Abstract
Using molecular dynamics simulations, we investigate the interaction of α-tocopherol (α-toc) with dipalmitoylphosphatidylcholine (DPPC), dimyristoylphosphatidylcholine (DMPC), palmitoyloleoylphosphatidylcholine (POPC), and palmitoyloleoylphosphatidylethanolamine (POPE) lipid bilayers. The goal is to develop a better understanding of the positioning and orientation of α-toc inside the bilayers; properties of significant relevance to α-toc anti-oxidant activity. We investigated bilayer systems with 128 lipids in the presence of either single or 14 α-toc molecules. The single α-toc bilayer systems were investigated via biased MD simulations in which the potential of mean force (PMF) and diffusivity were obtained as functions of the distance between α-toc head group and bilayer center. The higher α-toc concentration systems were investigated with unbiased MD simulations. For all four bilayers at both concentrations, the simulations show that the most probable location of the α-toc hydroxyl group is just below the lipid carbonyl group. Overall, the simulation results are in good agreement with existing experimental data except for the DMPC bilayer system for which some experiments predict α-toc to be located closer to bilayer center. The flip-flop frequency calculated shows that the α-toc flip-flop rate is sensitive to bilayer lipid type. In particular, α-toc has a much lower flip-flop rate in a POPE bilayer compared to the three PC lipid bilayers due to the smaller area per lipid in the POPE bilayer. For DMPC and POPC, the α-toc flip-flop rates are significantly higher at higher α-toc concentration and this appears to be related to the local structural disruption caused by α-toc clusters spanning the bilayer.
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Afri M, Ehrenberg B, Talmon Y et al (2004) Active oxygen chemistry within the liposomal bilayer. Part III: locating Vitamin E, ubiquinol and ubiquinone and their derivatives in the lipid bilayer. Chem Phys Lipids 131:107–121. https://doi.org/10.1016/j.chemphyslip.2004.04.007
Aranda FJ, Coutinho A, Berberan-Santos MN et al (1989) Fluorescence study of the location and dynamics of α-tocopherol in phospholipid vesicles. Biochim Et Biophys Acta BBA Biomembr 985:26–32. https://doi.org/10.1016/0005-2736(89)90098-9
Atkinson J, Harroun T, Wassall SR et al (2010) The location and behavior of α-tocopherol in membranes. Mol Nutr Food Res 54:641–651. https://doi.org/10.1002/mnfr.200900439
Ausili A, de Godos AM, Torrecillas A et al (2017) The vertical location of α-tocopherol in phosphatidylcholine membranes is not altered as a function of the degree of unsaturation of the fatty acyl chains. Phys Chem Chem Phys 19:6731–6742. https://doi.org/10.1039/C6CP08872D
Ausili A, Torrecillas A, de Godos AM et al (2018) Phenolic group of α-tocopherol anchors at the lipid–water interface of fully saturated membranes. Langmuir 34:3336–3348. https://doi.org/10.1021/acs.langmuir.7b04142
Bennett WFD, Tieleman DP (2012) Molecular simulation of rapid translocation of cholesterol, diacylglycerol, and ceramide in model raft and nonraft membranes. J Lipid Res 53:421–429. https://doi.org/10.1194/jlr.M022491
Berendsen HJC, Postma JPM, van Gunsteren WF et al (1984) Molecular dynamics with coupling to an external bath. J Chem Phys 81:3684–3690. https://doi.org/10.1063/1.448118
Bisby RH, Ahmed S (1989) Transverse distribution of α-tocopherol in bilayer membranes studied by fluorescence quenching. Free Radical Biol Med 6:231–239. https://doi.org/10.1016/0891-5849(89)90049-X
Boonnoy P, Karttunen M, Wong-ekkabut J (2018) Does α-tocopherol flip-flop help to protect membranes against oxidation? J Phys Chem B 122:10362–10370. https://doi.org/10.1021/acs.jpcb.8b09064
Bussi G, Donadio D, Parrinello M (2007) Canonical sampling through velocity rescaling. J Chem Phys 126:014101. https://doi.org/10.1063/1.2408420
