離子對雙親分子(ion pair amphiphile, IPA) 是一種具有與磷脂質(phospholipid)相似雙親性質的複合體(amphiphilic complex)。由離子對雙親分子所構成的陰陽離子液胞(catanionic vesicle)被視為傳統磷脂質微脂粒(liposome)的替代品。對於磷脂質微脂粒
與陰陽離子液胞而言,相轉移溫度(T m ) 為控制其穩定性一個重要的參數。螢光偏極化法(fluorescence polarization)為常用於偵測雙層膜相轉移變化的實驗方法。運用螢光探針分子如 1,6-二苯基-1,3,5-己三烯(1, 6- diphenyl-1,3,5-hexatriene, DPH),常見的dipalmitoylphosphatidylcholine (DPPC) 磷脂質雙層膜的相轉移溫度能由 DPH 的螢光非等向性值(fluorescence anisotropy)的變化來決定。然而,使用相同螢光探針卻無法正
確測量 decyltrimethylammonium-tetradecylsulfate (DeTMA-TS) IPA 雙層膜的相轉移特性。本研究將使用分子動態模擬(molecule dynamics, MD)分析 IPA 雙層膜的相態變化
特性,並探討雙層膜相態變化與螢光分子動態特性間的耦合與去耦合機制。首先,為了適當描述雙層膜相態特性,本研究修正了 CHARMM36 united-atom 模型(C36-UA m )。在描述 IPA 雙層膜的相轉移溫度上,C36-UA m 較全原子 C36 模型有更佳的表現。運用 C36-UA m 模型進行 IPA 雙層膜的相態模擬,在分析不對稱 IPA 雙層膜的結構性質後發現,在凝膠相的雙層膜中,由於碳鏈的不對稱性,較長碳鏈末端會在雙層膜中間形成低序度區域,並降低凝膠態雙層膜的整體機械強度。而在螢光探針分子動態特性的部分,可以由分子旋轉自相關函數(rotational autocorrelation function, RACF)來估計螢光非等向性值,並進一步藉由水平構型比例來修正估計值。修正後的非等向性數值與實驗值相符,驗證了 DPH 水平構型的對螢光非等向性值之影響。另一方面, 以 1-[4-三甲基銨苯基]-,6-苯基-1,3,5-己三烯 (1-[4-(trimethylamino)phenyl]-6-phenylhexa-l,3,5-triene, TMA-DPH)作為螢光探針時,由於其分子的雙親特性,可與雙層膜碳鏈平行排列,故不需以水平構型進行修正螢光非等向數值。儘管 TMA-DPH 在 IPA 雙層膜中的螢光非等向數值在不同相態之間的變化幅度較小,但在不對稱 IPA 雙層膜系統中,相比於易出現水平構型的 DPH,TMA-DPH 仍然具有在相變
化時快速改變非等向性數值的特性來反映雙層膜的相轉移行為。綜合模擬結果,螢光探針分子動態特性與 IPA 雙層膜相態變化的去耦合現象,可以歸因於螢光探針分子於雙層膜中的水平構型。因此,要以螢光去極化法正確測量 IPA 雙層膜的相轉移溫度,在螢光探針的選擇上,必須考慮探針分子水平構型的可能性。而在短鏈或不對稱鏈的 IPA 雙層膜系統中,TMA-DPH 之非等向性隨溫度的變化較能適當的反應出雙層膜的相轉移特性。

Ion pair amphiphile (IPA) is a novel molecular complex composed of a pair of oppositely charged surfactants with similar amphiphilicity of phospholipid. The natural aggregate of IPA, catanionic vesicle, has been expected to be substitutes of liposome. For both liposome and catanionic vesicle, bilayer phase transition temperature (T m ) is one of the most decisive parameters that manipulate the stability. One of the widely used techniques to determine T m is fluorescence polarization (FP). Using 1,6-diphenyl-1,3,5-hexatriene (DPH), FP method has been successful in determining T m of phospholipid bilayer via fluorescence anisotropy measurement. However, FP method failed to characterize the corresponding phase behavior of IPA bilayers. Here, we utilized molecule dynamics (MD) simulation to characterize the thermotropic phase behavior of IPA bilayers and the coupling and decoupling between the bilayer phase properties and fluorescence probe dynamics. First, we revised CHARMM36 united-atom model (C36-UA m ) to better describe the phase behavior of IPA bilayers. Compared with C36 atomic model, T m evaluated from C36-UA m showed better agreement with the experimental data of IPA bilayers. Applying C36-UA m model to simulate and analyze the IPA bilayer structural properties, we found that the bilayer region near the alkyl chain end of asymmetric IPA bilayer was temperature insensitive. The alkyl chain mismatch also reduces the mechanical properties of the asymmetric IPA bilayers. For the fluorescence probe dynamics, DPH anisotropy was evaluated using the rotational autocorrelation function (RACF). The DPH anisotropy thermogram required further reweighting using the flat conformation ratio (R flat ) of the probe to give better agreement with experimental data. In contrast, attributed to the amphiphilicity nature of 1-[4-(trimethyl-amino)phenyl]-6-phenylhexa-l,3,5-triene (TMA-DPH), TMA-DPH preferred to align with alkyl chains. Thus, the TMA-DPH anisotropy thermogram required no further reweighting procedure. Although TMA-DPH exhibits smaller changes of anisotropy compared with DPH during the phase transition, TMA-DPH does not suffer from the flat conformation issue as DPH and is able to show more distinctive anisotropy difference during the phase transition. In summary, the decoupling between probe dynamics and the thermotropic phase behavior of bilayer is mainly attributed to the presence of probe flat conformations. Therefore, to properly measure T m of IPA bilayers, one should therefore consider the influence of flat conformation of fluorescence probe. Alternatively, TMA-DPH should be a proper fluorescence probe candidate to detect phase transition for short chain or asymmetric IPA bilayer systems.

