cheetham J. J., Wachtel E., Bach D., Epand R. M. Role of the stereochemistry of the hydroxyl group of cholesterol and the formation of nonbilayer structures in phosphatidylethanolamines. Biochemistry. 1989 Oct 31;28(22):8928–8934. doi: 10.1021/bi00448a036. [DOI] [PubMed] [Google Scholar]
  5. Demel R. A., Bruckdorfer K. R., van Deenen L. L. Structural requirements of sterols for the interaction with lecithin at the air water interface. Biochim Biophys Acta. 1972 Jan 17;255(1):311–320. doi: 10.1016/0005-2736(72)90030-2. [DOI] [PubMed] [Google Scholar]
  6. Edholm O., Nyberg A. M. Cholesterol in model membranes. A molecular dynamics simulation. Biophys J. 1992 Oct;63(4):1081–1089. doi: 10.1016/S0006-3495(92)81678-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Egberts E., Marrink S. J., Berendsen H. J. Molecular dynamics simulation of a phospholipid membrane. Eur Biophys J. 1994;22(6):423–436. doi: 10.1007/BF00180163. [DOI] [PubMed] [Google Scholar]
  8. Ho C., Slater S. J., Stubbs C. D. Hydration and order in lipid bilayers. Biochemistry. 1995 May 9;34(18):6188–6195. doi: 10.1021/bi00018a023. [DOI] [PubMed] [Google Scholar]
  9. Hyslop P. A., Morel B., Sauerheber R. D. Organization and interaction of cholesterol and phosphatidylcholine in model bilayer membranes. Biochemistry. 1990 Jan 30;29(4):1025–1038. doi: 10.1021/bi00456a027. [DOI] [PubMed] [Google Scholar]
  10. Ipsen J. H., Karlström G., Mouritsen O. G., Wennerström H., Zuckermann M. J. Phase equilibria in the phosphatidylcholine-cholesterol system. Biochim Biophys Acta. 1987 Nov 27;905(1):162–172. doi: 10.1016/0005-2736(87)90020-4. [DOI] [PubMed] [Google Scholar]
  11. Karolis C., Coster H. G., Chilcott T. C., Barrow K. D. Differential effects of cholesterol and oxidised-cholesterol in egg lecithin bilayers. Biochim Biophys Acta. 1998 Jan 19;1368(2):247–255. doi: 10.1016/s0005-2736(97)00180-6. [DOI] [PubMed] [Google Scholar]
  12. Keough K. M., Giffin B., Matthews P. L. Phosphatidylcholine-cholesterol interactions: bilayers of heteroacid lipids containing linoleate lose calorimetric transitions at low cholesterol concentration. Biochim Biophys Acta. 1989 Jul 24;983(1):51–55. doi: 10.1016/0005-2736(89)90379-9. [DOI] [PubMed] [Google Scholar]
  13. Kusumi A., Pasenkiewicz-Gierula M. Rotational diffusion of a steroid molecule in phosphatidylcholine membranes: effects of alkyl chain length, unsaturation, and cholesterol as studied by a spin-label method. Biochemistry. 1988 Jun 14;27(12):4407–4415. doi: 10.1021/bi00412a030. [DOI] [PubMed] [Google Scholar]
  14. Kusumi A., Subczynski W. K., Pasenkiewicz-Gierula M., Hyde J. S., Merkle H. Spin-label studies on phosphatidylcholine-cholesterol membranes: effects of alkyl chain length and unsaturation in the fluid phase. Biochim Biophys Acta. 1986 Jan 29;854(2):307–317. doi: 10.1016/0005-2736(86)90124-0. [DOI] [PubMed] [Google Scholar]
  15. Kusumi A., Tsuda M., Akino T., Ohnishi S., Terayama Y. Protein-phospholipid-cholesterol interaction in the photolysis of invertebrate rhodopsin. Biochemistry. 1983 Mar 1;22(5):1165–1170. doi: 10.1021/bi00274a027. [DOI] [PubMed] [Google Scholar]
  16. McIntosh T. J. The effect of cholesterol on the structure of phosphatidylcholine bilayers. Biochim Biophys Acta. 1978 Oct 19;513(1):43–58. doi: 10.1016/0005-2736(78)90110-4. [DOI] [PubMed] [Google Scholar]
