Molecular Dynamics Study of Catanionic Bilayers Composed of Ion

May 7, 2012 - observed near the slip plane between the two bilayer leaflets. A stronger ..... This study was supported by the Joint Summer Visiting. P...
1 downloads 0 Views 578KB Size
Download PDF
Article pubs.acs.org/Langmuir

Molecular Dynamics Study of Catanionic Bilayers Composed of Ion Pair Amphiphile with Double-Tailed Cationic Surfactant An-Tsung Kuo,†,‡ Chien-Hsiang Chang,† and Wataru Shinoda*,‡ †

Department of Chemical Engineering, National Cheng Kung University, Tainan 701, Taiwan Nanosystem Research Institute (NRI), National Institute of Advanced Industrial Science and Technology (AIST), Central-2, Umezono 1-1-1, Tsukuba 305-8568, Japan

‡

S Supporting Information *

ABSTRACT: The physical stability of catanionic vesicles is important for the development of novel drug or DNA carriers. For investigating the mechanism by which catanionic vesicles are stabilized, molecular dynamics (MD) simulation is an attractive approach that provides microscopic structural information on the vesicular bilayer. In this study, MD simulation was applied to investigate the bilayer properties of catanionic vesicles composed of an ion pair amphiphile (IPA), hexadecyltrimethylammoniumdodecylsulfate (HTMA-DS), and a double-tailed cationic surfactant, ditetradecyldimethylammonium chloride (DTDAC). Structural information regarding membrane elasticity and the organization and conformation of surfactant molecules was obtained based on the resulting trajectory. Simulation results showed that a proper amount of DTDAC could be used to complement the asymmetric structure between HTMA and DS, resulting in an ordered hydrocarbon chain packing within the rigid membrane observed in the mixed HTMA-DS/DTDAC system. The coexistence of gel and fluid phases was also observed in the presence of excess DTDAC. MD simulation results agreed well with results obtained from experimental studies examining mixed HTMA-DS/DTDAB vesicles.

1. INTRODUCTION Recently, the number of studies examining vesicles has increased because of their potential as drug delivery carriers. Vesicles composed of lipid are called liposomes, which have a similar composition to cell membranes. Liposomes are relatively nontoxic and can be decomposed in vivo. Therefore, they are widely used as carriers for drug delivery.1,2 Additionally, it is relatively easy to modify the liposomal surface with targeting ligands or antibodies, which can further reduce side effects and improve drug efficacy.3 Thus, vesicles have been widely studied.1,4−7 However, the practical application of liposomes appears to be limited due to high costs. To solve this problem, catanionic vesicles prepared from inexpensive catanionic surfactants have recently been considered as a feasible replacement with significant potential to serve as novel drug or DNA carriers.8−11 Catanionic surfactants are defined as mixtures of cationic and anionic surfactants. After removing counterions from the mixtures, the catanionic surfactant residue is referred to as ion pair amphiphile (IPA).8 It has been reported that catanionic vesicles prepared from IPAs are not stable.12,13 Physical stability of catanionic vesicles can be improved using additives that increase electrostatic and/or steric repulsion between vesicles or that modify molecular packing or intermolecular interaction within vesicles.14−19 However, mechanisms for stabilizing catanionic vesicles prepared using mixtures of IPAs and © 2012 American Chemical Society

additives remain unclear at the molecular level. MD simulations may be useful for investigating the microscopic structure of vesicular bilayers. A large number of MD studies examining lipid bilayers using fully atomistic as well as coarse-grained descriptions have been reported.20−29 These MD studies have provided insight into bilayer structural and elastic properties such as lipid conformation, elastic modulus, and density profiles,22,25−27 improving the understanding of lipid bilayers from a molecular viewpoint. Catanionic vesicles prepared from hexadecyltrimethylammonium-dodecylsulfate (HTMA-DS) showed poor physical stability, and a double-chained cationic surfactant, ditetradecyldimethylammonium bromide (DTDAB), was shown to be efficient in enhancing the stability of vesicles.30 However, the mechanism underlying this increase in vesicle stability is not understood. In order to explore the physical properties of catanionic vesicles composed of HTMA-DS and DTDAB, a series of MD simulations of bilayers with several different compositions of HTMA-DS and DTDAB (DTDAC, ditetradecyldimethylammonium chloride, was used in this study) were conducted. Structural properties, together with the membrane area elastic modulus, were analyzed. The effect of composition Received: February 14, 2012 Revised: April 13, 2012 Published: May 7, 2012 8156

dx.doi.org/10.1021/la300651u | Langmuir 2012, 28, 8156−8164

Langmuir

Article

Rahman barostat.42,43 Long-range electrostatic potential was calculated using the Ewald or particle mesh Ewald method, and Lennard-Jones (LJ) pair potentials were evaluated within a cutoff distance of 1.2 nm with a smooth switching function above 1 nm. All bonds involving hydrogen atoms were constrained to their equilibrium lengths based on the SHAKE/RATTLE algorithm.44 The time step size of 2 fs was used for all MD simulations. MD simulation lengths were 50 and 90 ns for single- and binary-component bilayer systems, respectively. The last 40 ns MD trajectory of each system was used to analyze bilayer structure.

is also discussed. The goal of this study was to examine stabilization mechanisms of vesicle bilayers.

