離子對雙親分子 (ion pair amphiphile, IPA) 是由二種帶異性電荷之界面活性劑經 等莫爾比例混合後去除對離子形成之複合物，其分子結構與磷脂質類似，在製藥與 DNA轉染等領域有良好的應用潛力。文獻指出，改變IPA的二種組成界面活性分子 之碳長鏈不對稱性以及碳長鏈總長，對IPA雙層膜的相態行為產生明顯影響。本研 究利用分子動態模擬，從微觀的角度解析長烷鏈三甲基–長烷鏈硫酸鹽 (CmTMA+ – CnS–) IPA複合分子之碳長鏈不對稱性以及碳長鏈總長，對於其所組成的雙層膜結構 之結構特性與機械性質的影響。基於硫酸鹽與三甲基結構上的差異，IPA長烷鏈的 不對稱性藉由可藉由不對稱指數ΔC = m - (n + 1)來定義。IPA的|ΔC|越大，會使得位 於雙層膜中心的碳鏈擁有較高的移動自由度而導致雙層膜之排列整齊度與機械性質 下降。而長烷鏈總長越長，則會因為凡得瓦作用力增強而導致雙層膜擁有較高序度 與較強機械性質。本研究提供了許多IPA雙層膜在分子層次上的資訊，有益於日後 新型IPA之設計。
本研究亦使用分子動態模擬，針對環糊精 (cyclodextrin, CD) 與聚胺酸雙親分子 (C16Thr20) 形成之溫度敏感型水膠進行熱力學分析，從微觀的角度分析此種水膠的成 膠機制以及成膠自由能變化。模擬結果顯示環糊精與聚胺酸雙親分子在室溫 (298 K) 以及高溫(398 K) 之下皆可形成穩定的包嵌複合體結構，代表水膠之凝膠–溶膠 轉化並非由環糊精/聚胺酸雙親分子包嵌複合體結構崩解所造成，並以此反推其轉化 機制主因是水膠結構中的氫鍵網絡破壞。另一方面，環糊精/聚胺酸雙親分子的包嵌 行為主要受到熱焓變化所驅動 (ΔH) 。而此包嵌複合體之形成為熱力學穩定且自發 性反應。同時根據2：1環糊精/長烷鏈(C16)之包嵌自由能計算，我們發現在水溶液 環境中，長烷鏈傾向於逐一與環糊精分子組裝成為包嵌複合體，而非由環糊精二聚 體與長烷鏈複合。利用包嵌自由能及熱力學特性分析有助於了解包嵌複合體的包嵌 機制，並可作為實驗結果之佐證。

Ion pair amphiphile (IPA), a lipid-like complex composed of a pair of cationic and anionic surfactants, has been suggested as an inexpensive phospholipid substitute with great potentials in various pharmaceutical applications. In this work, we utilized molecular dynamics (MD) simulation to systematically explore the effects of various alkyl chain combinations of the alkyltrimethylammonium – alkylsulfate IPAs, i.e. CmTMA+ – CnS–, on the corresponding IPA bilayer structural and mechanical properties at the molecular level. Based on the intrinsic molecular structures of the trimethylammonium and the sulfate groups and the observed transversed matching pattern, the CmTMA+ – CnS– IPA alkyl chain asymmetry can be characterized by the asymmetric index, ΔC = m - (n + 1). Larger |ΔC| gives rise to higher conformational fluctuations of the alkyl chains which reduces the overall packing order and the mechanical strength. Besides, higher total chain length leads to increased v.d.W interaction and thus improves the alkyl chain ordering and bilayer mechanical properties.
We also applied MD simulation to study the thermodynamical properties of the thermo-responsive supermolacular hydrogels comprised of β-CD and peptide amphiphiles (C16Thr20). The binding free energy of β-CD:C16Thr20 inclusion complex at 298 K and 333 K (above degelation temperature) is -29.60 and -26.33 kJ/mol, respectively. This result indicates the temperature, at which the degelation occurs, is not high enough to break apart the β-CD:C16Thr20 complex. This suggests that the degelation of C16Thr20 hydrogel is mainly due to the decreased hydrogen bonding network within the structures rather than the β-CD:C16Thr20 complex dissociation. Furthermore, the thermodynamic analysis showed that the β-CD:C16Thr20 complex formation is mainly driven by enthalpy. The free energy data of the thermodynamic cycle for the (β-CD)2:C16 inclusion complex formation illustrated that the C16 chain can form stable complex with two β-CDs, consistent with the reported experimental analysis. Based on the free energy data, the (β-CD)2:C16 complex is more likely formed via the sequentially threading of the β-CDs onto the C16 chain.