Chodera JD (2015) A simple method for automated equilibration detection in molecular simulations. bioRxiv. https://doi.org/10.1101/021659
Diplock AT, Lucy JA (1973) The biochemical modes of action of vitamin E and selenium: a hypothesis. FEBS Lett 29:205–210. https://doi.org/10.1016/0014-5793(73)80020-1
Essex JW, Hann MM, Richards WG (1994) Molecular dynamics simulation of a hydrated phospholipid bilayer. Philos Trans R Soc Lond B Biol Sci 344:239–260. https://doi.org/10.1098/rstb.1994.0064
Fukuzawa K, Ikebata W, Shibata A et al (1992) Location and dynamics of α-tocopherol in model phospholipid membranes with different charges. Chem Phys Lipid 63:69–75. https://doi.org/10.1016/0009-3084(92)90024-J
Fukuzawa K, Ikebata W, Sohmi K (1993) Location, antioxidant and recycling dynamics of α-tocopherol in liposome membranes. J Nutr Sci Vitaminol 39:S9–S22. https://doi.org/10.3177/jnsv.39.Supplement_S9
Gerhard H (2005) Position-dependent diffusion coefficients and free energies from Bayesian analysis of equilibrium and replica molecular dynamics simulations. New J Phys 7:34. https://doi.org/10.1088/1367-2630/7/1/034
Gomez-Fernandez JC, Villalain J, Aranda FJ et al (1989) Localization of α-tocopherol in membranes. Ann N Y Acad Sci 570:109–120. https://doi.org/10.1111/j.1749-6632.1989.tb14912.x
Gramlich G, Zhang J, Nau WM (2004) Diffusion of α-tocopherol in membrane models: probing the kinetics of vitamin e antioxidant action by fluorescence in real time. J Am Chem Soc 126:5482–5492. https://doi.org/10.1021/ja039845b
Herrera E, Barbas C (2001) Vitamin E: action, metabolism and perspective. J Physiol Biochem 57:43–56. https://doi.org/10.1007/BF03179812
Hess B, Bekker H, Berendsen HJC et al (1997) LINCS: a linear constraint solver for molecular simulations. J Comput Chem 18:1463–1472. https://doi.org/10.1002/(SICI)1096-987X(199709)18:12%3C1463::AID-JCC4%3E3.0.CO;2-H
Jo S, Rui H, Lim JB et al (2010) Cholesterol flip-flop: insights from free energy simulation studies. J Phys Chem B 114:13342–13348. https://doi.org/10.1021/jp108166k
Kagan VE, Quinn PJ (1988) The interaction of α-tocopherol and homologues with shorter hydrocarbon chains with phospholipid bilayer dispersions. Eur J Biochem 171:661–667. https://doi.org/10.1111/j.1432-1033.1988.tb13837.x
Kamal-Eldin A, Appelqvist LA (1996) The chemistry and antioxidant properties of tocopherols and tocotrienols. Lipids 31:671–701
Kumar S, Rosenberg JM, Bouzida D et al (1992) The weighted histogram analysis method for free-energy calculations on biomolecules. I. The method. J Comput Chem 13:1011–1021. https://doi.org/10.1002/jcc.540130812
Lefevre T, Picquart M (1996) Vitamin E-phospholipid interactions in model multilayer membranes: a spectroscopic study. Biospectroscopy 2:391–403. https://doi.org/10.1002/(SICI)1520-6343(1996)2:6%3C391::AID-BSPY5%3E3.0.CO;2-6
Leng X, Kinnun Jacob J, Marquardt D et al (2015) α-Tocopherol is well designed to protect polyunsaturated phospholipids: MD simulations. Biophys J 109:1608–1618. https://doi.org/10.1016/j.bpj.2015.08.032
Leng X, Zhu F, Wassall SR (2018) Vitamin E has reduced affinity for a polyunsaturated phospholipid: an umbrella sampling molecular dynamics simulations study. J Phys Chem B 122:8351–8358. https://doi.org/10.1021/acs.jpcb.8b05016
Li H, Chowdhary J, Huang L et al (2017) Drude polarizable force field for molecular dynamics simulations of saturated and unsaturated zwitterionic lipids. J Chem Theory Comput 13:4535–4552. https://doi.org/10.1021/acs.jctc.7b00262
Lin J, Novak B, Moldovan D (2012) Molecular dynamics simulation study of the effect of DMSO on structural and permeation properties of DMPC lipid bilayers. J Phys Chem B 116:1299–1308. https://doi.org/10.1021/jp208145b
Marquardt D, Williams JA, Kučerka N et al (2013) Tocopherol activity correlates with its location in a membrane: a new perspective on the antioxidant vitamin E. J Am Chem Soc 135:7523–7533. https://doi.org/10.1021/ja312665r
