Molecular Dynamics Study of the Effect of Surfactant on a

John C. Shelley, Mee Y. Shelley, Robert C. Reeder, Sanjoy Bandyopadhyay, Preston B. .... Steve O Nielsen , Carlos F Lopez , Goundla Srinivas , Michael...
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J. Phys. Chem. B 2001, 105, 5979-5986

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Molecular Dynamics Study of the Effect of Surfactant on a Biomembrane Sanjoy Bandyopadhyay,*,† John C. Shelley,‡ and Michael L. Klein† Center for Molecular Modeling, Department of Chemistry, UniVersity of PennsylVania, Philadelphia, PennsylVania 19104-6323, and Schro¨ dinger Inc., 1500 SW First AVenue, Suite 1180, Portland, Oregon 97201 ReceiVed: January 22, 2001; In Final Form: April 17, 2001

To understand the effects of surfactants on membrane properties, constant pressure and temperature (NPT) molecular dynamics (MD) simulations have been performed on the fully hydrated liquid crystalline lamellar phase (LR) of pure dimyristoylphosphatidylcholine (DMPC) at 30 °C and its mixture with a 6.6% mol fraction of sodium dodecyl sulfate (SDS) surfactant. The presence of the surfactant causes a decrease in the area per lipid molecule (A) accompanied by an increase in lamellar d-spacing. We identify a strong interaction between the surfactant headgroup and the lipid zwitterionic phosphocholine (PC) group, which leads to a significant change in the orientation of the P- f N+ headgroup dipole toward the bilayer interior. The surfactant hydrocarbon chain is more ordered in the membrane as compared to the pure SDS bilayer phase. These findings should be amenable to experimental verification.

I. Introduction Surfactants are the major constituents of the detergents employed in domestic and industrial cleaning processes. The use of detergents inevitably leads to the release of surfactants in the environment, particularly in natural water. Thus the questions of how surfactants interact with biomembranes and influence their properties are central issues for both toxicology and environmental science. Besides being used as detergents, surfactants are also used as an important tool in membrane biochemistry. Biomembranes are composed of a large number of constituents, of which phospholipids are the major components.1 Systematic studies of phospholipid bilayers as model membranes have enhanced our understanding of many fundamental membrane properties.2,3 Another long standing issue in membrane science is the effect of foreign molecules on phospholipid membranes. Surfactants form an important class of such foreign molecules. The study of phospholipid/surfactant mixed bilayer systems is important not only for many potentially useful biochemical processes such as membrane solubilization4-6 and protein extraction,7 but also as model systems for understanding crucial issues such as the structure and dynamic properties of such complex systems,8-10 the hydration force,11 and the partition of these foreign molecules in the bilayer matrix.12 Because of technical limitations, it is not an easy task to carry out well-controlled experiments on lipid bilayer systems with or without additives. Klose and co-workers4,8-11 have reported extensive studies on the structural and hydration properties of mixed multilayers containing phospholipid palmitoyloleoylphosphatidylcholine (POPC) and nonionic surfactants C12En (monododecyl ethers of poly(oxyethylene) glycols), using X-ray and neutron diffraction8,10 and deuterium NMR.9,11 They studied in detail the effects of the surfactants on the bilayer structure by varying the surfactant concentrations and the length of their * Author to whom correspondence should be addressed. Tel: (215) 5734773. Fax: (215) 573-6233. E-mail: [email protected]. † University of Pennsylvania. ‡ Schro ¨ dinger Inc.