Avakyan, V. G., Nazarov, V. B., Alfimov, M. V., Bagatur’yants, A. A., Voronezheva, N. I. “The role of intra- and intermolecular hydrogen bonds in the formation of β-cyclodextrin head-to-head and head-to-tail dimers. The results of ab initio and semiempirical quantum- chemical calculations.” Russ. Chem. Bull. 50, 206–216 (2001).

Auletta, T. et al. “Beta-cyclodextrin host-guest complexes probed under thermodynamic equilibrium: thermodynamics and AFM force spectroscopy.” J Am Chem Soc 126, 1577– 1584 (2004).

Aiello, C., Andreozzi, P., La Mesa, C., Risuleo, G. “Biological activity of SDS-CTAB cat- anionic vesicles in cultured cells and assessment of their cytotoxicity ending in apoptosis.” Colloids Surfaces B Biointerfaces 78, 149–154 (2010).

Anwekar, H., Patel, S., Singhai, A.K. “Liposome- as drug carriers.” Int. J. Pharm. Life Sci. 2, 945–951 (2011).

Akbarzadeh, A., Rezaei-Sadabady, R., Davaran, S., Joo, S.W., Zarghami, N., Hanifehpour, Y., Samiei, M., Kouhi, M., Nejati-Koshki, K., “Liposome: classification, preparation, and applications.” Nanoscale Res. Lett. 8, 102 (2013).

Bramer, T., Dew, N., “Edsman, K. Pharmaceutical applications for catanionic mixtures.” J. Pharm. Pharmacol. 59, 1319–34 (2007).

Brocos, P., Díaz-Vergara, N., Banquy, X. Pérez-Casas, S. Costas, M. Piñeiro, Á. “Similarities and differences between cyclodextrin-sodium dodecyl sulfate host-guest complexes of different stoichiometries: Molecular dynamics simulations at several temperatures.” J. Phys. Chem. B 114, 12455–12467 (2010).

Cornell, W.D., Cieplak, P., Bayly, C.I., Gould, I.R., Merz, K.M., Ferguson, D.M., Spellmeyer, D.C., Fox, T., Caldwell, J.W., Kollman, P.A. “A second generation force field for the simulation of proteins, nucleic acids, and organic molecules.” J. Am. Chem. Soc. 117, 5179–5197 (1995).

Chipot, C., Pohorille, A., “ Free energy calculations: Theory and applications in chemistry and biology,” Springer Series in Chemical Physics, 86, (2007).

Cai, W., Sun, T., Liu, P., Chipot, C., Shao, X. “Inclusion mechanism of steroid drugs into β-cyclodextrins. insights from free energy calculations.” J. Phys. Chem. B 113, 7836–7843 (2009).

Cézard, C., Trivelli, X., Aubry, F., Djedaïni-Pilard, F., Dupradeau, F.Y. “Molecular dynamics studies of native and substituted cyclodextrins in different media: 1. Charge derivation and force field performances.” Phys. Chem. Chem. Phys. 13, 15103–21 (2011).

Den Otter, W. K., Briels, W. J. “The calculation of free-energy differences by constrained molecular-dynamics simulations.” J. Chem. Phys. 109, 4139–4146 (1998).

Deng, Y., Roux, B. “Calculation of standard binding free energies: Aromatic molecules in the T4 lysozyme L99A mutant.” J. Chem. Theory Comput. 2, 1255–1273 (2006).

Essmann, U., Perera, L., Berkowitz, M.L., Darden, T., Lee, H., Pedersen, L.G. “A smooth particle mesh Ewald method.” J Chem Phys 103, 8577–8593 (1995).

Elisseeff, J. “Hydrogels: Structure starts to gel.” Nat. Mater. 1, 183–185 (2009).

Fukuda, H., Kawata, K., Okuda, H., Regen, S. L. “Bilayer-forming ion-Pair amphiphiles from single-chain surfactants.” J. Am. Chem. Soc. 112, 1635–1637 (1990).

Feller, S.E., Pastor, R.W. “Constant surface tension simulations of lipid bilayers: The sensitivity of surface areas and compressibilities.” J. Chem. Phys. 111, 1281 (1999).

Frenkel, D., Smit, B., “Understanding molecular simulation (second edition),” Academic Press, 85, (2002).

Filippini, G., Goujon, F., Bonal, C., Malfreyt, P. “Energetic competition effects on thermodynamic properties of association between β-CD and Fc group: A potential of mean force approach. “J. Phys. Chem. C 116, 22350–22358 (2012).

