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Department of Chemical Engineering, University of Amsterdam, Amsterdam, The Netherlands
Correspondence: Address reprint requests to Berend Smit, Professor of Computational Chemistry, University of Amsterdam, Dept. of Chemical Engineering, Nieuwe Achtergracht 166, Amsterdam 1018WV, The Netherlands. Tel.: 31-20-525-5067. E-mail: b.smit{at}science.uva.nl.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTS AND DISCUSSIONCONCLUDING REMARKSACKNOWLEDGEMENTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTS AND DISCUSSIONCONCLUDING REMARKSACKNOWLEDGEMENTSREFERENCES |
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). This is an extreme example of the effect alcohol can have on the structure of a membrane. In an ordinary membrane the hydrophobic thickness is approximately twice the length of the hydrophobic tails of a phospholipid, in the interdigitated phase the hydrophobic thickness is reduced to the sum of the length of the hydrophobic tails of a single phospholipid and the alcohol. Understanding these induced structural changes is therefore not only of fundamental interest but might also give us a better understanding of the functioning of cell membranes.
Various factors have been identified to induce interdigitation (Slater and Huang, 1988). Besides adding small amphiphilic molecules, like anesthetics (Hata et al., 2000) or alcohol, other factors are changes in the environment, like in the changes in the hydrostatic pressure or in the pH of the solution (Furuike et al., 1999) or changes in the molecular structure of the lipid—for example by introducing an ester-linkage in the headgroup of the phospholipids (Lewis et al., 2001; Winter et al., 2001). In this work we focus on the effect of adding small amphiphilic molecules. Short-chain alcohols (methanol through heptanol) are known to induce interdigitation (Rowe, 1983; McIntosh et al., 1983, 2001; Adachi et al., 1995; Simon and McIntosh, 1984). In the first instance it was found that these alcohols have two different effects on the transition from the low temperature gel phase to the high temperature fluid phase, dependent on concentration (Rowe, 1983). At low concentrations of alcohol, the main transition temperature shifts to a lower temperature, whereas at high concentrations this transition temperature shifts to a higher temperature compared to a pure lipid bilayer. This effect was called the "biphasic effect." Subsequently, Simon and McIntosh (1984) observed in their study the formation of the interdigitated phase at high concentrations of alcohol, which explains the biphasic effect. At low concentrations of alcohol the disorder of the lipid tails increases, leading to a lower transition temperature. At high concentrations the more tightly packed interdigitated phase is formed, resulting in an increase of the transition temperature.
Interdigitation can be understood if we consider the location of the alcohol molecules in the bilayer. The alcohol molecules replace the interfacial water molecules: the OH group binds to the phosphate group of the lipid headgroup and the hydrophobic tail sticks into the hydrophobic core of the bilayer. Since the OH-group binds to the phosphate moiety of the lipid headgroup (Chiou et al., 1992), lateral space is created between the headgroups, leading to voids in the hydrophobic core. These voids are energetically unfavorable and thus the system will minimize the energy by the formation of an interdigitated phase. By interdigitation the system gains energy due to the stronger van der Waals interaction in the interdigitated phase compared to the noninterdigitated phase (Simon and McIntosh, 1984; Ohki et al., 1990; Feller et al., 2002) and due to an entropy gain by replacing the highly ordered water molecules at the interface by alcohol molecules (Simon and McIntosh, 1984; Rowe and Campion, 1994; McIntosh et al., 2001). Since the tail ends of the alcohol molecules shield the tail ends of the lipids from the interfacial water, the energy cost in the formation of the interdigitated phase is minimized.
Phase diagrams of various lipids and alcohols are constructed (Nambi et al., 1988; Ohki et al., 1990; Vierl et al., 1994; Löbbecke and Cevc, 1995; see also this article, Fig. 1, for a schematic sketch of an experimental phase diagram). At high temperatures the fluid L
phase is stable. At low temperatures, various structures are found, dependent on temperature and alcohol concentration. At low concentrations, we find the transition from the highly ordered subgel or Lc phase via the gel phase Lß' to the rippled phase Pß'. In all these phases the tails have a tilt with respect to the bilayer normal. At high concentrations of alcohol the rippled phase disappears, and the interdigitated phase LßI is formed, in which the tails do not show a tilt. In between these extremes a coexistence region is observed between the rippled phase or the gel phase and the interdigitated phase.
