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The Journal of Membrane Biology

, Volume 251, Issue 3, pp 521–534 | Cite as

Cholesterol Protects the Oxidized Lipid Bilayer from Water Injury: An All-Atom Molecular Dynamics Study

  • Michael C. Owen
  • Waldemar Kulig
  • Tomasz Rog
  • Ilpo Vattulainen
  • Birgit Strodel
Article
Part of the following topical collections:
  1. Lipid Membranes and Reactions at Lipid Interfaces: Theory, experiments, and applications

Abstract

In an effort to delineate how cholesterol protects membrane structure under oxidative stress conditions, we monitored the changes to the structure of lipid bilayers comprising 30 mol% cholesterol and an increasing concentration of Class B oxidized 1-palmitoyl-2-oleoylphosphatidylcholine (POPC) glycerophospholipids, namely, 1-palmitoyl-2-(9′-oxo-nonanoyl)-sn-glycero-3-phosphocholine (PoxnoPC), and 1-palmitoyl-2-azelaoyl-sn-glycero-3-phosphocholine (PazePC), using atomistic molecular dynamics simulations. Increasing the content of oxidized phospholipids (oxPLs) from 0 to 60 mol% oxPL resulted in a characteristic reduction in bilayer thickness and increase in area per lipid, thereby increasing the exposure of the membrane hydrophobic region to water. However, cholesterol was observed to help reduce water injury by moving into the bilayer core and forming more hydrogen bonds with the oxPLs. Cholesterol also resists altering its tilt angle, helping to maintain membrane integrity. Water that enters the 1-nm-thick core region remains part of the bulk water on either side of the bilayer, with relatively few water molecules able to traverse through the bilayer. In cholesterol-rich membranes, the bilayer does not form pores at concentrations of 60 mol% oxPL as was shown in previous simulations in the absence of cholesterol.

Keywords

Lipid oxidation Cholesterol protection Oxidative stress Oxidized membranes Pore formation 

Notes

Acknowledgements

M. O. thanks the Helmholtz Postdoc Programme. I.V. thanks the European Research Council [Advanced Grant CROWDED-PRO-LIPIDS (Grant No. 290974)]. B.S. thanks the Deutsche Forschungsgemeinschaft for financial support through the Collaborative Research Center SFB 1208 (“Identity and Dynamics of Membrane Systems—from Molecules to Cellular Functions,” Düsseldorf, project A07). The CSC—IT Centre for Science (Espoo, Finland) is acknowledged for excellent computational resources (Project Number tty3995). We also acknowledge grants of computer capacity from the Finnish Grid and Cloud Infrastructure (persistent identifier urn:nbn:fi:research-infras-201).

Compliance with Ethical Standards

Conflict of interests

The authors declare that they have no conflict of interests.

Supplementary material

232_2018_28_MOESM1_ESM.pdf (835 kb)
Supplementary material 1 (PDF 835 KB)