Heimburg, T., Würz, U., Marsh, D. “Binary phase diagram of hydrated dimyristoylglycerol-dimyristoylphosphatidylcholine mixtures.” Biophys. J. 63, 1369–1378 (1992).

Humphrey, W., Dalke, A.; Schulten, K., “VMD - Visual molecular dynamics,” J. Molec. Graphics. 14, 33 (1996).

Harada, A., Li, J., Kamachi, M., Kitagawa, Y., Katsube, Y. “Structures of polyrotaxane models.” Carbohydr. Res. 305, 127–129 (1997).

Hess, B., Bekker, H., Berendsen, H.J.C., Fraaije, J.G.E.M. “LINCS: A linear constraint solver for molecular simulations.” J. Comput. Chem. 18, 1463–1472 (1997).

Hiemenz, P.C., Rajagopalan, R. “Principles of colloid and surfaces chemistry.” New York: Marcel Dekker, Inc. (1997).

Harada, A. “Cyclodextrin-based molecular.” Acc. Chem. Res. 34, 456–464 (2001).

Hess, B., Kutzner, C., Van Der Spoel, D., Lindahl, E. “GRGMACS 4: Algorithms for highly efficient, load-balanced, and scalable molecular simulation.” J. Chem. Theory Comput. 4, 435–447 (2008).

Huang, T.M., “Synthesis of high adhesive and thermo-sensitive acrylate hydrogels and its controlled drug release study.” National Taiwan University, Department of Chemical Engineering, Master Thesis, (2008).

Hsu Y.Y. “Thermo-responsive supramolecular hydrogels formed by cyclodextrin and peptide amphiphiles.” National Cheng Kung University, Department of Chemical Engineering, Master Thesis, (2015).

Israelachvili, J.N., Mitchell, D.J., Ninham, B.W. “Theory of self-assembly of hydrocarbon amphiphiles into micelles and bilayers.” J. Chem. Soc. Faraday Trans. 2 72, 1525 (1976).

Jorgensen, W.L., Chandrasekhar, J., Madura, J.D., Impey, R. W., Klein, M. L. “Comparison of simple potential functions for simulating liquid water.” J. Chem. Phys. 79, 926 (1983).

Jorgensen, W.L., Thomas, L.L. “Perspective on free-energy perturbation calculations for chemical equilibria” J Chem Theory Comput. 4, 869–876 (2009).

Kirkwood, J.G. “Statistical mechanics of fluid mixtures.” J. Chem. Phys. 3, 300–313 (1935).

Kaler, E.W., Murthy, A.K., Rodriguez, B.E., Zasadzinski, J.A.N. “Spontaneous vesicle formation in aqueous mixtures of single-tailed surfactants.” Science 245, 1371–1374 (1989).

Kozlov, M.M.; Helfrich, W. “Effects of a cosurfactant on the stretching and bending elasticities of a surfactant monolayer.” Langmuir 8, 2792–2797 (1992).

Kirschner, K.N., Yongye, A.B., Tschampel, S.M., González-Outeiriño, J., Daniels, C.R., Foley, B.L., Woods, R.J. “GLYCAM06: A generalizable biomolecular force field. carbohydrates.” J. Comput. Chem. 29, 622–655 (2008).

Khelashvili, G., Pabst, G., Harries, D. “Cholesterol orientation and tilt modulus in DMPC bilayers.” J. Phys. Chem. B 114, 7524–7534 (2010).

Klauda, J.B., Venable, R.M., Freites, J. A., O'Connor, J.W., Tobias, D.J., Mondragon- Ramirez, C., Vorobyov, I., MacKerell, A.D., Pastor, R.W. “Update of the CHARMM allatom additive force field for lipids: Validation on six lipid types.” J. Phys. Chem. B 114, 7830–7843 (2010).

Khelashvili, G., Harries, D. “How cholesterol tilt modulates the mechanical properties of saturated and unsaturated lipid membranes.” J. Phys. Chem. B 117, 2411–2421 (2013).

Khelashvili, G., Kollmitzer, B., Heftberger, P., Pabst, G., Harries, D. “Calculating the bending modulus for multicomponent lipid membranes in different thermodynamic phases.” J. Chem. Theory Comput. 9, 3866–3871 (2013).

Kuo, A.T., Chang, C.H., Shinoda, W. “Molecular dynamics study of catanionic bilayers composed of ion pair amphiphile with double-tailed cationic surfactant.” Langmuir 28, 8156–8164 (2012).

Kuo, A.T., Chang, C.H. “Cholesterol-induced condensing and disordering effects on a rigid catanionic bilayer: A molecular dynamics study.” Langmuir 30, 55–62 (2014).