[1] L. R.White, J. N. Israelachvili, and B. W. Ninham, Dispersion interaction of crossed mica cylinders: a reanalysis of the Israelachvili–Tabor experiments, Journal of the Chemical Society, Faraday Transactions 1: Physical Chemistry in Condensed Phases, pp.2526–2536, 1976.
[2] S. Šegota, and D. Težak, Spontaneous formation of vesicles, Advances in Colloid and Interface Science, 121, pp.51–75, 2006.
[3] P. C. Hiemenz, and R. Rajagopalan, Principles of Colloid and Surface Chemistry, Third Edit, 1997.
[4] D. Stamp, and R. L. Juliano, Factors affecting the encapsulation of drugs within liposomes, Canadian Journal of Physiology and Pharmacology, 57, pp.535–539, 1979.
[5] F. Olson, E. Mayhew, D. Maslow, Y. Rustum, and F. Szoka, Characterization, toxicity and therapeutic efficacy of adrïamycin encapsulated in liposomes, European Journal of Cancer and Clinical Oncology, 18, pp.167–176, 1982.
[6] A. Samad, Y. Sultana, and M. Aqil, Liposomal Drug Delivery Systems: An Update Review, Current Drug Delivery, 4, pp.297–305, 2007.
[7] A. Sharma, and U. S. Sharma, Liposomes in drug delivery: Progress and limitations, International Journal of Pharmaceutics, 154, pp.123–140, 1997.
[8] L. Sercombe, T. Veerati, F. Moheimani, S. Y. Wu, A. K. Sood, and S. Hua, Advances and challenges of liposome assisted drug delivery, Frontiers in Pharmacology, 6, pp.1–13, 2015.
[9] P. Jokela, B. Jönsson, and A. Khan, Phase equilibria of catanionic surfactant-water systems, Journal of Physical Chemistry, 91, pp.3291–3298, 1987.
[10] H. Fukuda, K. Kawata, H. Okuda, and S. L. Regen, Bilayer-Forming Ion-Pair Amphiphiles from Single-Chain Surfactants1, Journal of the American Chemical Society, 112, pp.1635–1637, 1990.
[11] T. Bramer, N. Dew, and K. Edsman, Pharmaceutical applications for catanionic mixtures, Journal of Pharmacy and Pharmacology, 59, pp.1319–1334, 2007.
[12] G. W. Stockton, and I.C.P. Smith, A deuterium nuclear magnetic resonance study of the condensing effect of cholesterol on egg phosphatidylcholine bilayer membranes. I. Perdeuterated fatty acid probes, Chemistry and Physics of Lipids, 17, pp.251–263, 1976.
[13] P. L. Yeagle, Cholesterol and the cell membrane, BBA - Reviews on Biomembranes, 822, pp.267–287, 1985.
[14] H. Ohvo-Rekilä, B. Ramstedt, P. Leppimäki, and J.Peter Slotte, Cholesterol interactions with phospholipids in membranes, Progress in Lipid Research, 41, pp.66–97, 2002.
[15] J. Henriksen, A. C. Rowat, E. Brief, Y. W. Hsueh, J. L. Thewalt, M. J. Zuckermann, and J. H. Ipsen, Universal behavior of membranes with sterols, Biophysical Journal, 90, pp.1639–1649, 2006.
[16] M. B. Yatvin, W. Kreutz, B. A. Horwitz, and M.Shinitzky, pH-sensitive liposomes: Possible clinical implications, Science, 210, pp.1253–1255, 1980.
[17] E. Touitou, N. Dayan, L. Bergelson, B. Godin, and M. Eliaz, Ethosomes - Novel vesicular carriers for enhanced delivery: Characterization and skin penetration properties, Journal of Controlled Release, 65, pp.403–418, 2000.
[18] Y. S. Liu, C. F. Wen, and Y. M. Yang, Development of ethosome-like catanionic vesicles for dermal drug delivery, Journal of the Taiwan Institute of Chemical Engineers, 43, pp.830–838, 2012.
[19] C. H. Chen, C. A. Tian, and C. C. Chiu, The effects of Alkyl chain combinations on the structural and mechanical properties of biomimetic ion pair amphiphile bilayers, Bioengineering, 4, pp.1–15, 2017.
[20] 賴宇芳, Combined Effects of Ethanol Co-solvent and Cholesterol Additive on the Structural, Mechanical and Phase Properties of Ion Pair Amphiphile Bilayers: A Molecular Dynamics Study, Natioanl Cheng Kung University, 2020.