2. SIMULATION METHODS Molecular structure models of sodium dodecylsulfate (SDS), hexadecyltrimethylammonium chloride (HTMAC), and ditetradecyldimethylammonium chloride (DTDAC) were constructed using Discovery Studio 3.131 (Figure 1). Before

3. RESULTS AND DISCUSSION 3.1. Averaged Molecular Area and Elastic Area Expansion Modulus. The time evolution of the average molecular area during the last 40 ns is plotted in Figure 2a for each system of different compositions. The molecular areas of DTDAC-rich systems were significantly larger than those of other (HTMA-DA-rich) systems. Area fluctuations were small for the latter systems, which were clearly different from those typically observed in fluid membranes.45 Time-averaged areas are listed in Table 2. Compared with DTDAC, HTMA-DS showed a much smaller molecular area, and the addition of DTDAC to the bilayer did not significantly change the molecular area until XDTDAC = 0.75. This observation may be attributable to the strong attraction between the head groups of HTMA-DS molecules. Probability distributions of the averaged molecular area obtained from all simulated bilayers are plotted in Figure 2b. A broad dispersion was observed in the DTDAC system due to large fluctuation, indicating that the DTDAC bilayer is more flexible at 298 K. To further compare the membrane area elasticity, the elastic area expansion modulus, KA, was calculated with the relationship derived using the linear response theory46,47

Figure 1. Molecular structures of dodecylsulfate (DS), hexadecyltrimethylammonium (HTMA), and ditetradecyldimethylammonium chloride (DTDAC). An ion pair amphiphile (IPA), HTMA-DS, is formed by HTMA+ and DS−.

constructing the initial structure model of HTMA-DS (IPA), the HTMA and DS ions were placed at an appropriately close distance (distance between N and S was ∼0.4 nm). Next, Packmol32 was applied to build the initial structure of HTMADS, DTDAC, and mixed HTMA-DS/DTDAC bilayers. Each bilayer system was composed of 128 surfactant and 3464 water molecules (Table 1).

KA =

Table 1. Compositions of the Different Bilayers Examined XDTDAC

HTMA

DS

0 0.25 0.50 0.75 1.00

128 96 64 32

128 96 64 32

DTDA

Cl

32 64 96 128

32 64 96 128

kT ⟨A⟩ N ⟨δA2 ⟩

where A is the averaged cross-sectional area per molecule and N is the number of molecules aligned in a bilayer leaflet. The bracket denotes the ensemble average. This equation denotes that membrane area expansion modulus is inversely proportional to area fluctuation. The calculated moduli of all bilayers are listed in Table 2. Elastic modulus decreases with an increase in DTDAC mole fraction, XDTDAC. The KA values of bilayer systems with XDTDAC ≤ 0.5 are larger than those of pure DTDAC bilayers by ∼1 order of magnitude. Thus, the bilayers may be more stable toward external mechanical forces when XDTDAC ≤ 0.5. 3.2. Overall Bilayer Structure. A snapshot of each bilayer is shown in Figure 3. Panel a shows a snapshot of the HTMADS bilayer. Hydrocarbon chains of the HTMA-DS bilayer are in a regular arrangement, though slightly disordered packing is observed near the slip plane between the two bilayer leaflets. A stronger electrostatic attraction between oppositely charged head groups of HTMA+ and DS− may contribute to the close lateral packing of surfactants. However, the asymmetric structure of HTMA and DS in regard to chain length, which differs by four carbons, creates a space large enough for the longer chain to reorient in the hydrophobic core. This results in less tight packing near the slip plane.

All-atom MD simulations were carried out using MPDyn software33 and NAMD.34 The CHARMM PARAM27R force field35,36 was used for the surfactants, and the TIP3P model37 was employed for water. It should be commented here for the choice of DTDAC instead of DTDAB in our MD simulations. This is basically just for the lack of bromide ion parameters in the CHARMM PARAM27R force field. No significant difference between the properties of Br−and Cl− was found in previous MD simulations.38,39 Thus, together with the fact that a similar physical property was found for DODAC and DODAB vesicles experimentally,40 it is expected that the effect of the choice of Cl− instead of Br− should be quite minor. The MD simulation was carried out using an isothermal−isobaric (NPT) ensemble. The temperature of the simulated system was controlled at 298 K using a Nosé-Hoover chain thermostat,41 and pressure was controlled at 1 bar using a Parrinello− 8157

dx.doi.org/10.1021/la300651u | Langmuir 2012, 28, 8156−8164

Langmuir

Article

Figure 2. (a) Time evolution of the averaged molecular area and (b) its probability distribution.