Kuo, A.T., Chang, C.H. “Elucidating the effects of cholesterol on the molecular packing of double-chained cationic lipid langmuir monolayers by infrared reflection-absorption spectroscopy.” J. Oleo Sci. 64, 455–65 (2015).

Lasic, D.D. “Novel applications of liposomes.” Trends Biotechnol. 16, 307–321 (1998).

López, C.A., de Vries, A.H., Marrink, S.J. “Molecular mechanism of cyclodextrin mediated cholesterol extraction.” PLoS Comput. Biol. 7, 1-11 (2011).

López, C.A., de Vries, A.H., Marrink, S.J. “Computational microscopy of cyclodextrin mediated cholesterol extraction from lipid model membranes.” Sci. Rep. 3, 1–6 (2013).

Liu, P., Chipot, C., Shao, X.G., Cai, W.S. “How do α-Cyclodextrins self-organize on a polymer chain?” J. Phys. Chem. C 116, 17913–17918 (2012).

Lewis, R.N.A.H., McElhaney, R.N. “Membrane lipid phase transitions and phase organization studied by Fourier transform infrared spectroscopy.” Biochim. Biophys. Acta 1828, 2347–58 (2013).

Lee, W.H., Tang, Y.L., Chiu, T.C., Yang, Y.M. “Synthesis of ion-pair amphiphiles and calorimetric study on the gel to liquid-crystalline phase transition behavior of their bilayers.” J. Chem. Eng. Data 60, 1119–1125 (2015).

Martyna, G.J., Klein, M.L., Tuckerman, M. “Nose–Hoover chains: The canonical ensemble via continuous dynamics.” J. Chem. Phys. 97, 2635–2643 (1992).

Martyna, G.J., Tobias, D.J., Klein, M.L. “Constant pressure molecular dynamics algorithms.” J. Chem. Phys. 101, 4177 (1994).

Marques, E.F., Regev, O., Khan, A., Lindman, B. “Self-organization of double-chained and pseudodouble-chained surfactants: Counterion and geometry effects.” Adv. Colloid Interface Sci. 100-102, 83–104 (2003).

Martinez, L., Andrade, R., Birgin, E.G., Martínez, J.M. “PACKMOL: A package for building initial configurations for molecular dynamics simulations.” J. Comput. Chem. 30, 2157–2164 (2009).

Parrinello, M., Rahman, A. “Polymorphic transitions in single crystals: A new molecular dynamics method.“ J. Appl. Phys. 52, 7182–7190 (1981).

Picas, L., Rico, F., Scheuring, S. “Direct measurement of the mechanical properties of lipid phases in supported bilayers.” Biophys. J. 102, L01–L03 (2012).

Pronk, S., Páll, S., Schulz, R., Larsson, P., Bjelkmar, P., Apostolov, R., Shirts, M.R., Smith, J.C., Kasson, P.M., Van Der Spoel, D., Hess, B., Lindahl, E. “GROMACS 4.5: A highthroughput and highly parallel open source molecular simulation toolkit.” Bioinformatics 29, 845–854 (2013).

Rekharsky, M.V., Inoue, Y. “Complexation thermodynamics of cyclodextrins.” Chem. Rev. 98, 1875–1918 (1998).

Rosa, M., del Carmen Morán, M., da Graca Miguel, M., Lindman, B. “The association of DNA and stable catanionic amino acid-based vesicles.” Colloids Surfaces A: Physicochem. Eng. Asp. 301, 361–375 (2007).

Rodgers, J.M., Sørensen, J., De Meyer, F.J.M., Schiøtt, B., Smit, B. “Understanding the phase behavior of coarse-grained model lipid bilayers through computational calorimetry.” J. Phys. Chem. B 116, 1551–1569 (2012).

Schindler, H., Seelig, J. “Deuterium order parameters in relation to thermodynamic properties of a phospholipid bilayer. A statistical mechanical interpretation.” Biochemistry 14, 2283–2287 (1975).

Seelig, J. “Deuterium magnetic resonance: Theory and application to lipid membranes.” Q. Rev. Biophys. 10, 353–418 (1977).

Schneider, H.J., Hacket, F., Rüdiger, V., Ikeda, H., Ru, V., Ikeda, H., “NMR studies of cyclodextrins and cyclodextrin complexes.” Chem. Rev. 98, 1755–1786 (1998).

Szejtli, J. “Introduction and general overview of cyclodextrin chemistry.” Chem. Rev. 98, 1743–1753 (1998).