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Pß' than on the main transition Pß' L. At low concentrations of alcohol this transition is shifted to lower temperatures and after the critical concentration 
(the concentration at which interdigitation is complete) the rippled phase disappears (Veiro et al., 1987). Questions in the formation of the interdigitated phase which are still not (completely) solved are the distribution of the alcohols in the bilayer, the exact molecular structure of the alcohol-induced interdigitated phase, and the concentration of alcohol in the lipid bilayer at which interdigitation occurs.
These experimental uncertainties motivated us to use molecular simulation to study the effect of alcohol. State-of-the-art molecular dynamics simulations give detailed structural information on the position of alcohol molecules in a lipid bilayer (Koubi et al., 2003; Tang and Xu, 2002), but are too time-consuming to observe structural changes in the membrane. As an alternative we use a hierarchical approach in which realistic all-atom simulations are used to determine the effective interaction parameters of a mesoscopic model. At this mesoscopic level simulations are 4–5 orders-of-magnitude more efficient (Groot and Rabone, 2001; Shelley et al., 2001), allowing us to compute complete phase diagrams. Whereas previous mesoscopic simulations were aimed at qualitative insights, here we demonstrate that such a hierarchical mesoscopic model yields semiquantitative predictions of the structure of a membrane. In Kranenburg et al. (2003a,b) we showed that a bilayer, consisting of monotail lipids, can spontaneously form the interdigitated LßI phase. Interdigitation does not occur in bilayers of symmetrical chain phospholipids, but has to be induced by attaching an additional group to the head of a double tail lipid. To understand the molecular mechanisms underlying the formation of the interdigitated phase, we extend our mesoscopic model to study the effect of alcohol on the structure of a membrane. Experimentally it is very difficult to measure the concentration of alcohol in the membrane directly. Thus, the main advantage of our mesoscopic approach aimed at such a system is that we can directly determine the mole fraction of alcohol molecules needed to induce a fully interdigitated phase.
Model and computational details
In our lipid-water-alcohol model, we distinguish three types of particles, w, h, and t, to mimic water and the head- and tail-atoms of a lipid, respectively. The hydrophilic and hydrophobic particles interact via a soft-repulsion model commonly used in dissipative particle dynamics (DPD) (Groot and Warren, 1997; Frenkel and Smit, 2002). In a DPD simulation a particle represents the center of mass of a cluster of atoms. The total force on such a particle consists of dissipative, random, and conservative forces. The dissipative and random forces are chosen such that a proper canonical distribution is sampled (Frenkel and Smit, 2002). For the conservative force we use the conventional soft-repulsive interaction, given by
 | (1) |
).
We consider lipids consisting of a headgroup with three hydrophilic segments and two tails with variable length (see Fig. 2), which mimics phospholipid distearoyl-phosphatidylcholine (DSPC). We assume that a DPD particle occupies a volume of 90 Å3, which results in a mapping in which DSPC is represented by three hydrophilic head beads and two 7-bead tails (h3(t7)2). For a correct description of the experimental chain length dependence of the area per lipid, it is essential to properly reproduce the conformations of the lipid. Molecular dynamics simulations of a single phospholipid in water using a realistic all-atom representation are used to generate configurations of the lipid, which were subsequently used to optimize the intramolecular interactions (bond-bending and bond-vibration) of the DPD model (Kranenburg et al., 2004b). We used similar parameters to Groot and Warren (1997) for the soft-repulsions in the conservative DPD interactions (aww = att = 25, aht = awt = 80, ahh = 35, and ahw = 15); the intramolecular interactions include a bond-bending potential,
 | (2) |
= 6 and 0 = 180° for the tails and between the tails and the headgroup k = 6 and 0 = 90°. Two consecutive beads are connected by harmonic springs,
 | (3) |
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= 6.0 and 0 = 180° was also applied between three consecutive beads of these alcohols.