Table 2. Averaged Molecular Area A [Å2] and Elastic Area Expansion Modulus, KA [dyn/cm] XDTDAC

A

KA

0 0.25 0.50 0.75 1.00

42.4 41.2 42.6 47.4 66.0

2365 2141 1692 600 201

experiments48 and simulation studies.49−52 This structure may be also due to the coexistence of gel and fluid phases in the bilayer membrane. This system will be further discussed. 3.3. Radial Distribution Function between Head Groups. Figure 4a shows the radial distribution function (RDF), g(r), between head groups in the HTMA-DS bilayer. The initial peaks of gNN(r), gNS(r), and gSS(r) are displayed at 0.625, 0.445, and 0.625 nm, respectively. The distance between the same types of charged surfactants is 1.4 times that between surfactants with opposite charges. Thus, a compact arrangement of HTMA-DS head groups was formed due to electrostatic attractions between HTMA and DS. However, the initial peak of the RDF of the DTDAC bilayer appears at a larger distance (0.795 nm) between DTDAC head groups (Figure 4b). Several chloride ions diffuse into the water (Figure 3e); thus, electrostatic repulsion between positively charged ammonium groups cannot be effectively screened. Consequently, DTDAC molecules are not able to form a tightly packed membrane. In mixed HTMA-DS/DTDAC bilayers, distances between DTDAC head groups are 0.745 nm at XDTDAC = 0.25, 0.685 nm at XDTDAC = 0.5, and 0.755 nm at XDTDAC = 0.75 (Figure 4). Thus, a nonmonotonic dependence on the DTDAC mole fraction is observed with a pronounced minimum at XDTDAC = 0.5. Although repulsive electrostatic interactions increase with increasing XDTDAC, DS− with negative charges can effectively screen repulsion in the bilayer at XDTDAC ≤ 0.5; thus, molecules can pack tightly in these mixed HTMA-DS/DTDAC bilayers. For the bilayer with XDTDAC = 0.75, repulsion between positively charged head groups was not effectively inhibited due to the relatively smaller amount of DS− present. As a result, membrane properties significantly change at this molar fraction.

In the pure DTDAC bilayer, an irregular arrangement of loosely packed chains is shown in Figure 3e. Some chloride ions diffuse into water, and water molecules penetrate deeply into the bilayer. Electrostatic repulsion between the head groups may dominate the intermolecular interactions. As a result, surfactant molecules may not be tightly packed in the bilayer, resulting in high fluidity of the bilayer. These snapshots clearly reveal various chain structures of HTMA-DS and DTDAC bilayers. In the HTMA-DS bilayer, the chains are fully stretched with no overlap at the slip plane of the two leaflets. In contrast, a disordered chain alignment makes the slip plane unclear in the DTDAC bilayer. Thus, the HTMA-DS may form a rigid membrane while DTDAC forms a fluid membrane at 298 K. Panels b and c of Figure 3 show snapshots of mixed HTMADS/DTDAC bilayers at XDTDAC = 0.25 and 0.5, respectively. The gel-like structure is maintained at these compositions at 298 K, indicating that the hydrophobic chains of DTDAC molecules are aligned along the tightly packed HTMA-DS bilayer at these concentrations. However, the snapshot of mixed HTMA-DS/DTDAC bilayer at XDTDAC = 0.75 (Figure 3d) reveals a ripple phase, which was also observed in other

Figure 3. Snapshots of the bilayer systems during MD simulations. (a) HTMA-DS, (b) XDTDAC = 0.25, (c) XDTDAC = 0.50, (d) XDTDAC = 0.75, and (e) DTDAC. The substances were colored as follows: (blue) HTMA, (red) DS, (orange) DTDA, (purple) Cl−, and (lilac) water. H atoms on the surfactants are not shown. 8158

dx.doi.org/10.1021/la300651u | Langmuir 2012, 28, 8156−8164

Langmuir

Article

Figure 4. Radial distribution functions between specified atom pairs: (a) HTMA-DS, (b) DTDAC, (c) XDTDAC = 0.25, (d) XDTDAC = 0.5, and (e) XDTDAC = 0.75.

The peak positions in gNS(r) for HTMA-DS and DTDA-DS at different DTDAC mole fractions are similar (∼0.45 nm), suggesting that DS− could associate with DTDA+ as well as HTMA + in mixed HTMA-DS/DTDAC bilayers. With increasing XDTDAC, however, the distance between the DS head groups was increased, though the distance between HTMA head groups was not largely changed. The result implies that the association between DS and DTDA was enhanced with increasing XDTDAC. 3.4. Hydrocarbon Chain Order Parameter. The deuterium order parameter, SCD, was used to investigate the segmental order of hydrocarbon chains. SCD =

Order parameter profiles calculated for HTMA, DS, and DTDA in each system are illustrated in Figure 5. SCD profiles of HTMA and DS hydrocarbon chains in the HTMA-DS bilayer plateaus at ∼0.4, except for a significant decrease at the tail segments. The plateau value, which is similar to that observed in the lipid or surfactant bilayer in gel or liquid ordered phases, is much higher than that observed in normal lipid bilayers in the liquid crystal phase (∼0.2).53 This result implies a high ratio of trans conformers in the hydrocarbon chains. The ratio of trans conformers in the hydrocarbon chains except for the tail segments is actually calculated to be over 90%, which is the typical value found for the gel phase.54 The detailed results of the probability analysis of gauche/trans states in the hydrocarbon tails of surfactants are given in the Supporting Information. However, asymmetry between the HTMA and DS resulted from the additional four carbons in the HTMA hydrocarbon chain, causing disordered packing around the tail group.