References

  1. Allen W, Lemkul J, Bevan D (2009) GridMAT-MD: a grid-based membrane analysis tool for use with molecular dynamics. J Comput Chem 30(12):1952–1958CrossRefPubMedGoogle Scholar
  2. Beranova L, Cwiklik L, Jurkiewicz P, Jungwirth P, Hof M (2010) Oxidation changes physical properties of phospholipid bilayers: fluorescence spectroscopy and molecular simulations. Langmuir 26:6140–6144CrossRefPubMedGoogle Scholar
  3. Berendsen HJC, van der Spoel D, van Drunen R (1995) GROMACS: a message-passing parallel molecular dynamics implementation. Comput Phys Commun 91:43–56CrossRefGoogle Scholar
  4. Boonnoy P, Jarerattanachat V, Karttunen M, Wong-ekkabut J (2015) Bilayer deformation, pores, and micellation induced by oxidized lipids. J Phys Chem Lett 6:4884–4888CrossRefPubMedGoogle Scholar
  5. Cwiklik L, Jungwirth P (2010) Massive oxidation of phospholipid membranes leads to pore creation and bilayer disintegration. Chem Phys Lett 486:99–103CrossRefGoogle Scholar
  6. Das D, Noroand MG, Olmstead PD (2009) Simulation studies of stratum corneum lipid mixtures. Biophys J 97:1941–1951CrossRefPubMedPubMedCentralGoogle Scholar
  7. Davis JH (1983) The description of membrane lipid conformation, order and dynamics by 2H-NMR. Biochim Biophys Acta 737:117–171CrossRefPubMedGoogle Scholar
  8. Deiger H-P, Hermetter A (2008) Oxidized phospholipids: emerging lipid mediators in pathophysiology. Curr Opin Lipidol 19:289–294CrossRefGoogle Scholar
  9. Downey JM (1990) Free radicals and their involvement during log-term myocardial ischemia and reperfusion. Annu Rev Physiol 52:487–504CrossRefPubMedGoogle Scholar
  10. Essman U, Perera L, Berkowitz ML, Darden HLT, Pedersen LG (1995) A smooth particle mesh Ewald method. J Phys Chem 103:8577–8592CrossRefGoogle Scholar
  11. Fruhwirth GO, Loidl A, Hermetter A (2007) Oxidized phospholipids: from molecular properties to disease. Biochim Biophys Acta 1772:718–736CrossRefPubMedGoogle Scholar
  12. Gaede HC, Gawrisch K (2003) Lateral diffusion rates of lipid, water, and a hydrophobic drug in a multilamellar liposome. Biophys J 85:1734–1740CrossRefPubMedPubMedCentralGoogle Scholar
  13. Gapsys V, de Groot BL, Briones R (2013) Computational analysis of local membrane properties. J Comput Aid Mol Des 27:845–858CrossRefGoogle Scholar
  14. Grzelinska I, Bartosz G, Gwozdzinski K, Leyko W (1979) A spin-label study of the effect of gamma radiation on erythrocyte membrane. Int J Radiat Biol 36:325–334Google Scholar
  15. Gunstone FD, Harwood JL, Dijkstra AJ (2007) The lipid handbook with CD-ROM, 3rd edn, CRC Press, Boca RatonGoogle Scholar
  16. Hess B, Kutzner C, van der Spoel D, Lindahl E (2008) GROMACS 4: algorithms for highly efficient, load-balanced, and scalable molecular simulation. J Chem Theory Comput 4:435–447CrossRefPubMedGoogle Scholar
  17. Hoover WG (1985) Canonical dynamics: equilibrium phase-space distributions. Phys Rev A 31:1695–1697CrossRefGoogle Scholar
  18. Ikeda M, Kihara A, Igarashi Y (2006) Lipid asymmetry of the eukaryotic plasma membrane: functions and related enzymes. Biol Pharm Bull 8:1542–1546CrossRefGoogle Scholar
  19. Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML (1983) Comparison of simple potential functions for simulating liquid water. J Chem Phys 79:926–935CrossRefGoogle Scholar
  20. Jorgensen WL, Maxwell DS, Tirado-Rives J (1996) Development and testing of the OPLS all-atom force field on conformational energetics and properties of organic liquids. J Am Chem Soc 118:11225–11236CrossRefGoogle Scholar
  21. Jurkiewicz P, Olzyńska A, Cwiklik L, Conte E, Jungwirth P, Megli FM, Hof M (2012) Biophysics of lipid bilayers containing oxidatively modified phospholipids: insights from fluorescence and EPR experiments and from MD simulations. Biochim Biophys Acta 1818:2388–2402CrossRefPubMedGoogle Scholar
  22. Kaminski GA, Friesner RA, Tirado-Rives J, Jorgensen WL (2001) Evaluation and reparametrization of the OPLS-AA force field for proteins via comparison with accurate quantum chemical calculations on peptides. J Phys Chem 105:6474–6487CrossRefGoogle Scholar
  23. Khandelia H, Mouritsen OG (2009) Lipid gymnastics: evidence of complete acyl chain reversal in oxidized phospholipids from molecular simulations. Biophys J 96:2734–2743CrossRefPubMedPubMedCentralGoogle Scholar
  24. Khandelia H, Loubet B, Olzynska A, Jurkiewicz P, Hof M (2014) Paring of cholesterol with oxidized phospholipid species in lipid bilayers. Soft Matter 10:639–647CrossRefPubMedGoogle Scholar