A biological membrane is not subject to external constraints and therefore adopts a configuration which is tensionless. Lipowski and co-workers (Goetz and Lipowsky, 1998; Goetz et al., 1999) emphasize the importance of simulating at exactly the area for which the interfacial tension is zero and determine this area iteratively. We use a different approach in which we mimic the experiment by simulating an ensemble in which we impose the interfacial tension. After a randomly selected number of DPD steps we perform a Monte Carlo move in which we change the area of our bilayer in such a way that the total volume of the system remains constant. This move is accepted with a probability (Venturoli and Smit, 1999)
 | (4) |
the interfacial tension, A the area of the bilayer, and ß = 1/kBT. To obtain the tensionless state, the bilayer is set to zero to ensure that the membrane adopts the equilibrium area per lipid (Kranenburg et al., 2003a,b). The importance of this method is that it allows us to observe directly phase transitions in which the area per lipid changes.
The system was initialized by placing 200 phospholipids and 20–200 model alcohols randomly in a simulation box. 3200–6700 water particles were added to ensure that a bilayer does not have any interaction with its periodic image. At a temperature of T* = 1.0 a bilayer was formed, using DPD steps only. After the formation of the bilayer we allowed the bilayer to adopt a tensionless configuration by applying both DPD and Monte Carlo, in which the area of the bilayer is changed. We then slowly cooled the system from T* = 1.0 to T* = 0.1. A typical simulation required 100,000 cycles of which 20,000 cycles were needed for equilibration. Per cycle it is chosen with a probability of 70% whether to perform 50 DPD time steps or to make an attempt to change the area of the box. This equilibration time was set by monitoring the area per lipid at low temperatures. It takes relatively long before this property reaches a new equilibrium value once the temperature or the number of alcohols was changed. Since the bilayers are formed by self-assembly the leaflets of the bilayer can end up with a very different number of alcohols or lipids. If this difference was >10% we reinitialized the system until a membrane was obtained with a more equal distribution of alcohols and lipids over the two leaflets. To test the reproducibility of our simulations, we repeated the self-assembly from different initial condition and by heating of the system and subsequent cooling. Within the statistical uncertainty, these simulations with different initial conditions gave identical results. More details on the simulations can be found in Venturoli and Smit (1999) and Kranenburg et al. (2003b).
In our simulations we use the conventional reduced units, i.e., using rc as the unit of length and a = 1 as the unit of energy. For some properties it is interesting to make a direct comparison with experiments. The conversion factor for the length scale from the assumption is that a DPD particle occupies a volume of 90 Å3. For the temperature scale the conversion is less straightforward. The coarse-graining procedure of Groot can be used at any temperature; that is, if we are interested at higher temperature we can again match the compressibility and Flory-Huggins solubility parameters at the temperature of interest. This leads to temperature-dependent parameters that make the interpretation of the results more difficult. To avoid these difficulties we have used the experimental phase transition temperatures (without alcohol) to relate the DPD energy and temperature scales to the experimental system. With these parameters our simulations predict an area per surfactant of 69 Å2 of the membrane in the L or fluid phase, independent of the chain length. This is in good agreement with the experimental values which are in the range 58–72 Å2. For the area per lipid in the gel phase we find Al = 46.6 Å2, whereas the experimental value is Al = 47.2 Å2 (Tristram-Nagle et al., 2002).