1 1 ⟨3 cos2 θ − 1⟩ = ⟨3(eCD ̂ ·eẑ )2 − 1⟩ 2 2

where êCD is the unit bond vector from carbon to deuterium (hydrogen) atoms in the hydrocarbon segment and is the unit vector along the bilayer normal. Brackets denote an averaging for all molecules and time. 8159

dx.doi.org/10.1021/la300651u | Langmuir 2012, 28, 8156−8164

Langmuir

Article

recent experimental study that vesicles prepared by mixing HTMA-DS and DTDAB showed higher rigidity at 298 K. For XDTDAC = 0.75, although the order parameter for DTDA showed an obvious increase, ordering of DS alkyl chains decreased. Interestingly, an increased order parameter of the tail portion of the HTMA alkyl chains was also observed. 3.5. Probability Distribution. Figure 6 plots the probability distributions of selected atoms along the bilayer normal. In the HTMA-DS bilayer, the distribution functions of the nitrogen (N) and sulfur (S) in HTMA-DS head groups are almost identical to each other, showing peaks at z = ± 1.9 nm (Figure 6a). The similar distribution profiles for N and S indicate strong electrostatic binding between ammonium and sulfate groups. This binding gives rise to the tight packing of HTMA and DS in the bilayer. The density profile for the terminal carbons of DS shows a minimum between two peaks, while that of HTMA shows a single peak at the center of the bilayer. Asymmetry in hydrocarbon chain lengths together with head group binding of HTMA and DS produces defects in the neat alignment of hydrophobic chains near the slip plane (Figure 3a). The DS with the shorter chain cannot reach to the slip plane (the center of the hydrophobic region), so the longer chains of HTMA must bend to fill the space, showing a lower order parameter and a higher ratio of gauche conformation in the tail segments (Figure 5b and Supporting Information). The probability distributions of selected atoms along the bilayer normal in the DTDAC bilayer are shown in Figure 6b. Water deeply penetrates into the DTDAC bilayer, and some chloride ions diffuse into the aqueous solution. Electrostatic repulsion between the head groups increases the surface area per surfactant while decreasing the thickness and, as a result, the strength of the bilayer membrane.58,59 Thus, the DTDAC bilayer is more flexible compared with the HTMA-DS bilayer. In the mixed IPA/DTDAC bilayer, it is thought that DTDAC can accommodate the asymmetric structure of HTMA-DS. This should be reflected in the probability distributions of the head groups along the bilayer normal. Figure 6 clearly reveals that the head groups of different surfactants in the mixed bilayer have different peak positions in the distributions. The peak-to-peak distances are listed in Table 3. Peak-to-peak distances for DTDAC and HTMA head groups are the shortest and longest, respectively, in the range of XDTDAC ≤ 0.5. This indicates that the order of peak head group positions is DTDA, DS, and HTMA toward the outside of the membrane. The sulfate group of DS located between the amine groups of HTMA and DTDA can effectively decrease electrostatic repulsion between positively charged amine groups. In contrast, a minimum between the two peaks in the density profile for the terminal carbon of DS gradually becomes unclear as the DTDAC molar fraction increases. At XDTDAC = 0.5, nearly identical density profiles are found for all terminal carbons of DS, DTDA, and HTMA (Figure 6). This suggests that DTDA may eliminate the defects in chain packing of the HTMA-DS bilayer by adjusting the conformation to fit to the ordered hydrocarbon chain alignment. This explains why the highest order parameters for HTMA and DS are found at XDTDAC = 0.5 (Figure 5). Interestingly, a similar distribution is observed for the head groups of DS and DTDA with XDTDAC ≤ 0.5 (Figure 6), indicating a stronger association of DTDA, rather than HTMA, to DS, and thus HTMA is squeezed slightly outward. This illustrates that the IPA is clearly not in the form of HTMA-DS.

Figure 5. Order parameter profiles along the hydrocarbon chains of surfactants at different DTDAC mole fractions: (a) DS, (b) HTMA, and (c) DTDA.