Shin, K., Dong, T., He, Y., Taguchi, Y., Oishi, A., Nishida, H., Inoue, Y. “Inclusion complex formation between α-cyclodextrin and biodegradable aliphatic polyesters.” Macromol. Biosci. 4, 1075–1083 (2004).

Shinoda, W., Mikami, M., Baba, T., Hato, M. “Molecular dynamics study on the effect of chain branching on the physical properties of lipid bilayers: Structural stability.” J. Phys. Chem. B 108, 9346–9356 (2003).

Shinoda, W., Shinoda, K., Baba, T., Mikami, M. “Molecular dynamics study of bipolar tetraether lipid membranes.” Biophys. J. 89, 3195–3202 (2005).

Šegota, S., Težak, D. “Spontaneous formation of vesicles.” Adv. Colloid Interface Sci. 121, 51–75 (2006).

Soussan, E., Cassel, S., Blanzat, M., Rico-Lattes, I. “Drug delivery by soft matter: Matrix and vesicular carriers.” Angew. Chemie - Int. Ed. 48, 274–288 (2009).

Tu, K., Tobias, D.J., Blasie, J.K., Klein, M.L. “Molecular dynamics investigation of the structure of a fully hydrated gel-phase dipalmitoylphosphatidylcholine bilayer.” Biophys. J. 70, 595–608 (1996).

Tondre, C., Caillet, C. “Properties of the amphiphilic films in mixed cationic/anionic vesicles: A comprehensive view from a literature analysis.” Adv. Colloid Interface Sci. 93, 115–134 (2001).

Taulier, N., Chalikian, T.V. “γ-Cyclodextrin forms a highly compressible complex with 1- adamantanecarboxylic” Acid. J. Phys. Chem. B 112, 9546–9549 (2008).

Taira, T., Suzaki, Y., Osakada, K. “Thermosensitive hydrogels composed of cyclodextrin pseudorotaxanes. Role of [3]pseudorotaxane in the gel formation.” Chem. Commun. 7027– 7029 (2009).

Van Der Spoel, D., Lindahl, E., Hess, B., Groenhof, G., Mark, A.E., Berendsen, H.C. “GROMACS: Fast, flexible, and free.” J. Comput. Chem. 26, 1701–1718 (2005).

Vermeer, L.S., De Groot, B.L., Réat, V., Milon, A., Czaplicki, J. “Acyl chain order parameter profiles in phospholipid bilayers: Computation from molecular dynamics simulations and comparison with 2H NMR experiments.” Eur. Biophys. J. 36, 919–931 (2007).

Wang, J., Wolf, R.M., Caldwell, J.W., Kollman, P.A., Case, D.A. “Development and testing of a general Amber force field.” J. Comput. Chem. 25, 1157–1174 (2004).

Wu, Y.L., Li, J. “Synthesis of supramolecular nanocapsules based on threading of multiple cyclodextrins over polymers on gold nanoparticles.” Angew. Chemie - Int. Ed. 48, 3842– 3845 (2009).

Watson, M.C., Brandt, E.G., Welch, P.M., Brown, F.L.H. “Determining biomembrane bending rigidities from simulations of modest size.” Phys. Rev. Lett. 109, 1–5 (2012).

Yatcilla, M.T., Herrington, K.L., Brasher, L.L., Kaler, E.W., Chiruvolu, S., Zasadzinski, J.A.N. “Phase behavior of aqueous mixtures of cetyltrimethylammonium bromide (CTAB) and sodium octyl sulfate (SOS).” J. Phys. Chem. 100, 5874–5879 (1996).

Yu, Y.M., Chipot, C., Cai, W.S., Shao, X., Poincare, H. “Molecular dynamics study of the inclusion of cholesterol into cyclodextrins.” J. Phys. Chem. B 6372–6378 (2006).

Zwanzig, R.W. “High-temperature equation of state by a perturbation method. I. Nonpolar Gases.” J. Chem. Phys. 22, 1420–1426 (1954).

Zhang, H., Tan, T., Feng, W., van der Spoel, D. Molecular recognition in different environments: β-cyclodextrin dimer formation in organic solvents. J. Phys. Chem. B 116,12684–12693 (2012).

Zhang, H., Tan, T., Hetényi, C., Van Der Spoel, D. “Quantification of solvent contribution to the stability of noncovalent complexes.” J. Chem. Theory Comput. 9, 4542–4551 (2013).

Zhang, H., Tan, T., Hetényi, C., Lv, Y., Van Der Spoel, D. “Cooperative binding of cyclodextrin dimers to isoflavone analogues elucidated by free energy calculations.” J. Phys. Chem. C 118, 7163–7173 (2014).