  17. Murari R., Murari M. P., Baumann W. J. Sterol orientations in phosphatidylcholine liposomes as determined by deuterium NMR. Biochemistry. 1986 Mar 11;25(5):1062–1067. doi: 10.1021/bi00353a017. [DOI] [PubMed] [Google Scholar]
  18. Pasenkiewicz-Gierula M., Subczynski W. K., Kusumi A. Influence of phospholipid unsaturation on the cholesterol distribution in membranes. Biochimie. 1991 Oct;73(10):1311–1316. doi: 10.1016/0300-9084(91)90094-h. [DOI] [PubMed] [Google Scholar]
  19. Pasenkiewicz-Gierula M., Subczynski W. K., Kusumi A. Rotational diffusion of a steroid molecule in phosphatidylcholine-cholesterol membranes: fluid-phase microimmiscibility in unsaturated phosphatidylcholine-cholesterol membranes. Biochemistry. 1990 May 1;29(17):4059–4069. doi: 10.1021/bi00469a006. [DOI] [PubMed] [Google Scholar]
  20. Pasenkiewicz-Gierula M., Takaoka Y., Miyagawa H., Kitamura K., Kusumi A. Charge pairing of headgroups in phosphatidylcholine membranes: A molecular dynamics simulation study. Biophys J. 1999 Mar;76(3):1228–1240. doi: 10.1016/S0006-3495(99)77286-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Recktenwald D. J., McConnell H. M. Phase equilibria in binary mixtures of phosphatidylcholine and cholesterol. Biochemistry. 1981 Jul 21;20(15):4505–4510. doi: 10.1021/bi00518a042. [DOI] [PubMed] [Google Scholar]
  22. Robinson A. J., Richards W. G., Thomas P. J., Hann M. M. Behavior of cholesterol and its effect on head group and chain conformations in lipid bilayers: a molecular dynamics study. Biophys J. 1995 Jan;68(1):164–170. doi: 10.1016/S0006-3495(95)80171-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Sankaram M. B., Thompson T. E. Modulation of phospholipid acyl chain order by cholesterol. A solid-state 2H nuclear magnetic resonance study. Biochemistry. 1990 Nov 27;29(47):10676–10684. doi: 10.1021/bi00499a015. [DOI] [PubMed] [Google Scholar]
  24. 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]
  25. Scott H. L. Lipid-cholesterol interactions. Monte Carlo simulations and theory. Biophys J. 1991 Feb;59(2):445–455. doi: 10.1016/S0006-3495(91)82238-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Scott H. L., McCullough W. S. Lipid-cholesterol interactions in the P beta' phase. Application of a statistical mechanical model. Biophys J. 1993 May;64(5):1398–1404. doi: 10.1016/S0006-3495(93)81506-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Simons K., Ikonen E. Functional rafts in cell membranes. Nature. 1997 Jun 5;387(6633):569–572. doi: 10.1038/42408. [DOI] [PubMed] [Google Scholar]
  28. Slater S. J., Ho C., Taddeo F. J., Kelly M. B., Stubbs C. D. Contribution of hydrogen bonding to lipid-lipid interactions in membranes and the role of lipid order: effects of cholesterol, increased phospholipid unsaturation, and ethanol. Biochemistry. 1993 Apr 13;32(14):3714–3721. doi: 10.1021/bi00065a025. [DOI] [PubMed] [Google Scholar]
  29. Smaby J. M., Brockman H. L., Brown R. E. Cholesterol's interfacial interactions with sphingomyelins and phosphatidylcholines: hydrocarbon chain structure determines the magnitude of condensation. Biochemistry. 1994 Aug 9;33(31):9135–9142. doi: 10.1021/bi00197a016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Smaby J. M., Momsen M. M., Brockman H. L., Brown R. E. Phosphatidylcholine acyl unsaturation modulates the decrease in interfacial elasticity induced by cholesterol. Biophys J. 1997 Sep;73(3):1492–1505. doi: 10.1016/S0006-3495(97)78181-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Subczynski W. K., Antholine W. E., Hyde J. S., Kusumi A. Microimmiscibility and three-dimensional dynamic structures of phosphatidylcholine-cholesterol membranes: translational diffusion of a copper complex in the membrane. Biochemistry. 1990 Aug 28;29(34):7936–7945. doi: 10.1021/bi00486a023. [DOI] [PubMed] [Google Scholar]