The hydrocarbon chain order parameter of the DTDAC bilayer is significantly different from that of the HTMA-DS bilayer. Order parameters for two hydrophobic chains are identical. Order parameters for the first two segments (carbon numbers 1 and 2) are relatively low due to the bent shape of the chains linked to the single amine group. The SCD shows a plateau for carbon atoms 3−11 at a value of ∼0.2, which is a typical value for a fluid membrane (Figure 5c).53 The difference between the HTMA-DS and DTDAC bilayers in the SCD profiles suggests the presence of different phases observed in these bilayers:50,55 the former is in the gel phase, while the latter is in the fluid phase. An examination of order parameters for mixed HTMA-DS/ DTDAC bilayers (Figure 5) shows a nonmonotonic dependence on the DTDAC mole fraction, reaching a maximum at XDTDAC = 0.5. A specific number of DTDAC molecules with a positive charge would increase ordering of the hydrocarbon chains. This phenomenon was also observed for lipid bilayers. 56,57 Compared to either pure HTMA-DS or DTDAC bilayers, the order parameter showed a small increase for DS and HTMA and a significant increase for DTDA at XDTDAC = 0.25 and 0.5. Particularly, the order parameter of the HTMA chain tail (carbon numbers > ∼8) increased. Thus, by adding DTDAC molecules, defects in chain packing resulting from the asymmetric chain length between HTMA and DS may be repaired. Higher ordering of the hydrocarbon chain results in increased membrane rigidity.46,47 It was also observed in our 8160

dx.doi.org/10.1021/la300651u | Langmuir 2012, 28, 8156−8164

Langmuir

Article

Figure 6. Probability distributions of the selected atoms along the bilayer normal: (a) HTMA-DS, (b) DTDAC, (c) XDTDAC = 0.25, (d) XDTDAC = 0.5, and (e) XDTDAC = 0.75. The lines for “C” represent the distribution of the terminal carbon of each surfactant.

tailed cationic surfactant from IPA to combine with a singletailed anionic surfactant. Thus, single-tailed cationic surfactants can be squeezed out from the monolayers or vesicles.30,60 As DTDAC mole fraction is increased to XDTDAC = 0.75, area expansion modulus rapidly decreases, and a locally disordered hydrophobic chain is observed. The membrane properties are quite different because a ripple-like structure appears at XDTDAC = 0.75 (Figure 3d). Considering the formation of the ripple phase in bilayers, three conditions have been suggested:61 (1) intrinsic steric repulsion between the head groups of monomers, (2) mildly weak packing on the hydrocarbon chains of monomers, and (3) relatively weak interaction between the head groups. The addition of DTDAC into HTMA-DS bilayers would increase the electrostatic repulsion between the head groups in the bilayers. Thus, at XDTDAC = 0.75, the enhanced electrostatic repulsion between the head groups led to a slightly disordered structure. It may be suggested that more intrinsic repulsion in the head group

Table 3. Peak-to-Peak Distances of Probability Distributions Profiles XDTDAC

dNN,HTMA (nm)

dSS,DS (nm)

dNN,DTDA (nm)

0 0.25 0.50 0.75 1.00

3.94 3.95 4.04 4.08 2.5

3.87 3.61 3.53 3.33

3.53 3.45 3.48

Instead, DTDA-DS is the IPA in the presence of DTDAC. Apparently, the similarity in tail lengths of DTDA and DS aids their coupling and promotes the ousted HTMA. The ousting of HTMA would interact with water well. Thus, the hydration of the squeezed HTMA might lead to the wobbling of HTMA hydrocarbon chain, resulting in an increase of gauche ratio in the middle of HTMA hydrocarbon chain (Supporting Information). It has also been observed in experimental studies that double-tailed cationic surfactants can displace a single8161

dx.doi.org/10.1021/la300651u | Langmuir 2012, 28, 8156−8164

Langmuir

Article

of mixed HTMA-DS/DTDAC bilayers was observed at XDTDAC ≤ 0.5, suggesting that DTDAC can adjust the asymmetry between HTMA and DS. Lateral domain formation in the membrane was observed at XDTDAC = 0.75. This is observed as the coexistence of gel-like and interdigitated domain structures. This study examined the role of di-alkyl chain cationic surfactants in catanionic vesicles on the molecular scale, which will be useful for preparing catanionic vesicles.

region and somewhat weak packing in the hydrophobic region within bilayers result in the ripple-like structure. One may anticipate the finite size effect on this observation because the observed lateral heterogeneity in the membrane can expand to a size larger than the simulation box. To evaluate the effect of finite size on the membrane structure when XDTDAC = 0.75, we also conducted an NPT-MD simulation of the system extended laterally by a factor of 4. The simulation box size is ∼11 nm in the x and y directions. The simulation time length was 150 ns. Molecular area decreased over the first 50 ns of the MD beginning from a fluid membrane structure. After 50 ns, the area converged well and a heterogeneous membrane structure appeared. Figure 7 shows a final snapshot

■

ASSOCIATED CONTENT

* Supporting Information S

Results of the probability analysis of gauche/trans states in the hydrocarbon tails of surfactants; Figure S1. This material is available free of charge via the Internet at http://pubs.acs.org.

■

AUTHOR INFORMATION

Corresponding Author

*Tel (+) 81-29-861-6251; Fax (+) 81-29-851-5426; e-mail w. [email protected]. Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS This study was supported by the Joint Summer Visiting Program of the National Science Council (Taiwan) and Interchange Association (Japan), the Strategic Programs for Innovative Research (SPIRE), MEXT, and the Computational Materials Science Initiative (CMSI), Japan.