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RESULTS AND DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTS AND DISCUSSIONCONCLUDING REMARKSACKNOWLEDGEMENTSREFERENCES |
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Phase behavior
In our simulations we observe that at high temperatures the bilayer is in the L phase. With decreasing temperatures, different phases are formed, depending on the concentration of alcohol in the bilayer (Nalc). In Fig. 3 snapshots are shown of the various low temperature phases of the lipid h3(t7)2 at three concentrations of the model alcohol ht2. At low alcohol concentrations (Fig. 3 a), we find the noninterdigitated (sub)gel phase Lc as the low temperature phase. The alcohols are homogeneously distributed at the interface, but the concentration is too low to induce interdigitation. Experimentally, it is observed that in this region of the phase diagram the tilt angle of the lipid tails increases to a maximum of 50° (Nagel et al., 1992; Vierl et al., 1994) to compensate the additional space between the tails. We do not observe an increase in the tilt angle: the average tilt angle is constant (26°) with increasing number of alcohols from 0 to 30. In the L phase there is considerable lateral diffusion. In the gel phases the lateral diffusion is far less. At high alcohol concentrations the interdigitated gel LßI is formed, in which the lipid tails do not have a tilt with respect to the bilayer normal. The tails of the lipids of one monolayer are fully interpenetrated into the opposing layer and the tail ends are facing the tail end of the alcohol (see Fig. 3 c). In between these two extremes we find that there is coexistence between the interdigitated and noninterdigitated phases (Fig. 3 b). The alcohols are mainly located in the interdigitated part of the bilayer. To check the consistency of the results we repeated some simulations by heating the systems. We found that for these systems the equilibration from an interdigitated phase to the L phase took longer than the reverse path. The transition occurred at the same temperature, and no hysteresis was observed.
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phase. The low-temperature phase is, dependent on alcohol concentration, the Lß phase, the LßI phase, or a coexistence between these two phases. We observe that the length of the alcohol molecule had little influence on the LßI L transition, but the shorter the alcohol, the more stable the LßI phase. At lower temperatures the concentration of alcohol required to obtain the fully interdigitated phase increases, which is in agreement with the experimental observations of Nambi et al. (1988).
We also observe the biphasic effect on the main transition from the gel phases (Lß', Lß' + Lß', or LßI) to the fluid L phase in our simulations: at a low mole fraction alcohol, the transition temperature shifts to a lower temperature. Increasing the number of alcohols leads to an increasing melting temperature. If interdigitation is complete, the melting temperature is almost constant. Comparing the different chain lengths of the alcohols shows that the transition from the fully interdigitated phase to the fluid phase slightly decreases with increasing chain length. Experimentally, this transition temperature is difficult to locate, since large hysteresis of this main transition was noted (Rosser et al., 1999; Tenchov et al., 1989; Rowe, 1985; Vierl et al., 1994). In a pure lipid bilayer, we observed the rippled phase Pß' (Kranenburg et al., 2004b). Much larger systems are required than that studied in this work, to study the affect of alcohol in the stability of this phase. Therefore, we did not investigate this part of the phase diagram in detail.
Experimentally, a coexistence region between the noninterdigitated gel phase or the rippled phase and the interdigitated LßI is observed, if the concentration of alcohol is increased at a constant temperature (Vierl et al., 1994; Löbbecke and Cevc, 1995; Ohki et al., 1990). Nagel et al. (1992) observed the coexistence of the Lß' and LßI phases in a DPPC/ethanol system. Mou et al. (1994) assume that this coexistence can occur due to an inhomogeneous distribution of the alcohol in the bilayer. If the ethanol molecules could aggregate to certain regions, the local ethanol concentration in certain areas is increased to above the critical value, so that a mosaic pattern of interdigitation can be formed. Even at very low alcohol concentrations, very narrow domains of the interdigitated phase are formed (Mou et al., 1994). Our simulations confirm that the alcohol molecules are indeed inhomogeneously distributed in the lipid bilayer. We find that, at a constant temperature, in the observed coexistence region the mole fraction of alcohols in the interdigitated phase is constant. The mole fraction of alcohols in the noninterdigitated part increases with increasing number of alcohols. This explains the experimentally observed coexistence region: at a fixed temperature, the part of the bilayer that is interdigitated increases and the noninterdigitated part decreases with increasing alcohol concentration.