  25. Kourie JI (1998) Interaction of reactive oxygen species with ion transport mechanisms. Am J Physiol 275:C1–C24CrossRefGoogle Scholar
  26. Kulig W, Pasenkiewicz-Gierula M, Róg T (2016) Cholesterol interactions with cis and trans unsaturated phosphatidylcholines. Molecular dynamics simulation study. Chem Phys Lipids 195:12–20CrossRefPubMedGoogle Scholar
  27. Maciejewski A, Pasenkiewicz-Gierula M, Cramariuc O, Vattulainen I, Rog T (2014) Refined OPLS all-atom force field for saturated phosphatidylcholine bilayers at full hydration. J Phys Chem B 118:4571–4581CrossRefPubMedGoogle Scholar
  28. Mason PR, Walter MF, Mason PE (1997) Effect of oxidative stress on membrane structure: small angle X-ray diffraction analysis. Free Radic Biol Med 23:419–425CrossRefPubMedGoogle Scholar
  29. Mattila JP, Sabatini K, Kinnunen PKJ (2008) Interaction of cytochrome c with 1-palmitoyl-2-azelaoyl-sn-glycero-3-phosphocholine: evidence for acyl chain reversal. Langmuir 24:4157–4160CrossRefPubMedGoogle Scholar
  30. Megli FM, Russo L, Conte E (2009) Spin labeling EPR studies of the properties of oxidized phospholipid-containing lipid vesicles. BBA Biomembranes 1788:371–379CrossRefPubMedGoogle Scholar
  31. Megli FM, Conte E, Ishikawa T (2011) Cholesterol attenuates and prevents bilayer damage and breakdown in lipoperoxidized model membranes. A spin labeling EPR study. Biochim Biophys Acta 1808:2267–2274CrossRefPubMedGoogle Scholar
  32. Nosé S (1984) A unified formulation of the constant temperature molecular dynamics methods. J Chem Phys 81:511–519CrossRefGoogle Scholar
  33. Parrinello M, Rahman A (1981) A polymorphic transitions in single crystals: a new molecular dynamics method. J Appl Phys 52:7182–7190CrossRefGoogle Scholar
  34. Pham-Huy LA, He H, Pham-Huy C (2008) Free radicals, antioxidants in disease and health. Int J Biomed Sci 4:89–96PubMedPubMedCentralGoogle Scholar
  35. Plochberger B, Stockner T, Chiantia S, Brameshuber M, Weghuber J, Hermetter A, Schwille P, Schutz GJ (2010) Cholesterol slows down the lateral mobility of an oxidized phospholipid in a supported bilayer. Langmuir 26:17322–17329CrossRefPubMedPubMedCentralGoogle Scholar
  36. Sabatini K, Juha-Pekka M, Megli FM, Kinnunen PKJ (2006) Characterization of two oxidatively modified phospholipids in mixed monolayers with DPPC. Biophys J 90:4488–4499CrossRefPubMedPubMedCentralGoogle Scholar
  37. Spector AA, Yorek MA (1985) Membrane lipid composition and cellular function. Lipid Res 26:1015–1035Google Scholar
  38. Uchida K (2003) 4-Hydroxy-2-nonenal: a product and mediator of oxidative stress. Prog Lipid Res 42:318–343CrossRefPubMedGoogle Scholar
  39. Van der Paal J, Neyts EC, Verlackt CCW, Bogaerts A (2016) Effect of lipid peroxidation on membrane permeability of cancer and normal cells subjected to oxidative stress. Chem Sci 7:489–498CrossRefPubMedGoogle Scholar
  40. Van der Spoel D, Lindahl E, Hess B, the GRMACS development team (2014) GROAMCS User Manual version 4.6.7, http://www.gromacs.org
  41. Volinsky R, Cwiklik L, Jurkiewicz P, Hof M, Jungwirth P, Kinnunen PKJ (2011) Oxidized phosphatidylcholines facilitate phospholipid flip-flop in liposomes. Biophys J 101:1376–1384CrossRefPubMedPubMedCentralGoogle Scholar
  42. Wong-Ekkabut J, Xu ZT, Triampo W, Tang IM, Tieleman DP, Monticelli L (2007) Effect of lipid peroxidation on the properties of lipid bilayers: a molecular dynamics study. Biophys J 93:4225–4236CrossRefPubMedPubMedCentralGoogle Scholar
  43. Wratten M, van Ginkel G, van’t Veld AA, Bekker A, van Faasen EE, Sevanian A (1992) Structural and dynamic effects of oxidatively modified phospholipids in unsaturated lipid membranes. Biochemistry 31:10901–10907CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Institute of Complex Systems: Structural Biochemistry (ICS-6)Forschungszentrum JülichJülichGermany
  2. 2.CEITEC – Central European Institute of TechnologyMasaryk UniversityBrnoCzech Republic
  3. 3.Department of PhysicsUniversity of HelsinkiHelsinkiFinland
  4. 4.Department of PhysicsTampere University of TechnologyTampereFinland
  5. 5.MEMPHYS - Center for Biomembrane Physics, University of Southern DenmarkOdenseDenmark
  6. 6.Institute of Theoretical and Computational ChemistryHeinrich Heine University DüsseldorfDüsseldorfGermany

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