headgroups. It was observed that the presence of surfactants at low concentration in the membrane tighten the membrane packing, by reducing the area per lipid molecule at the bilayer/ water interface.11 The perturbation of phospholipid bilayer membranes containing saturated hydrocarbon chains such as DMPC and DPPC (dipalmitoylphosphatidylcholine) by the surfactant C12E8 were also investigated using NMR, light scattering, and calorimetry.6 Recently, temperature-dependent structural changes of a phospholipid/surfactant mixture during the lamellar-to-hexagonal phase transition have been studied using X-ray diffraction techniques.13 Because of the complex nature of phospholipid membrane/ additive systems, very little theoretical modeling has been attempted in this area. Only recently, theoretical models have been developed to study the partitioning of foreign molecules in phospholipid membranes.12,14 Computer simulation can play an important alternative approach in elucidating the properties of such complex systems. In recent past, there have been several attempts to model membranes and membrane/surfactant systems using simplified models.15-17 Due to the development of accurate force fields,18 and sophisticated simulation methodologies,19 atomic based MD simulations can play a powerful role in elucidating the properties of these systems at a microscopic level and are therefore considered as natural complements to experiments. Over past few years, there have been several reports on MD simulations of pure phospholipid membranes.20-28 However, because of the inherent complexity, there was practically no attempt in atomistic simulation of lipid membranes containing long chain additives, such as surfactants. Only recently, after reporting our work, we came across the MD studies of Schneider and Feller29 on a phospholipid-detergent mixture. In this article, we studied in detail the properties of a membrane/surfactant mixture using all-atom MD simulations. We used a DMPC lipid bilayer as the model membrane and a well-known anionic surfactant SDS, as the additive. Two long simulations (simulation I and simulation II) have been carried out. In simulation I we studied the pure DMPC lipid bilayer in

10.1021/jp010243t CCC: $20.00 © 2001 American Chemical Society Published on Web 05/25/2001

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its liquid cryatalline lamellar phase (LR) at a temperature of 30 °C. In simulation II we studied the lamellar phase of the DMPC/ SDS mixture containing a mol fraction of 6.6% surfactant at the same temperature. We compared in detail the results obtained from the two simulations as well as with available experimental data to understand the effects of surfactants on membranes. We have organized the article as follows. In the next section we discuss the system setup and the simulation details. This will be followed by the results obtained from our studies and their interpretation. In the last section we will summarize the important findings from our study. II. System Setup and Simulation Details To carry out the MD simulation described herein we employed a recently developed molecular dynamics package (PINY-MD)30 using the CHARMM27 all-atom force fields and potential parameters for lipids.18 The TIP3P model31 was employed for water, which is consistent with the chosen lipid force fields. The motions involving the hydrogen atoms were frozen in all simulations since those degrees of freedom are not expected to alter the properties studied and it allowed us to employ a larger time step while integrating the classical equations of motion. Two different simulations were carried out to investigate the effects of the surfactant SDS on a DMPC lipid bilayer. In simulation I, a fully hydrated liquid crystalline lamellar phase (LR) of pure DMPC lipid was studied. This simulation was initiated from a configuration taken from our earlier work.32 The system contained 64 lipid molecules (32 per monolayer) and an aqueous layer separating the lipid headgroups containing 1645 water molecules. This composition corresponds to a fully hydrated DMPC lipid bilayer at 30 °C with water per lipid molecule, nw ) 25.7.33 The system was then equilibrated at constant temperature, T ) 30 °C (303 K), and pressure, P ) 1 atm (NPT), for 1.5 ns. This equilibration period was followed by an NPT production run of 2 ns duration. A well-equilibrated configuration was taken from this simulation to build the mixed DMPC/SDS bilayer system (simulation II). At first, 4 DMPC lipids (2 per layer) were replaced by 4 dodecyl sulfate (DS) chains. The phosphate group positions of the replaced DMPC lipids were substituted by the sulfate headgroups of the DS chains. Then four water molecules in the aqueous layer were randomly selected and replaced by four sodium counterions of the surfactants. Thus the resulting system contained 60 lipids plus 4 SDS and 1641 water molecules. This composition corresponds to a surfactant mole fraction of 6.6%. A short MD run of 20 ps was first performed, keeping the water molecules and the sodium ions fixed. Next, the water molecules and the sodium ions were allowed to move and the system was equilibrated at constant volume and temperature (30 °C) for about 150 ps. The equilibration was further continued for another 1 ns duration at constant temperature (30 °C) and pressure (1 atm). Such a long NPT equilibration was required to get good convergence of energy and the simulation cell dimensions. After equilibration, a 1.9 ns NPT production run was carried out to calculate different properties of the system. All the NPT runs were performed in flexible simulation boxes with orthorhombic angular constraints.19 The simulations utilized the Nose´-Hoover chain thermostat extended system method,19 using separate thermostats for the lipid, surfactant, and water molecules. A recently developed reversible multiple time step algorithm, RESPA,19 allowed us to employ a MD time step of 4 fs. This was achieved using a three-stage force decomposition into intramolecular (torsion/