All experimental investigations study the interdigitation as a function of the concentration of alcohol in the bulk. The critical concentration at which interdigitation is complete () decreases with increasing length of the alcohol (Löbbecke and Cevc, 1995; Rowe, 1983; Rowe and Campion, 1994). However, the concentration in bulk is not necessarily equal to the concentration of alcohol in the lipid bilayer. To relate the concentration of alcohol in bulk with the concentration of alcohol in the bilayer, the membrane buffer or partition coefficient Kp is often used. Kp describes the ratio of the solute concentration in the bulk water and in the lipid bilayer and its value increases with increasing chain length of the alcohol, caused by the hydrophobic effect (Rowe et al., 1998; Rowe and Campion, 1994; Connors, 1987). Experimentally, the distribution of alcohol between water and lipid vesicles can be determined and it is assumed that this distribution is equal to Kp in a lipid bilayer. There is little consensus in the literature whether this procedure yields a reliable estimate of the alcohol concentration in the bilayer (Simon et al., 1977; Trandum and Westh, 2000; Trandum et al., 1999; Westh and Trandum, 1999; Westh et al., 2001). For example, it is assumed that the structure of the vesicle bilayer is representative for the bilayer phases; however, depending on the temperature, an alcohol molecule has a different affinity for the different phases in the order LßI (or L) > L (or LßI) > Pß' > Lß' (Rowe and Campion, 1994; Nambi et al., 1988; Löbbecke and Cevc, 1995; Zhang and Rowe, 1992), which is not taken into account.
Using computer simulations, we impose a number of alcohols in the bilayer. Comparing the phase diagrams of h3(t7)2 with three different alcohols shows that there is little difference between the concentration of alcohols of ht and ht2 needed to obtain the fully interdigitated phase LßI, but that the concentration of the alcohol ht3 is higher. We observe that for the alcohols ht2 and ht3 all alcohols are at the interface, independent of the number of alcohols. These results are in agreement with the conclusions of Rowe and Campion (1994). They found, using the bilayer partition coefficient, that for pentanol the concentration of alcohol in the bilayer is almost constant, but that for hexanol and heptanol, higher concentrations are needed. For the alcohol ht we observe that at the highest number used, some alcohols diffuse into the bulk water, forming micelles. This is consistent with the experimentally observed values of Kp, that indicates that adsorption of the alcohols at the interface is due to the hydrophobic effect.
Structure of the interdigitated phase
The structure of the interdigitated phase is still not well known. Adachi et al. (1995) proposed a model in which the terminal methyl group of the alcohol faces a terminal methyl group of a lipid chain (see Fig. 5). The assumption is based on the observation that the membrane thickness increases by 
0.08 nm per one methylene unit in both the alcohol molecules and the phospholipids. This distance of 0.1 nm is the length of one CH2-unit in the stretched chain of an alkane (Pauling, 1960). The small difference might be due to fluctuations in the hydrophobic chains. Furthermore, Adachi et al. (1995) show that two alcohol molecules can occupy a volume surrounded by the PC headgroups of one layer. From this it follows that the number of alcohol molecules should be twice as high as the number of lipids in the bilayer. Given the concentrations in the experimental procedure to determine the concentration at the interface, it is of interest to use simulations to investigate this interpretation of the experimental data in detail.
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for which the DPD parameters are optimized. Our model reproduces the chain length dependence of the L phase better. We observe that the slope of the best fits of these two data sets are almost the same, which is in agreement with the experimentally obtained results (Adachi et al., 1995; Adachi, 2000). Based on this dependence of the hydrophobic thickness on the total number of beads, Adachi et al. (1995) proposed the model depicted in Fig. 5, in which the alcohol/lipid ratio equals 2:1. However, our simulations show the same dependence, but at much lower concentrations. In Fig. 6, only the results for the ratio Nalc/Nlipid = 1:1 are given, but the same graph is obtained for lower alcohol concentrations, provided that the concentration is sufficient to induce the fully interdigitated LßI phase.
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. This can be explained by taking into account an energy balance between the noninterdigitated and interdigitated phase. By the incorporation of alcohols at the membrane interface, voids are created in the hydrophobic core, which are energetically unfavorable (see Fig. 7, left image). The more alcohol, the higher the energy of the membrane. In the interdigitated phase the tail ends of the lipid are in contact with the interfacial water (see Fig. 7, right image). Adding alcohol reduces these energetically unfavorable interactions and hence increasing the alcohol concentration decreases the energy of the membrane. Clearly at the 2:1 ratio, the energy of the interdigitated phase will be lowest, but at much lower alcohol concentrations the energy can already be lower compared to the Lß' phase.