■

Figure 7. A final snapshot of 150 ns NPT-MD simulation of a largescale system of a mixed HTMA-DS/DTDAC membrane at XDTDAC = 0.75. The light blue surface denotes water. The chloride is omitted for clarity.

REFERENCES

(1) Lasic, D. Novel applications of liposomes. Trends Biotechnol. 1998, 16, 307−321. (2) Winterhalter, M.; Lasuc, D. Liposome stability and formation: Experimental parameters and theories on the size distribution. Chem. Phys. Lipids 1993, 64, 35−43. (3) Ahmad, I.; Longenecker, M.; Samuel, J.; Allen, T. Antibodytargeted delivery of doxorubicin entrapped in sterically stabilized liposomes can eradicate lung cancer in mice. Cancer Res. 1993, 53, 1484−1488. (4) Samad, A.; Sultana, Y.; Aqil, M. Liposomal drug delivery systems: an update review. Curr. Drug Delivery 2007, 4, 297−305. (5) Scott, R. W.; Degrado, W. F.; Tew, G. N. De novo designed synthetic mimics of antimicrobial peptides. Curr. Opin. Biotechnol. 2008, 19, 620−627. (6) Balazs, D. A.; Godbey, W. Liposomes for use in gene delivery. J. Drug Delivery 2011, 2011, 1−12. (7) Cavasino, F.; DiStefano, S.; Sbriziolo, C. Binding of some alkylsubstituted ferrocenes to vesicular aggregates studied by a kinetic method. J. Chem. Soc., Faraday Trans. 1997, 93, 1585−1589. (8) 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. 2001, 93, 115−134. (9) Dias, R.; Lindman, B.; Miguel, M. DNA interaction with catanionic vesicles. J. Phys. Chem. B 2002, 106, 12600−12607. (10) Rosa, M.; del Carmen Morán, M.; da Graça Miguel, M.; Lindman, B. The association of DNA and stable catanionic amino acidbased vesicles. Colloids Surf., A 2007, 301, 361−375. (11) Bramer, T.; Dew, N.; Edsman, K. Pharmaceutical applications for catanionic mixtures. J. Pharm. Pharmacol. 2007, 59, 1319−1334. (12) Hirano, K.; Fukuda, H.; Regen, S. Polymerizable ion-paired amphiphiles. Langmuir 1991, 7, 1045−1047. (13) Chung, M.; Chung, Y. Polymerized ion pair amphiphile that shows remarkable enhancement in encapsulation efficiency and very slow release of fluorescent markers. Colloids Surf., B 2002, 24, 111− 121.

of the MD run. Locally different surfactant structures can be clearly observed in the membrane. DS and HTMA are likely found in the bilayer region with an extended chain, where the gel-like ordered chain alignment is found. The DTDA-rich domain shows an interdigitated structure with a less ordered chain alignment. The most disordered chain of DTDA is most likely to be found at the joint region connecting the gel-like and interdigitated domains. These DTDA moieties fill the gap of the membrane thickness at the joint, preventing exposure of the hydrophobic chains to water. The present membrane structure is similar to that observed referred to as the “ripple phase” in the previous MD study.49 We could clearly observe the effect of size on the ripple-like domain; but we could not conclude that this is the ripple phase domain. Nevertheless, heterogeneous lateral domain formation is commonly obtained for different system sizes (Figures 3d and 7), revealing the inherent heterogeneity of the membrane of mixed surfactants at XDTDAC = 0.75.

4. CONCLUSION We conducted a series of all-atom molecular dynamic simulations to investigate the structure of catanionic membranes formed using HTMA-DS and DTDAC. The HTMA-DS bilayer contains tightly packed chains in the membrane core, showing gel-like structural properties due to the dominant electrostatic attractions between HTMA and DS. In contrast, DTDAC molecules in the bilayer show fluid-like disordered packing of hydrophobic chains primarily due to electrostatic repulsion between charged head groups. An ordered structure 8162