Marquardt D, Williams JA, Kinnun JJ et al (2014) Dimyristoyl phosphatidylcholine: a remarkable exception to α-tocopherol’s membrane presence. J Am Chem Soc 136:203–210. https://doi.org/10.1021/ja408288f
Marquardt D, Kucerka N, Katsaras J et al (2015) α-Tocopherol’s location in membranes is not affected by their composition. Langmuir 31:4464–4472. https://doi.org/10.1021/la502605c
Meng F (2013) Molecular simulation of α-tocopherol passing across DPPC lipid using potential of mean force and accelerated molecular dynamics method. J Theor Comput Chem 12:1341011. https://doi.org/10.1142/S0219633613410113
Miyamoto S, Kollman PA (1992) Settle: an analytical version of the SHAKE and RATTLE algorithm for rigid water models. J Comput Chem 13:952–962. https://doi.org/10.1002/jcc.540130805
Podloucká P, Berka K, Fabre G et al (2013) Lipid bilayer membrane affinity rationalizes inhibition of lipid peroxidation by a natural lignan antioxidant. J Phys Chem B 117:5043–5049. https://doi.org/10.1021/jp3127829
Qiao R, Roberts AP, Mount AS et al (2007) Translocation of C60 and its derivatives across a lipid bilayer. Nano Lett 7:614–619. https://doi.org/10.1021/nl062515f
Qin S-S, Yu Z-W (2011) Molecular dynamics simulations of α-tocopherol in model biomembranes. Acta Phys Chim Sin 27:213–227. https://doi.org/10.3866/pku.whxb20110109
Qin S-S, Yu Z-W, Yu Y-X (2009) Structural and kinetic properties of alpha-tocopherol in phospholipid bilayers, a molecular dynamics simulation study. J Phys Chem B 113:16537–16546. https://doi.org/10.1021/jp9074306
Sharma VK, Mamontov E, Tyagi M et al (2016) Effect of α-tocopherol on the microscopic dynamics of dimyristoylphosphatidylcholine membrane. J Phys Chem B 120:154–163. https://doi.org/10.1021/acs.jpcb.5b10417
Sklearn.cluster.DBSCAN (2021). https://scikit-learn.org/stable/modules/generated/sklearn.cluster.DBSCAN.html.
Srivastava S, Phadke RS, Govil G et al (1983) Fluidity, permeability and antioxidant behaviour of model membranes incorporated with α-tocopherol and vitamin E acetate. Biochim Et Biophys Acta BBA Biomembr 734:353–362. https://doi.org/10.1016/0005-2736(83)90135-9
Swift RV, Amaro RE (2013) Back to the future: can physical models of passive membrane permeability help reduce drug candidate attrition and move us beyond QSPR? Chem Biol Drug Des 81:61–71. https://doi.org/10.1111/cbdd.12074
Tieleman P University of Calgary Biocomputing Group Downloads. 2021 http://wcm.ucalgary.ca/tieleman/downloads
Traber MG, Atkinson J (2007) Vitamin E, antioxidant and nothing more. Free Radic Biol Med 43:4–15. https://doi.org/10.1016/j.freeradbiomed.2007.03.024
Wassall SR, Thewalt JL, Wong L et al (1986) Deuterium NMR study of the interaction of α-tocopherol with a phospholipid model membrane. Biochemistry 25:319–326. https://doi.org/10.1021/bi00350a006
Zingg J-M, Meydani M (2019) Interaction between vitamin E and polyunsaturated fatty acids. In: Weber P, Birringer M, Blumberg JB, Eggersdorfer M, Frank J (eds) Vitamin E in human health. Springer International Publishing, Cham, pp 141–159. https://doi.org/10.1007/978-3-030-05315-4_11
Acknowledgements
The authors gratefully acknowledge the support from the U.S. Department of Agriculture, Grant # 2009-35603-05055, and by U.S. National Science Foundation under EPSCoR RII Track-2 Program, Grant # OIA-1632854. The computer resources were provided by Louisiana Optical Network Infrastructure (LONI) and High Performance Computing (HPC) at LSU.
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Kavousi, S., Novak, B.R., Tong, X. et al. Molecular dynamics simulation study of the positioning and dynamics of α-tocopherol in phospholipid bilayers. Eur Biophys J 50, 889–903 (2021). https://doi.org/10.1007/s00249-021-01548-y
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DOI: https://doi.org/10.1007/s00249-021-01548-y