Figure 1. Time evolution of the interlamellar spacing, d (a), and the area per lipid molecule, A (b), during the last 1.5 ns of the MD runs for the pure lipid (solid line) and the lipid/surfactant mixed system (dashed line).

bend-bond), short-range intermolecular (a 7 Å RESPA cutoff distance) and long-range intermolecular forces.34,35 Electrostatic interactions were calculated by using the particle-mesh Ewald (PME) method.36 The PME and RESPA were combined following the method suggested by Marchi and co-workers.37,38 The minimum image convention39 was employed to calculate the Lennard-Jones interactions and the real-space part of the Ewald sum, using a spherical truncation of 7 and 10 Å, respectively, for the short- and the long-range parts of the force decomposition. “SHAKE/ROLL” and “RATTLE/ROLL” methods19 were implemented to constrain all bonds involving H atoms to their equilibrium values. III. Results and Discussion In this section we first show how our simulation results on pure lipid bilayer system (simulation I) compare with experimental data. This is then followed by detailed analysis of the properties of the mixed lipid/surfactant system (simulation II), and compare the results with those of the pure bilayer systems and available experiments. A. Bilayer Structure. The structure of a bilayer is characterized by two important properties: the interlamellar spacing (d) and the surface area per molecule (A), which are measured experimentally from X-ray diffraction studies. NPT simulations with flexible cell dimensions allow one to calculate these quantities and compare with available X-ray data to verify the accuracy and authenticity of the simulations performed. Time evolution of the interlamellar spacing and the surface area per molecule of the pure and mixed systems over the last 1.5 ns are shown in Figure 1. These quantities fluctuated in both the simulations but did not show any drift during the production runs. The average values computed from the simulations are compared in Table 1 along with X-ray diffraction studies of Petrache et al.33 on the lamellar phage of a pure DMPC lipid under identical conditions. The estimated values of these structural quantities of the pure bilayer system are in excellent agreement (within 1-2%) with X-ray measurements. As it is clear from Table 1, the effect of incorporating SDS at low concentration into the bilayer was to increase the interlamellar d-spacing from 61.5 Å in pure lipid to 65.1 Å in the mixture. This was accompanied by a decrease in the average area (A)

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TABLE 1: Comparison of the Lamellar Spacing (d) and Area Per Lipid (A) for the Pure DMPC Lipid and DMPC/ SDS Mixed System. The Values in Parenthesis Are the Experimental Values for Pure DMPC Lipids33 quantity

pure

mix

d (Å) A (Å2)

61.5 ( 0.39 (62.7) 59.2 ( 0.4 (59.7)