[21] R. Koynova, and M. Caffrey, Phases and phase transitions of the phosphatidylcholines, Biochimica et Biophysica Acta, 1376, pp.91–145, 1998.
[22] C. Vautrin, M. Dubois, T. Zemb, S. Schmölzer, H. Hoffmann, and M.Gradzielski, Chain melting in swollen catanionic bilayers, Colloids and Surfaces A: Physicochemical and Engineering Aspects, 217, pp.165–170, 2003.
[23] M. F. Schneider, D. Marsh, W. Jahn, B. Kloesgen, andT.Heimburg, Network formation of lipid membranes: Triggering structural transitions by chain melting, Proceedings of the National Academy of Sciences of the United States of America, 96, pp.14312–14317, 1999.
[24] A.Blicher, K.Wodzinska, M.Fidorra, M.Winterhalter, andT.Heimburg, The temperature dependence of lipid membrane permeability, its quantized nature, and the influence of anesthetics, Biophysical Journal, 96, pp.4581–4591, 2009.
[25] C. F. Wen, Y. L. Hsieh, C. W. Wang, T. Y. Yang, C. H. Chang, and Y. M. Yang, Effects of ethanol and cholesterol on thermotropic phase behavior of ion-pair amphiphile bilayers, Journal of Oleo Science, 67, pp.295–302, 2018.
[26] M. Havlikova, J. Szabova, L. Mravcova, T. Venerova, C. H. Chang, M. Pekar, A. Jugl, and F. Mravec, Cholesterol Effect on Membrane Properties of Cationic Ion Pair Amphiphile Vesicles at Different Temperatures, Langmuir, 37, pp.2436–2444, 2021.
[27] J. Suurkuusk, B. R. Lentz, Y. Barenholz, R. L. Biltonen, and T. E. Thompson, A Calorimetric and Fluorescent Probe Study of the Gel-Liquid Crystalline Phase Transition in Small, Single-Lamellar Dipalmitoylphosphatidylcholine Vesicles, Biochemistry, 15, pp.1393–1401, 1976.
[28] W. H. Lee, Y. L. Tang, T. C. Chiu, and Y. M. Yang, Synthesis of ion-pair amphiphiles and calorimetric study on the gel to liquid-crystalline phase transition behavior of their bilayers, Journal of Chemical and Engineering Data, 60, pp.1119–1125, 2015.
[29] 鄭嘉瑜, A Study of Cholesterol Effect on Ion-Pair Amphiphile Vesicular Bilayer Rigidity by Using Fluorescence Polarization Technique, Natioanl Cheng Kung University, 2019.
[30] A. Tardieu, V. Luzzati, and F. C. Reman, Structure and polymorphism of the hydrocarbon chains of lipids: A study of lecithin-water phases, Journal of Molecular Biology, 75, pp.711–733, 1973.
[31] H. Kodoma, and S.Komura, Frustration-induced ripple phase in bilayer membranes, Journal de Physique II, 3, pp.1305–1311, 1993.
[32] T. Heimburg, A model for the lipid pretransition: Coupling of ripple formation with the chain-melting transition, Biophysical Journal, 78, pp.1154–1165, 2000.
[33] C. Tondre, and C. Caillet, Properties of the amphiphilic films in mixed cationic/anionic vesicles: A comprehensive view from a literature analysis, Advances in Colloid and Interface Science, 93, pp.115–134, 2001.
[34] T. Heimburg, Mechanical aspects of membrane thermodynamics. Estimation of the mechanical properties of lipid membranes close to the chain melting transition from calorimetry, Biochimica et Biophysica Acta - Biomembranes, 1415, pp.147–162, 1998.
[35] M. Kranenburg, and B.Smit, Phase behavior of model lipid bilayers, Journal of Physical Chemistry B, 109, pp.6553–6563, 2005.
[36] S. S. Qin, Z. W. Yu, and Y. X. Yu, Structural characterization on the gel to liquid-crystal phase transition of fully hydrated DSPC and DSPE bilayers, Journal of Physical Chemistry B, 113, pp.8114–8123, 2009.
[37] N. Filipović-Vinceković, M. Bujan, I. Šmit, L. Tušek-Božić, and I. Štefanić, Phase transitions from catanionic salt to mixed cationic/anionic vesicles, Journal of Colloid and Interface Science, 201, pp.59–70, 1998.
[38] V. Tomašić, S. Popović, and N. Filipović-Vinceković, Solid state transitions of asymmetric catanionic surfactants, Journal of Colloid and Interface Science, 215, pp.280–289, 1999.
[39] V. Tomašić, L. Tušek-Božić, A. Višnjevac, B. Kojić-Prodić, and N. Filipović-Vinceković, Physicochemical properties of dodecylammonium picrate, Journal of Colloid and Interface Science, 227, pp.427–436, 2000.
[40] D. Jurašin, M. Vinceković, A. Pustak, I. Šmit, M. Bujan, and N. Filipović-Vinceković, Lamellar to hexagonal columnar liquid crystalline phase transition in a catanionic surfactant mixture: Dodecylammonium chloride-sodium bis(2-ethylhexyl) sulfosuccinate, Soft Matter, 9, pp.3349–3360, 2013.