dx.doi.org/10.1021/la300651u | Langmuir 2012, 28, 8156−8164

Langmuir

Article

(14) Walker, S.; Zasadzinski, J. Electrostatic control of spontaneous vesicle aggregation. Langmuir 1997, 13, 5076−5081. (15) Chung, M.; Chung, Y.; Chun, B. Highly pH-sensitive ion pair amphiphile vesicle. Colloids Surf., B 2003, 29, 75−80. (16) Kuo, J.-H. S.; Jan, M.-S.; Chang, C.-H.; Chiu, H.-W.; Li, C.-T. Cytotoxicity characterization of catanionic vesicles in RAW 264.7 murine macrophage-like cells. Colloids Surf., B 2005, 41, 189−196. (17) Marques, E.; Brito, R.; Wang, Y.; Silva, B. Thermotropic phase behavior of triple-chained catanionic surfactants with varying headgroup chemistry. J. Colloid Interface Sci. 2006, 294, 240−247. (18) Kuo, J.-H. S.; Chang, C.-H.; Lin, Y.-L.; Wu, C.-J. Flow cytometric characterization of interactions between U-937 human macrophages and positively charged catanionic vesicles. Colloids Surf., B 2008, 64, 307−313. (19) Kaur, R.; Kumar, S.; Aswal, V. K.; Mahajan, R. K. Interactional and aggregation behavior of twin tail cationic surfactants with pluronic L64 in aqueous solution. Colloid Polym. Sci. 2012, 290, 127−139. (20) Tieleman, D.; Marrink, S.; Berendsen, H. A computer perspective of membranes: molecular dynamics studies of lipid bilayer systems. Biophys. Biochim. Acta 1997, 1331, 235−270. (21) Tobias, D.; Tu, K.; Klein, M. Atomic-scale molecular dynamics simulations of lipid membranes. Curr. Opin. Colloid Interface Sci. 1997, 2, 15−26. (22) Shinoda, W.; Namiki, N.; Okazaki, S. Molecular dynamics study of a lipid bilayer: Convergence, structure, and long-time dynamics. J. Chem. Phys. 1997, 106, 5731−5743. (23) Feller, S. Molecular dynamics simulations of lipid bilayers. Curr. Opin. Colloid Interface Sci. 2000, 5, 217−223. (24) Marrink, S.; de Vries, A.; Mark, A. Coarse grained model for semiquantitative lipid simulations. J. Phys. Chem. B 2004, 108, 750− 760. (25) Shinoda, W.; DeVane, R.; Klein, M. L. Zwitterionic lipid assemblies: molecular dynamics studies of monolayers, bilayers, and vesicles using a new coarse grain force field. J. Phys. Chem. B 2010, 114, 6836−6849. (26) de Vries, A.; Mark, A.; Marrink, S. The binary mixing behavior of phospholipids in a bilayer: A molecular dynamics study. J. Phys. Chem. B 2004, 108, 2454−2463. (27) 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 2003, 107, 14030−14035. (28) Shinoda, W.; Mikami, M.; Baba, T.; Hato, M. Molecular dynamics study on the effects of chain branching on the physical properties of lipid bilayers: 2. Permeability. J. Phys. Chem. B 2004, 108, 9346−9356. (29) Shinoda, W.; Nakamura, T.; Nielsen, S. O. Free energy analysis of vesicle-to-bicelle transformation. Soft Matter 2011, 7, 9012−9020. (30) Chen, B.-W. Stability of Positively Charged Catanionic Vesicles in the Presence of Bovine Serum Albumin; Master thesis, National Cheng Kung University: Taiwan, 2007. (31) Discovery Studio Modeling Environment, Release 3.1; Accelrys Software Inc.: San Diego, 2011. (32) Martinez, L.; Andrade, R.; Birgin, E. G.; Martinez, J. M. PACKMOL: a package for building initial configurations for molecular dynamics simulations. J. Comput. Chem. 2009, 30, 2157−2164. (33) Shinoda, W.; Mikami, M. Rigid-body dynamics in the isothermal-isobaric ensemble: A test on the accuracy and computational efficiency. J. Comput. Chem. 2003, 24, 920−930. (34) Phillips, J.; Braun, R.; Wang, W.; Gumbart, J.; Tajkhorshid, E.; Villa, E.; Chipot, C.; Skeel, R.; Kale, L.; Schulten, K. Scalable molecular dynamics with NAMD. J. Comput. Chem. 2005, 26, 1781−1802. (35) MacKerell, A. D., Jr.; Bashford, D.; Bellott, M.; Dunbrack, R. J., Jr.; Evanseck, J. D.; Field, M. J.; Fischer, S.; Gao, J.; Guo, H.; Ha, S.; Joseph-McCarthy, D.; Kuchnir, L.; Kuczera, K.; Lau., F. T. K.; Mattos, C.; Michnick, S.; Ngo, T.; Nguyen, D. T.; Prodhom, B.; Reiher, W. E., III; Roux, B.; Schlenkrich, M.; Smith, J. C.; Stote, R.; Straub, J.; Watanabe, M.; Wiorkiewicz-Kuczera, J.; Yin, D.; Karplus, M. All-atom