65.1 ( 0.47 58.1 ( 0.41

per molecule. In fact, the average lateral surface area measured for the mixture is the area occupied by one DMPC lipid plus 0.06 surfactants. Thus, it is interesting to note that the addition of the surfactant into the bilayer at present concentration (6.6%) led to a decrease in A. This indicates that the addition of surfactants at a low concentration in membrane tightens the membrane packing and hence likely leading to a more rigid structure. These results are in accordance with recent experimental findings for mixed lipid/surfactant systems containing palmitoyloleoylphosphatidylcholine (POPC) lipid and neutral surfactant C12E4 (tetra(oxyethylene) dodecyl ether), at low surfactant concentrations.9,11 Figure 2 shows snapshots (cross-sectional view perpendicular to the bilayer plane) of the configuration of the mixed DMPC/ SDS system near the beginning and at the end of simulation II. The important feature to note from Figure 2 is the structure of the headgroup regions at the bilayer interface. It is apparent from the snapshots that the nearly flat interface at the beginning has undergone some perturbations during the simulation. Such perturbations of the structure of the interface in the vicinity of the DS chains indicate strong interactons between the surfactant and the lipid headgroups. Another interesting feature is that three of the four dodecyl sulfate surfactant chains (1,2, and 4) seemed to have been embedded slightly inside the bilayer as compared to their initial positions, whereas one surfactant chain remained near its initial position. Next, we will further investigate the interfacial structure and the location of the surfactants in the bilayer. B. Electron Density Profiles and Surfactant Locations. In Figure 3 we have plotted the average electron density profiles (EDP) of different components of the lipids in the pure (a) and the mixed systems (b), along the direction normal to the plane of the bilayer surface (z). The different components of the lipids for which the EDPs are computed separately include, the choline headgroup (N(CH3)3), phosphate group (PO4), and the carbonyl groups of the two chains (C(1)OO and C(2)OO). The total EDPs as well as the contributions from the lipid molecules and water are also computed and plotted for both the systems. The EDPs of the sulfate headgroup (SO4), the dodecyl sulfate chains, and the sodium counterions for the mixed system are displayed in Figure 3c. All the EDPs are computed from the simulation trajectories by placing a Gaussian distribution of electrons on each atomic center with a variance equal to the van der Waals radius, for each configuration, and averaging over all the configurations. The profile for the pure lipid system (Figure 3a) is symmetric, as expected for a well-equilibrated bilayer trajectory, and agrees well with experimental data.33 The total EDP in Figure 3a shows the characteristics typical of a pure lipid bilayer system, with a high density at the interface due to the contributions from the phosphocholine (PC) headgroup and the carbonyl groups of the lipids, a lower density in the bulk aqueous region, and a slight depletion near the hydrocarbon core of the bilayer.21,24,40 The overall distribution of the profiles for the lipid in the mixed system (Figure 3b) is similar to that of the pure system (Figure 3a). However, in the mixed system there is a slight shift of the headgroup and carbonyl group profiles with longer tails toward

the hydrocarbon core region of the bilayer. The location of the surfactants in the mixed system can be discerned from Figure 3c. It is clear that the sulfate headgroups of the surfactant chains are hydrated and are mainly situated slightly deeper into the bilayer, near the carbonyl groups of the lipids (three out of four, see Figure 2b). The distribution of the sodium ions shows that the majority of them remain bound near the bilayer interface. To understand how the distribution of the surfactants evolved during the simulation, in Figure 4 we plot the EDPs of the surfactants for the initial configuration (a), for the configuration at the end of the equilibration (b), and for the final configuration (c). The EDP of the lipid phosphate group is also plotted for comparison. It is clear that during equilibration the distribution of the surfactants changed from their initial distribution. Three DS chains (1,2, and 4 of Figure 2) have moved slightly deeper into the bilayer, whereas one DS chain (3) remained around its initial position. It is interesting to note that the distribution of the sodium ions, which were initially randomly placed in the bulk water (Figure 4a) evolved during the equilibration period. Three out of four sodium ions were found to have moved toward the interface and remained bound to it, whereas only one remained in bulk water (see Figure 2). C. Time Evolution of Surfactant Trajectories. The time evolution of the center of mass positions of the four DS surfactant chains along the bilayer normal (z) are plotted over the entire MD trajectory of simulation II in Figure 5. It is clear from the figure that surfactants 1, 2, and 4 moved deeper into the bilayer during the simulation, whereas surfactant 3 remained about 5 Å above the other surfactants toward the bilayer interface. This is in accordance with the snapshot in Figure 2b and the EDPs in Figure 4c. The projections of the trajectories of the surfactant chains in the plane of the bilayer (xy) showed small confined local dynamics (figure not shown), similar to that of the lipid chains.27,41 In Figure 6 we depict the positions of the four sodium counterions along z. We find that within about 1 ns of the simulation three out of four sodium ions (Figure 6a,b,d) move from the bulk aqueous region toward the bilayer interface and remained bound at the interface during the rest of the simulation period. The fourth sodium ion (shown in Figure 6c) did not bind to the interface and remained free in the aqueous solution. This agrees well with the sodium ion distributions as shown in Figure 4c. D. Deuterium Order Parameters. The orientational order of the lipid and the surfactant chains in the mixture can be studied by calculating the deuterium order parameter, SCD, as