[41] W. H. Chang, Y. T. Chuang, C. Y. Yu, C. H. Chang, and Y. M. Yang, Effects of Sterol-Like Additives on Phase Transition Behavior of Ion-Pair Amphiphile Bilayers, Journal of Oleo Science, 66, pp.1229–1238, 2017.
[42] R. L. Biltonen, and D. Lichtenberg, The use of differential scanning calorimetry as a tool to characterize liposome preparations, Chemistry and Physics of Lipids, 64, pp.129–142, 1993.
[43] C. H. Huang, and S. Li, Calorimetric and molecular mechanics studies of the thermotropic phase behavior of membrane phospholipids, Biochimica et Biophysica Acta-Reviews on Biomembranes, 1422, pp.273–307, 1999.
[44] E. F. Marques, A. Khan, and B. Lindman, A calorimetric study of the gel-to-liquid crystal transition in catanionic surfactant vesicles, Thermochimica Acta, 394, pp.31–37, 2002.
[45] A. Shioi, and T. A. Hatton, Model for formation and growth of vesicles in mixed anionic/cationic (SOS/CTAB) surfactant systems, Langmuir, 18, pp.7341–7348, 2002.
[46] J. Leng, S. U. Egelhaaf, and M. E. Cates, Kinetics of the micelle-to-vesicle transition: Aqueous lecithin-bile salt mixtures, Biophysical Journal, 85, pp.1624–1646, 2003.
[47] M. I. Viseu, K. Edwards, S. Campos, and M. B. Costa, Spontaneous Vesicles Formed in Aqueous Mixtures of Two Cationic Amphiphiles, Langmuir, 16, pp.2105–2114, 2000.
[48] Y. Jiang, F. Li, Y. Luan, W. Cao, X. Ji, L. Zhao, L. Zhang, and Z. Li, Formation of drug/surfactant catanionic vesicles and their application in sustained drug release, International Journal of Pharmaceutics, 436, pp.806–814, 2012.
[49] B. A. Brüning, S. Prévost, R. Stehle, R. Steitz, P. Falus, B. Farago, and T.Hellweg, Bilayer undulation dynamics in unilamellar phospholipid vesicles: Effect of temperature, cholesterol and trehalose, Biochimica et Biophysica Acta - Biomembranes, 1838, pp.2412–2419, 2014.
[50] B. R. Lentz, Membrane " fluidity " as detected by diphenylhexatriene probes, Chemistry and Physics of Lipids, 50, pp.171–190, 1989.
[51] J. R. Lakowicz, Principles of Fluorescence Spectroscopy, 3rd ed., Springer US, 2006.
[52] M. N. Berberan-Santos, Pioneering Contributions of Jean and Francis Perrin to Molecular Luminescence, 2001.
[53] J. R. Lakowicz, D. Hogen, and F. G. Prendergast, Differential Polarized Phase Fluorometric Investigations of Diphenylhexatriene in Lipid Bilayers. Quantitation of Hindered Depolarizing Rotations, Biochemistry, 18, pp.508–519, 1979.
[54] F. G. Prendergast, R. P. Haugland, and P. J. Callahan, 1-[4-(Trimethylamino)phenyl]-6-phenylhexa-1,3,5-triene: synthesis, fluorescence properties and use as a fluorescence probe of lipid bilayers, Biochemistry, 20, pp.7333–7338, 1981.
[55] S. C. Nelson, S. K. Neeley, E. D. Melonakos, J. D. Bell, and D. D. Busath, Fluorescence anisotropy of diphenylhexatriene and its cationic Trimethylamino derivative in liquid dipalmitoylphosphatidylcholine liposomes: Opposing responses to isoflurane, BMC Biophysics, 5, 2012.
[56] P.van der Ploeg, and H. J. C. Berendsen, Molecular dynamics simulation of a bilayer membrane, The Journal of Chemical Physics, 76, pp.3271–3276, 1982.
[57] E. Jakobsson, Computer simulation studies of biological membranes: Progress, promise and pitfalls, Trends in Biochemical Sciences, 22, pp.339–344, 1997.
[58] L. R. Forrest, and M. S. P. Sansom, Membrane simulations: bigger and better?, Current Opinion in Structural Biology, 10, pp.174–181, 2000.
[59] R. W. Pastor, R. M. Venable, and M. Karplus, Model for the structure of the lipid bilayer, Proceedings of the National Academy of Sciences of the United States of America, 88, pp.892–896, 1991.
[60] D. P. Tieleman, S. J. Marrink, and H. J. C. Berendsen, A computer perspective of membranes: Molecular dynamics studies of lipid bilayer systems, Biochimica et Biophysica Acta - Reviews on Biomembranes, 1331, pp.235–270, 1997.
[61] D. J. Tobias, K. Tu, and M. L. Klein, Atomic-scale molecular dynamics simulations of lipid membranes, Current Opinion in Colloid & Interface Science, 2, pp.15–26, 1997.
[62] C. A. Tian, and C. C. Chiu, Importance of hydrophilic groups on modulating the structural, mechanical, and interfacial properties of bilayers: A comparative molecular dynamics study of phosphatidylcholine and ion pair amphiphile membranes, International Journal of Molecular Sciences, 19, 2018.