empirical potential for molecular modeling and dynamics studies of proteins. J. Phys. Chem. B 1998, 102, 3586−3616. (36) Klauda, J.; Brooks, B.; MacKerell, A.; Venable, R.; Pastor, R. An ab initio study on the torsional surface of alkanes and its effect on molecular simulations of alkanes and a DPPC bilayer. J. Phys. Chem. B 2005, 109, 5300−5311. (37) 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. 1983, 79, 926−935. (38) Dang, L. Computational study of ion binding to the liquid interface of water. J. Phys. Chem. B 2002, 106, 10388−10394. (39) Vacha, R.; Siu, S. W. I.; Petrov, M.; Boeckmann, R. A.; BaruchaKraszewska, J.; Jurkiewicz, P.; Hof, M.; Berkowitz, M. L.; Jungwirth, P. Effects of alkali cations and halide anions on the DOPC lipid membrane. J. Phys. Chem. A 2009, 113, 7235−7243. (40) Nascimento, D.; Rapuano, R.; Lessa, M.; Carmona-Ribeiro, A. Counterion effects on properties of cationic vesicles. Langmuir 1998, 14, 7387−7391. (41) Martyna, G.; Klein, M.; Tuckerman, M. Nosé-Hoover chains: The canonical ensemble via continuous dynamics. J. Chem. Phys. 1992, 97, 2635−2643. (42) Martyna, G.; Tobias, D.; Klein, M. Constant pressure molecular dynamics algorithms. J. Chem. Phys. 1994, 101, 4177−4189. (43) Parrinello, M.; Rahman, A. Polymorphic transitions in singlecrystals - a new molecular-dynamics method. J. Appl. Phys. 1981, 52, 7182−7190. (44) Ryckaert, J.; Ciccotti, G.; Berendsen, H. Numerical-integration of cartesian equations of motion of a system with constraints molecular-dynamics of N-alkanes. J. Comput. Phys. 1977, 23, 327−341. (45) Lindahl, E.; Edholm, O. Mesoscopic undulations and thickness fluctuations in lipid bilayers from molecular dynamics simulations. Biophys. J. 2000, 79, 426−433. (46) Shinoda, W.; Shinoda, K.; Baba, T.; Mikami, M. Molecular dynamics study of bipolar tetraether lipid membranes. Biophys. J. 2005, 89, 3195−3202. (47) Feller, S.; Pastor, R. Constant surface tension simulations of lipid bilayers: The sensitivity of surface areas and compressibilities. J. Chem. Phys. 1999, 111, 1281−1287. (48) Sengupta, K.; Raghunathan, V.; Katsaras, J. Structure of the ripple phase of phospholipid multibilayers. Phys. Rev. E 2003, 68, 031710. (49) de Vries, A.; Yefimov, S.; Mark, A.; Marrink, S. Molecular structure of the lecithin ripple phase. Proc. Natl. Acad. Sci. U. S. A. 2005, 102, 5392−5396. (50) Debnath, A.; Ayappa, K. G.; Kumaran, V.; Maiti, P. K. The influence of bilayer composition on the gel to liquid crystalline transition. J. Phys. Chem. B 2009, 113, 10660−10668. (51) Jamroz, D.; Kepczynski, M.; Nowakowska, M. Molecular structure of the dioctadecyldimethylammonium bromide (DODAB) bilayer. Langmuir 2010, 26, 15076−15079. (52) Qin, S.-S.; Yu, Z.-W.; Yu, Y.-X. Structural characterization on the gel to liquid-crystal phase transition of fully hydrated DSPC and DSPE bilayers. J. Phys. Chem. B 2009, 113, 8114−8123. (53) Schindler, H.; Seelig, J. Deuterium order parameters in relation to thermodynamic properties of a phospholipid bilayer - statistical mechanical interpretation. Biochemistry 1975, 14, 2283−2287. (54) Pink, D.; Green, T.; Chapman, D. Raman-scattering in bilayers of saturated phosphatidylcholines - experiment and theory. Biochemistry 1980, 19, 349−356. (55) Egberts, E.; Marrink, S.; Berendsen, H. Molecular dynamics simulation of a phospholipid membrane. Eur. Biophys. J. 1994, 22, 423−436. (56) Gurtovenko, A. A.; Patra, M.; Karttunen, M.; Vattulainen, I. Cationic DMPC/DMTAP lipid bilayers: molecular dynamics study. Biophys. J. 2004, 86, 3461−3472. (57) Cascales, J.; Otero, T.; Smith, B.; Gonzalez, C.; Marquez, M. Model of an asymmetric DPPC/DPPS membrane: Effect of asymmetry on the lipid properties. A molecular dynamics simulation study. J. Phys. Chem. B 2006, 110, 2358−2363. 8163

dx.doi.org/10.1021/la300651u | Langmuir 2012, 28, 8156−8164

Langmuir

Article

(58) Ali, S.; Smaby, J.; Momsen, M.; Brockman, H.; Brown, R. Acyl chain-length asymmetry alters the interfacial elastic interactions of phosphatidylcholines. Biophys. J. 1998, 74, 338−348. (59) Illya, G.; Lipowsky, R.; Shillcock, J. Effect of chain length and asymmetry on material properties of bilayer membranes. J. Chem. Phys. 2005, 122, 244901. (60) Li, W.-T.; Yang, Y.-M.; Chang, C.-H. Langmuir monolayer behavior of an ion pair amphiphile with a double-tailed cationic surfactant. Colloids Surf., B 2008, 66, 187−194. (61) Yu, Z.; Quinn, P. Phase-stability of phosphatidylcholines in dimethylsulfoxide solutions. Biophys. J. 1995, 69, 1456−1463.

8164

dx.doi.org/10.1021/la300651u | Langmuir 2012, 28, 8156−8164