1 SCD ) 2

(1)

where β is the angle between the orientation of the vector along the C-D bond and the normal to the bilayer. A value of 1 for SCD means that the C-D bond vector is parallel to the bilayer normal, a value of -0.5 means that the reference vectors are perpendicular, and 0 suggests random orientation. Experimentally, SCD can be obtained from the residual quadrupole splitting, ∆ν, measured from deuterium magnetic resonance (DMR) measurements42 as

∆ν )

( )

3 e2qQ SCD 4 h

(2)

where e2qQ/h is the deuteron quadrupole splitting constant. Our simulations were carried out with explicit hydrogens on both lipids and surfactants. However, in classical MD simulation there is no difference in equilibrium distributions between hydrogen

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Figure 2. Snapshots of the configuration of the DMPC/SDS mixed system near the beginning (a), and at the end of simulation II. The surfactant molecules and the lipid headgroup P and N atoms are drawn as spheres, while the lipid chain atoms and water molecules are drawn as sticks. The atom coloring scheme is N, blue; P, yellow; S, gray; O, red; C(surfactant), green; C(lipid), black; water molecules, blue; and Na ions, deep blue. The lipid and surfactant H atoms are not drawn. The surfactant DS chains are numbered for reference and the system is replicated once on both sides of the central simulation cell for visual clarity.

or deuterium. Therefore, in our calculations we assume that the configurations of the deuterated chains are identical to those with explicit hydrogen atoms. In Figure 7a we plot the hydrocarbon chain order parameters of DMPC lipids as a function of the carbon atom number (Nc), both in pure and mixed bilayer systems. We also compare our results with the experimental results of Douliez et al.43 in this figure. The agreement between the experimental data and our calculations is excellent. The SCD values from our simulation on pure lipid also agrees well with previous simulations.20,22 It is evident from the figure that there is no significant influence on the order parameters along the lipid chains in the lipid/surfactant mixture at the present concentration of the surfactant. In Figure 7b, we display the order parameters of the dodecyl chains of the surfactant in

the mixed system and compare that with data obtained from a lamellar phase simulation of pure SDS surfactant.44 It is interesting to note that unlike the lipids, the order parameters for the surfactant dodecyl chains have changed significantly in the mixed system. Incorporation of a small amout of surfactant (6.6%) into the lipid bilayer significantly increased the ordering of the surfactant dodecyl chain. Such contrasting effects on the order parameters of the lipids and the surfactant chains in a mixture at low surfactant concentration agree well with recent experimental findings.9 The increase of ordering of the surfactants in the mixture is reflected in the distribution of the hydrocarbon chain lengths as shown in Figure 8a. It is clear that there is a significant increase in the length of the dodecyl chains of the surfactants

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Figure 5. Time evolution of the center of mass positions of the four dodecyl sulfate (DS) surfactant chains along the bilayer normal (z) over the entire MD trajectory of simulation II.

Figure 3. Electron density profiles measured along the bilayer normal, z, for different components of the DMPC lipid in the pure (a), and in the mixed system (b). The total electron density distributions and that arising from water are also shown. The density profiles of the surfactant headgroups (SO4), dodecyl sulfate chains (DS), and the sodium counterions in the mixed system are shown in (c). The distribution for water is added in (c) for clarity.