[63] O. Berger, O. Edholm, and F. Jähnig, Molecular dynamics simulations of a fluid bilayer of dipalmitoylphosphatidylcholine at full hydration, constant pressure, and constant temperature, Biophysical Journal, 72, pp.2002–2013, 1997.
[64] S. W. Chiu, M. M. Clark, E. Jakobsson, S. Subramaniam, and H. L. Scott, Optimization of Hydrocarbon Chain Interaction Parameters: Application to the Simulation of Fluid Phase Lipid Bilayers, The Journal of Physical Chemistry B, 103, pp.6323–6327, 1999.
[65] S. W. Chiu, S. Vasudevan, E. Jakobsson, R. J. Mashl, and H. L. Scott, Structure of Sphingomyelin Bilayers: A Simulation Study, Biophysical Journal, 85, pp.3624–3635, 2003.
[66] J. Hénin, W. Shinoda, and M. L. Klein, United-atom acyl chains for CHARMM phospholipids, Journal of Physical Chemistry B, 112, pp.7008–7015, 2008.
[67] S. J. Marrink, A. H. DeVries, and A. E. Mark, Coarse Grained Model for Semiquantitative Lipid Simulations, Journal of Physical Chemistry B, 108, pp.750–760, 2004.
[68] S. J. Marrink, J. Risselada, and A. E. Mark, Simulation of gel phase formation and melting in lipid bilayers using a coarse grained model, Chemistry and Physics of Lipids, 135, pp.223–244, 2005.
[69] J. C. Shelley, M. Y. Shelley, R. C. Reeder, S. Bandyopadhyay, and M. L. Klein, A coarse grain model for phospholipid simulations, Journal of Physical Chemistry B, 105, pp.4464–4470, 2001.
[70] W. Shinoda, R. Devane, and M. L. Klein, Multi-property fitting and parameterization of a coarse grained model for aqueous surfactants, Molecular Simulation, 33, pp.27–36, 2007.
[71] M. L. Klein, and W. Shinoda, Large-Scale Molecular Dynamics Simulations of Self-Assembling Systems, SCIENCE, 321, pp.798–801, 2008.
[72] W. Shinoda, R. Devane, and M. L. Klein, Coarse-grained molecular modeling of non-ionic surfactant self-assembly, Soft Matter, 4, pp.2454–2462, 2008.
[73] W. Shinoda, R. Devane, and M. L. Klein, Coarse-grained force field for ionic surfactants, Soft Matter, 7, pp.6178–6186, 2011.
[74] W. Shinoda, R. Devane, and M. L. Klein, Zwitterionic lipid assemblies: Molecular dynamics studies of monolayers, bilayers, and vesicles using a new coarse grain force field, Journal of Physical Chemistry B, 114, pp.6836–6849, 2010.
[75] Y. Hu, S. K. Sinha, and S. Patel, Investigating Hydrophilic Pores in Model Lipid Bilayers Using Molecular Simulations: Correlating Bilayer Properties with Pore-Formation Thermodynamics, Langmuir, 31, pp.6615–6631, 2015.
[76] R. Menichetti, K. H. Kanekal, and T. Bereau, Drug−Membrane Permeability across Chemical Space, ACS Central Science, 5, pp.290–298, 2018.
[77] C. Hoffmann, A. Centi, R. Menichetti, and T.Bereau, Molecular dynamics trajectories for 630 coarse-grained drug-membrane permeations, Scientific Data, 7, pp.1–7, 2020.
[78] E. Egberts, S. J. Marrink, and H. J. C. Berendsen, Molecular dynamics simulation of a phospholipid membrane, European Biophysics Journal, 22, pp.423–436, 1994.
[79] W. Shinoda, N. Namiki, and S. Okazaki, Molecular dynamics study of a lipid bilayer: Convergence, structure, and long-time dynamics, Journal of Chemical Physics, 106, pp.5731–5743, 1997.
[80] U. Essmann, and M. L. Berkowitz, Dynamical properties of phospholipid bilayers from computer simulation, Biophysical Journal, 76, pp.2081–2089, 1999.
[81] S. E. Feller, Molecular dynamics simulations of lipid bilayers, Current Opinion in Colloid and Interface Science, 5, pp.217–223, 2000.
[82] S. Lee, A. Tran, M. Allsopp, J. B. Lim, J. Hénin, J. B. Klauda, and O. Bond, CHARMM36 united atom chain model for lipids and surfactants, Journal of Physical Chemistry B, 118, pp.547–556, 2014.
[83] R. Tjörnhammar, and O. Edholm, Reparameterized united atom model for molecular dynamics simulations of gel and fluid phosphatidylcholine bilayers, Journal of Chemical Theory and Computation, 10, pp.5706–5715, 2014.
[84] S. Leekumjorn, and A. K. Sum, Molecular studies of the gel to liquid-crystalline phase transition for fully hydrated DPPC and DPPE bilayers, Biochimica et Biophysica Acta - Biomembranes, 1768, pp.354–365, 2007.