  32. Subczynski W. K., Hyde J. S., Kusumi A. Oxygen permeability of phosphatidylcholine--cholesterol membranes. Proc Natl Acad Sci U S A. 1989 Jun;86(12):4474–4478. doi: 10.1073/pnas.86.12.4474. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Subczynski W. K., Wisniewska A., Yin J. J., Hyde J. S., Kusumi A. Hydrophobic barriers of lipid bilayer membranes formed by reduction of water penetration by alkyl chain unsaturation and cholesterol. Biochemistry. 1994 Jun 21;33(24):7670–7681. doi: 10.1021/bi00190a022. [DOI] [PubMed] [Google Scholar]
  34. Tu K., Klein M. L., Tobias D. J. Constant-pressure molecular dynamics investigation of cholesterol effects in a dipalmitoylphosphatidylcholine bilayer. Biophys J. 1998 Nov;75(5):2147–2156. doi: 10.1016/S0006-3495(98)77657-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Urbina J. A., Moreno B., Arnold W., Taron C. H., Orlean P., Oldfield E. A carbon-13 nuclear magnetic resonance spectroscopic study of inter-proton pair order parameters: a new approach to study order and dynamics in phospholipid membrane systems. Biophys J. 1998 Sep;75(3):1372–1383. doi: 10.1016/S0006-3495(98)74055-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Urbina J. A., Pekerar S., Le H. B., Patterson J., Montez B., Oldfield E. Molecular order and dynamics of phosphatidylcholine bilayer membranes in the presence of cholesterol, ergosterol and lanosterol: a comparative study using 2H-, 13C- and 31P-NMR spectroscopy. Biochim Biophys Acta. 1995 Sep 13;1238(2):163–176. doi: 10.1016/0005-2736(95)00117-l. [DOI] [PubMed] [Google Scholar]
  37. Vanderkooi G. Computation of mixed phosphatidylcholine-cholesterol bilayer structures by energy minimization. Biophys J. 1994 May;66(5):1457–1468. doi: 10.1016/S0006-3495(94)80936-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Yeagle P. L., Hutton W. C., Huang C., Martin R. B. Phospholipid head-group conformations; intermolecular interactions and cholesterol effects. Biochemistry. 1977 Oct 4;16(20):4344–4349. doi: 10.1021/bi00639a003. [DOI] [PubMed] [Google Scholar]
  39. Yeagle P. L., Martin R. B. Hydrogen-bonding of the ester carbonyls in phosphatidycholine bilayers. Biochem Biophys Res Commun. 1976 Apr 5;69(3):775–780. doi: 10.1016/0006-291x(76)90942-6. [DOI] [PubMed] [Google Scholar]
  40. de Kruijff B. 13C NMR studies on [4-13C] cholesterol incorporated in sonicated phosphatidylcholine vesicles. Biochim Biophys Acta. 1978 Jan 19;506(2):173–182. doi: 10.1016/0005-2736(78)90388-7. [DOI] [PubMed] [Google Scholar]
  41. de Kruyff B., Demel R. A., Slotboom A. J., van Deenen L. L., Rosenthal A. F. The effect of the polar headgroup on the lipid-cholesterol interaction: a monolayer and differential scanning calorimetry study. Biochim Biophys Acta. 1973 Apr 25;307(1):1–19. doi: 10.1016/0005-2736(73)90020-5. [DOI] [PubMed] [Google Scholar]
  42. el-Sayed M. Y., Guion T. A., Fayer M. D. Effect of cholesterol on viscoelastic properties of dipalmitoylphosphatidylcholine multibilayers as measured by a laser-induced ultrasonic probe. Biochemistry. 1986 Aug 26;25(17):4825–4832. doi: 10.1021/bi00365a016. [DOI] [PubMed] [Google Scholar]

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

RESOURCES