Figure 6. Time evolution of the z-component of the positions of the four sodium counterions over the entire MD trajectory of simulation II.

Figure 4. Electron density profiles of different components of the surfactant chains and the counterions measured along the bilayer normal, z, for the initial (a), at the end of the equilibration run (b), and at the end of the equilibrium production run (c) in the mixed system (simulation II).

in the mixture, as compared to that in a pure surfactant bilayer.44 The average length of the surfactant dodecyl chain in the mixture was (12.81 ( 0.64) Å, compared to (11.68 ( 0.64) Å for the pure lamellar phase of the surfactant. For comparison, in Figure 8b we show the distance between the first and the twelveth carbon atoms, averaged over both chains, in the DMPC lipid hydrocarbon chains. Consistent with Figure 7, we find that there is no significant effect on the length of the chains due to the presence of the surfactants at present concentration. E. Lipid-Surfactant Interactions and Headgroup Orientations. Since the DS surfactant chains contain negatively charged headgroups, it would be interesting to study how they interact with the zwitterionic phosphocholine (PC) headgroups of the lipids. Such interactions may influence the orientations of the P- f N+ dipole vectors of the PC headgroups and thus

their spatial arrangements in the vicinity of the surfactant chains. To investigate such three-dimensional distributions, we have calculated the local density isosurfaces of the PC headgroup nitrogens as well as the water molecules around the sulfate headgroups of the surfactants. These distributions are illustrated in Figure 9. To generate the isosurfaces, first, the instantaneous positions of the atoms in question were replaced by normalized Gaussian distributions with a width of 0.4 Å, to obtain a smooth effective local density. A surface of the nuclear distribution was then obtained by linear interpolation of the contours generated over the entire MD trajectory. The contours shown enclose approximately 50% of the total density.32,45,46 The density isosurfaces suggest strong interactions between the negatively charged surfactant headgroups and the positively charged ends (N(CH3)3+) of the zwitterionic lipid PC groups. It is interesting to note how the water molecules form closed shells around the nonbonded oxygen atoms of the sulfate headgroups, whereas the N(CH3)3+ end of the lipid PC groups lie in the space between the sulfate oxygen atoms. It is also evident from the distributions, that the lipid N(CH3)3+ groups bound to the surfactant headgroups either directly or bridged by water molecules. To gain further insight, we estimated the number of PC headgroups that are nearest neighbors to the sulfur atoms of the surfactant headgroups, by integrating up to the first minimum (∼6.4 Å) of the corresponding radial distribution function. We observed that on average there are 2 PC groups per surfactant headgroup sulfur atom within this distance. From a similar estimation, we found that there are roughly 4.7 water molecules

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Figure 7. (a) Average lipid hydrocarbon chain deuterium order parameters, SCD, as a function of the position of the carbon atoms, in the pure DMPC LR phase (filled circle), and that in the mixture (filled square). For comparison, the experimental data on the pure DMPC LR phase43 are also shown (solid line). (b) The hydrocarbon chain order parameters of the surfactants in the mixture (solid diamond) are compared with pure LR phase of SDS (solid triangle).

Figure 9. Average density isosurfaces of the lipid headgroup nitrogen atoms (blue), and the water oxygen atoms (green) around a representative sulfate headgroup of the surfactant chain. The surfactant sulfate group is at the center of the figure, where the central sulfur atom is drawn in yellow, while the anionic and the ester oxygen atoms are drawn as red and gray spheres, respectively. The densities are shown from two opposite directions. Figure 8. Distribution of the dodecyl hydrocarbon chain length of the surfactants in pure SDS LR phase (solid line) and that in the mixed system (dotted line) are shown in (a). For comparison, the distance between the first and the twelveth carbon atoms, averaged over both chains, in the DMPC lipid hydrocarbon chains for pure DMPC (solid line), and for the mixture (dotted line) are shown in (b).