[85] B. Kowalik, T. Schubert, H. Wada, M. Tanaka, R. R. Netz, and E. Schneck, Combination of MD Simulations with Two-State Kinetic Rate Modeling Elucidates the Chain Melting Transition of Phospholipid Bilayers for Different Hydration Levels, Journalof Physical Chemistry B, 119, pp.14157–14167, 2015.
[86] L. Sun, and R. A. Böckmann, Membrane phase transition during heating and cooling: molecular insight into reversible melting, European Biophysics Journal, 47, pp.151–164, 2018.
[87] W. D. Stein, Transport and Diffusion across Cell Membranes, ACADEMIC PRESS, INC, 1986.
[88] H. J. C. Berendsen, and S. J. Marrink, Molecular dynamics of water transport through membranes: Water from solvent to solute, Pure and Applied Chemistry, 65, pp.2513–2520, 1993.
[89] S. J. Marrink, and H. J. C. Berendsen, Simulation of water transport through a lipid membrane, Journal of Physical Chemistry, 98, pp.4155–4168, 1994.
[90] C. T. Lee, J. Comer, C. Herndon, N. Leung, A. Pavlova, R.V. Swift, C. Tung, C. N. Rowley, R. E. Amaro, C. Chipot, Y. Wang, and J. C. Gumbart, Simulation-Based Approaches for Determining Membrane Permeability of Small Compounds, Journal of Chemical Information and Modeling, 56, pp.721–733, 2016.
[91] M. Palaiokostas, W. Ding, G. Shahane, and M. Orsi, Effects of lipid composition on membrane permeation, Soft Matter, 14, pp.8496–8508, 2018.
[92] O. DeVos, R. M. Venable, T. VanHecke, G. Hummer, R. W. Pastor, and A. Ghysels, Membrane Permeability: Characteristic Times and Lengths for Oxygen and a Simulation-Based Test of the Inhomogeneous Solubility-Diffusion Model, Journal of Chemical Theory and Computation, 14, pp.3811–3824, 2018.
[93] R. M. Cordeiro, Molecular Structure and Permeability at the Interface between Phase-Separated Membrane Domains, Journal of Physical Chemistry B, 122, pp.6954–6965, 2018.
[94] A. J. Robinson, W. G. Richards, P. J. Thomas, and M. M. Hann, Behavior of cholesterol and its effect on head group and chain conformations in lipid bilayers: a molecular dynamics study, Biophysical Journal, 68, pp.164–170, 1995.
[95] A. M. Smondyrev, and M. L. Berkowitz, Structure of dipalmitoylphosphatidylcholine/cholesterol bilayer at low and high cholesterol concentrations: Molecular dynamics simulation, Biophysical Journal, 77, pp.2075–2089, 1999.
[96] M. Jorge, Molecular dynamics simulation of self-assembly of n-decyltrimethylammonium bromide micelles, Langmuir, 24, pp.5714–5725, 2008.
[97] A. T. Kuo, C. H. Chang, and W. Shinoda, Molecular dynamics study of catanionic bilayers composed of ion pair amphiphile with double-tailed cationic surfactant, Langmuir, 28, pp.8156–8164, 2012.
[98] A. T. Kuo, and C. H. Chang, Cholesterol-induced condensing and disordering effects on a rigid catanionic bilayer: A molecular dynamics study, Langmuir, 30, pp.55–62, 2014.
[99] F. Huang, and C.Chiu, Interplay between alkyl chain asymmetry and cholesterol addition in the rigid ion pair amphiphile bilayer systems, Journal of Chemical Physics, 146, 2017.
[100] W. J. Tien, K. Y. Chen, F. Y. Huang, and C. C. Chiu, Effects of cholesterol on water permittivity of biomimetic ion pair amphiphile bilayers: Interplay between membrane bending and molecular packing, International Journal of Molecular Sciences, 20, pp.1–15, 2019.
[101] K. Ogata, W. Uchida, and S. Nakamura, Understanding thermal phases in atomic detail by all-atom molecular-dynamics simulation of a phospholipid bilayer, Journal of Physical Chemistry B, 118, pp.14353–14365, 2014.
[102] K. Kinosita, S. Kawato, and A. Ikegami, A theory of fluorescence polarization decay in membranes, Biophysical Journal, 20, pp.289–305, 1977.
[103] K. Kinosita, A. Ikegami, and S. Kawato, On the wobbling-in-cone analysis of fluorescence anisotropy decay, Biophysical Journal, 37, pp.461–464, 1982.
[104] G. Lipari, and A. Szabo, Effect of Librational Motion on Fluorescence Depolarization and Nuclear Magnetic Resonance Relaxation in Macromolecules and Membranes, Biophysical Journal, 30, pp.489–506, 1980.
[105] M. Ameloot, H. Hendrickx, Willy Herreman, H.Pottel, F.Van Cauwelaert, and W. van der Meer, Effect of Orientational Order on The Decay of the Fluorescence Anisotropy in Membrane Experimental Verification on Unilamellar Vesicles and Lipid/A-Lactalbumin Complexes, Biophysical Journal, 46, pp.525–539, 1984.
[106] W.van der Meer, H. Pottel, W. Herreman, M. Ameloot, H. Hendrickx, and H. Schroder, Effect of Orientational Order on the Decay of the Fluorescence Anisotropy in Membrane Suspensions A New Approximate Solution of the Rotational Diffusion Equation, Biophysical Journal, 46, pp.515–523, 1984.
[107] J. Repáková, P. Čapková, J. M. Holopainen, and I. Vattulainen, Distribution, orientation, and dynamics of DPH probes in DPPC bilayer, Journal of Physical Chemistry B, 108, pp.13438–13448, 2004.
[108] A. M. T. M. doCanto, J. R. Robalo, P. D. Santos, A. J. P. Carvalho, J. P. P. Ramalho, and L. M. S. Loura, Diphenylhexatriene membrane probes DPH and TMA-DPH: A comparative molecular dynamics simulation study, Biochimica et Biophysica Acta - Biomembranes, 1858, pp.2647–2661, 2016.
[109] M. Paloncýová, M. Ameloot, and S. Knippenberg, Orientational distribution of DPH in lipid membranes: A comparison of molecular dynamics calculations and experimental time-resolved anisotropy experiments, Physical Chemistry Chemical Physics, 21, pp.7594–7604, 2019.
[110] L. M. S. Loura, and J. P. P. Ramalho, Location and dynamics of acyl chain NBD-labeled phosphatidylcholine (NBD-PC) in DPPC bilayers. A molecular dynamics and time-resolved fluorescence anisotropy study, Biochimica et Biophysica Acta -Biomembranes, 1768, pp.467–478, 2007.
[111] R. R. Gullapalli, M. C. Demirel, and P. J. Butler, Molecular dynamics simulations of DiI-C18(3) in a DPPC lipid bilayer, Physical Chemistry Chemical Physics, 10, pp.3548–3560, 2008.
[112] L. W. Engel, and F. G. Prendergast, Values for and Significance of Order Parameters and “ Cone Angles ” of Fluorophore Rotation in Lipid Bilayers, Biochemistry, 20, pp.7338–7345, 1981.
[113] H.Bekker, H. J C Berendsen, R.van Drunen, D.van der Spoel, A. Sijbers, H. Keegstra, B. Reitsma, M. K. R. Renardus, S. Achterop, and E. J. Dijkstra, Gromacs : A parallel computer for molecular dynamics simulations, Physics Computing, pp.252–256, 1993.
[114] H. J. C. Berendsen, D.van der Spoel, and R. van Drunen, GROMACS: A message-passing parallel molecular dynamics implementation, Computer Physics Communications, 91, pp.43–56, 1995.
[115] E. Lindahl, B. Hess, and D.van der Spoel, GROMACS 3.0: A package for molecular simulation and trajectory analysis, Journal of Molecular Modeling, 7, pp.306–317, 2001.
[116] D.van der Spoel, E. Lindahl, B. Hess, G. Groenhof, A. E. Mark, and H. J. C. Berendsen, GROMACS: Fast, flexible, and free, Journal of Computational Chemistry, 26, pp.1701–1718, 2005.
[117] B. Hess, S. Uppsala, and E. Lindahl, GROMACS 4 : Algorithms for Highly Efficient , Load-Balanced , and Scalable Molecular Simulation, Journal of Chemical Theory and Computation, 4, pp.435–447, 2008.
[118] S. Pronk, S. Páll, R. Schulz, P. Larsson, P. Bjelkmar, R. Apostolov, M. R. Shirts, J. C. Smith, P. M. Kasson, D.van der Spoel, B. Hess, and E. Lindahl, GROMACS 4.5: A high-throughput and highly parallel open source molecular simulation toolkit, Bioinformatics, 29, pp.845–854, 2013.
[119] S.Páll, M. J. Abraham, K. Carsten, B. Hess, and E.Lindahl, Tackling Exascale Software Challenges in Molecular Dynamics Simulations with GROMACS., in: S.Markidis, E.Laure (Eds.), Solving Softw. Challenges Exascale, Springer, Cham, 2015: pp. 3–27.
[120] M. J. Abraham, T. Murtola, R. Schulz, S. Páll, J. C. Smith, B. Hess, and E. Lindah, Gromacs: High performance molecular simulations through multi-level parallelism from laptops to supercomputers, SoftwareX, 1–2, pp.19–25, 2015.
[121] K. Vanommeslaeghe, E. Hatcher, C. Acharya, S. Kundu, S. Zhong, J. Shim, E. Darian, O. Guvench, P. Lopes, I. Vorobyov, and A. D. MacKerell Jr., CHARMM General Force Field (CGenFF): A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields, Journal of Computational Chemistry, 31, pp.671–690, 2010.
[122] K. Vanommeslaeghe, and A. D. MacKerell, Automation of the CHARMM general force field (CGenFF) I: Bond perception and atom typing, Journal of Chemical Information and Modeling, 52, pp.3144–3154, 2012.
[123] K. Vanommeslaeghe, and A. D. MacKerell, Automation of the CHARMM General Force Field (CGenFF) II: Assignment of Bonded Parameters and Partial Atomic Charges, Journal of Chemical Information and Modeling, 52, pp.3155–3168, 2012.