per surfactant sulfur atom within a typical nearest neighbor distance of ∼4.6 Å, which is consistent with the existence of water molecules bridged between the surfactant and the lipid headgroups. In Figure 10 we display a representative configuration of a surfactant chain and its neighboring lipids taken from simulation II. The orientation of the PC headgroups of the lipids suggests strong interactions between the N(CH3)3+ end of the PC groups and the sulfate headgroups of the surfactant. The figure also shows an water molecule bridging between the surfactant and lipid headgroups. To further characterize the orientations of the zwitterionic P- f N+ headgroup dipoles in the presence of anionic surfactants, we calculated the orientations of these vectors with

respect to the bilayer normal (z). Figure 11 displays the probability distribution of the angle θ between the P- f N+ vector and the bilayer normal. For the pure lipid, a small fraction of the dipoles are oriented at small angles from the bilayer normal (θ < 30°), and there is a significant population of lipid molecules with the P- f N+ dipole orientations in the range 60° < θ < 90°, i.e., flat with respect to the bilayer surface. A small fraction of the dipoles are also oriented toward the interior of the bilayer (θ > 90°). Such essentially parallel alignment of the PC headgroups with the bilayer surface in the pure lipid is in agreement with experimental findings47 as well as previous simulations.21 It is interesting to note the effects of the surfactants on the distribution of angle θ. The distribution is broader in the presence of surfactants with a decrease in population at small angles (θ < 30°). However, the most striking effect is the increasing population of the lipid molecules with θ > 90°. This arises due to the strong interactions between the negatively charged surfactant headgroups and the PC headgroups

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J. Phys. Chem. B, Vol. 105, No. 25, 2001 5985 compared to the pure membranes were in agreement with experimental findings.9 However, it is important to keep in mind the limitations of the present study. The initial conditions may have some influence on the results, particularly the location of the surfactant headgroups in the bilayer. Additional studies are therefore necessary by varying the initial arrangements of the surfactants, to eliminate possible artifacts, and for drawing statistically more accurate conclusions about partitioning of the surfactants in the bilayer. It would also be interesting to investigate the structure of a DMPC/SDS mixed membrane at higher surfactant concentrations, as well as to study similar effects in related systems. Acknowledgment. This work was supported by generous grants from the National Science Foundation and the Procter & Gamble Company. We thank Steve Morall for useful discussions. References and Notes

Figure 10. A configuration taken from simulation II (mixed system) showing the orientation of a surfactant chain and its two nearest lipid molecules. A water molecule bridged between the surfactant and lipid headgroups is also shown.

Figure 11. The orientation distribution of the lipid P- f N+ headgroup dipoles with respect to the bilayer normal, z, for pure DMPC lipids in LR phase (solid line) and that in the mixture (dashed line).

of the lipids, particularly those lipids which come in close contact with the surfactant chains (see Figure 10). Such interactions cause the P- f N+ dipole vector to reorient toward the interior of the bilayer. IV. Conclusions Simulations of a pure DMPC lipid membrane and a mixed membrane containing low concentration (6.6%) of an anionic surfactant, SDS were carried out. We investigated, in detail, (i) the location of the surfactants in the membrane, (ii) their interactions with the lipid molecules, and (iii) the effects of the surfactants on the overall structure of the membrane and the orientation of the lipid molecules. We compared the results with pure lipid and surfactant membrane simulations and available experimental data. It was found that there is a decrease in the average surface area per lipid (A), coupled with an increase in the lamellar d-spacing in the mixed system. We observed that the ionic surfactant headgroups strongly interact with the zwitterionic PC headgroups of the lipids and prefer to locate slightly deeper into the bilayer at the present concentration. Such strong interactions led to a change in orientations of the P- f N+ dipole of the PC headgroups by pointing more toward the bilayer interior. The effects on the hydrocarbon chain order parameters for both the lipids and surfactants in the mixture

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