[124] L. Martinez, R. Andrade, E. G. Birgin, and J. M. Martinez, Packmol: A Package for Building Initial Configurations for Molecular Dynamics Simulations, Journal of Computational Chemistry, 30, pp.2157–2164, 2009.
[125] T. Darden, D. York, and L. Pedersen, Particle mesh Ewald : An N ⋅ log ( N ) method for Ewald sums in large systems in large systems, J. Chem. Phys., 98, 1993.
[126] U. Essmann, L. Perera, M. L. Berkowitz, T. Darden, H. Lee, L. G. Pedersen, T. Darden, H. Lee, and L. G. Pedersen, A smooth particle mesh Ewald method A smooth particle mesh Ewald method, J. Chem. Phys., 103, 1995.
[127] B. Hess, H. Bekker, H. J. C. Berendsen, and J. G. E. M. Fraaije, LINCS: A Linear Constraint Solver for molecular simulations, Journal of Computational Chemistry, 18, pp.1463–1472, 1997.
[128] M. Parrinello, and A. Rahman, Polymorphic transitions in single crystals: A new molecular dynamics method, Journal of Applied Physics, 52, pp.7182–7190, 1981.
[129] S. Nosé, A molecular dynamics method for simulations in the canonical ensemble A molecular dynamics method for simulations in the canonical ensemblet, Molecular Physics, 52, pp.255–268, 1984.
[130] S. Nosé, A unified formulation of the constant temperature molecular dynamics methods, The Journal of Chemical Physics, 81, pp.511–519, 1984.
[131] W. G. Hoover, Canonical dynamics: Equilibrium phase-space distributions William, PHYSICAL REVIEW A, 31, pp.1695–1697, 1985.
[132] Y. Sugita, and Y. Okamoto, Replica exchange molecular dynamics method for protein folding, Chemical Physics Letters, 314, pp.141–151, 1999.
[133] D. J. Earl, and M. W. Deem, Parallel tempering: Theory, applications, and new perspectives, Physical Chemistry Chemical Physics : PCCP, 7, pp.3910–3916, 2005.
[134] J. M. Stubbs, J. J. Potoff, and J. I. Siepmann, Transferable potentials for phase equilibria. 6. United-atom description for ethers, glycols, ketones, and aldehydes, Journal of Physical Chemistry B, 108, pp.17596–17605, 2004.
[135] H. Heller, M. Schaefer, and K. Schulten, Molecular dynamics simulation of a bilayer of 200 lipids in the gel and in the liquid-crystal phases, Journal of Physical Chemistry, 97, pp.8343–8360, 1993.
[136] H. Schindler, and J. Seelig, Deuterium order parameters in relation to thermodynamic properties of a phospholipid bilayer. Statistical mechanical interpretation, Biochemistry, 14, pp.2283–2287, 1975.
[137] J. Seelig, Deuterium magnetic resonance: Theory and application to lipid membranes, Quarterly Reviews of Biophysics, 10, pp.353–418, 1977.
[138] A. Seelig, and J. Seelig, Dynamic structure of fatty acyl chains in a phospholipid bilayer measured by deuterium magnetic resonance, Biochemistry, 13, pp.4839–4845, 1974.
[139] V. R. Kodati, R. Jastimi, and M. Lafleur, Contribution of the intermolecular coupling and librotorsional mobility in the methylene stretching modes in the infrared spectra of acyl chains, Journal of Physical Chemistry® , 98, pp.12191–12197, 1994.
[140] R. N. A. H. Lewis, and R. N. McElhaney, The structure and organization of phospholipid bilayers as revealed by infrared spectroscopy, Chemistry and Physics of Lipids, 96, pp.9–21, 1998.
[141] G. Khelashvili, G. Pabst, and D. Harries, Cholesterol orientation and tilt modulus in DMPC bilayers, Journal of Physical Chemistry B, 114, pp.7524–7534, 2010.
[142] G. Khelashvili, and D. Harries, How cholesterol tilt modulates the mechanical properties of saturated and unsaturated lipid membranes, Journal of Physical Chemistry B, 117, pp.2411–2421, 2013.
[143] J. R. Lakowicz, D. Hogen, and F. G. Prendergast, Fluorescence Anisotropy Measurements under Oxygen Quenching Conditions as a Method to Quantify the Depolarizing Rotations of Fluorophores. Application to Diphenylhexatriene in Isotropic Solvents and in Lipid Bilayers, Biochemistry, 18, pp.520–527, 1979.
[144] N. Kučerka, J. F. Nagle, J. N. Sachs, S. E. Feller, J. Pencer, A. Jackson, and J. Katsaras, Lipid bilayer structure determined by the simultaneous analysis of neutron and X-ray scattering data, Biophysical Journal, 95, pp.2356–2367, 2008.
[145] J. B. Klauda, R. M. Venable, J. A. Freites, J. W. O’Connor, D. J. Tobias, C. Mondragon-Ramirez, I. Vorobyov, J. Alexander D. MacKerell, and R. W. Pastor, Update of the CHARMM all-atom additive force field for lipids: Validation on six lipid types, J Phys Chem B., 114, pp.7830–7843, 2010.
[146] M. Derek, Handbook of Lipid Bilayers, CRC Press, 2013.