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1:2, instead of 2:1 as proposed by Adachi et al. (1995). We also observed that the hydrophobic tail of the alcohol has rotationally more freedom than the lipid tails, meaning that more than one phospholipid tail can be shielded from water by one alcohol molecule. With this model, we can also understand the dependence on alcohol length of the stability of the LßI phase. The longer the alcohol, the smaller the voids in the alcohol-saturated Lß' phase (see Fig. 8). The addition of a longer alcohol molecule perturbs the bilayer in the Lß' phase to a lesser extent compared to a smaller one. For the interdigitated phase, however, Fig. 6 shows that a longer alcohol results in a thicker hydrophobic core. A void in this phase exposes, therefore, more hydrophobic groups of the lipids to the water phase compared to the shorter alcohols. These combined effects explain why the longer the tail length of the alcohol, the more alcohol is needed to stabilize the LßI phase. Similarly, we can understand why a higher concentration of alcohol is needed before the Lc phase is destabilized by a longer alcohol.
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; Rowe and Cutrera, 1990; Nambi et al., 1988) and a coexistence region between an interdigitated and noninterdigitated phase was observed for most lipids (Vierl et al., 1994). There is no consensus in the literature whether a coexistence exists for the longest lipids. We performed simulations on bilayers consisting of h3(t6)2 and h3(t8)2 lipids, with alcohols varying in length from 1 to 3 beads in the tail. The obtained phase diagrams are similar to those depicted in Fig. 4. We find coexistence regions for each lipid-alcohol combination, which is in agreement with the results of Vierl et al. (1994). The size of the coexistence region decreases with increasing tail length of the phospholipid, because the concentration of alcohol to obtain the fully interdigitated phase decreases, whereas the alcohol concentration needed to destabilize the Lc and the Lß' phase is independent of the alcohol concentration. The energy cost of exposing the tail ends to water becomes less important with increasing tail length, and therefore, the interdigitated phase is stabilized.
Longer chain alcohols
Experiments show that interdigitation only occurs in mixtures of lipids with alcohols up to heptanol. From octanol, therefore, longer chain lengths of the alcohol do not induce the interdigitated phase. The explanation of these observations is that the energy cost of creating lateral space in the headgroup region, leading to the formation of voids in the hydrophobic core, is balanced by the increased disorder in the lower part of the tails (Löbbecke and Cevc, 1995; McIntosh et al., 2001; Huang and McIntosh, 1997). We performed some simulations on the lipid h3(t8)2 with the alcohols ht to ht4. For alcohols ht to ht3, we find similar phase diagrams to those shown in Fig. 4; increasing the length of the alcohol requires a higher alcohol concentration to stabilize the interdigitated phase. For ht4, however, we do not find an interdigitated phase, but the structure shown in Fig. 9. In this structure we observe the coexistence of the Lc (or Lß') phase with a new phase of which the hydrophobic thickness is approximately twice the hydrophobic length of the alcohol. In Kranenburg et al. (2003a,b), we have shown that single-tail lipids, which our model alcohol molecules resemble, can form a stable bilayer for sufficiently long tails. For these long-chain alcohols, the interdigitated phase has to compete with an alcohol-rich Lß or L phase.
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). A phase separation, like we find in our simulations, is not observed. At this point, it is important to note that we did not optimize the parameters of our model to reproduce the properties of an alcohol: we used the same head and tail interactions as for our lipids and for the longer chain lengths these molecules resemble the single-tail lipids that are studied in Kranenburg et al. (2003a,b). In the literature, it is known that a mixture of two lipids does phase-separate in a lipid bilayer. The mixing of, for instance, lipids with different tail lengths, leads to the formation of domains with the shorter lipid and domains containing the longer lipid (Risbo et al., 1995; Jorgensen et al., 1993). Since our model alcohols with tail lengths 
4 self-assemble in a bilayer, our observations agree with the observations of a mixture of two bilayer lipids. Since we only investigated a small system, we cannot distinguish the formation of domains from an ordinary phase transition; it would be interesting to investigate this phase separation with larger systems. |
CONCLUDING REMARKS |
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TOPABSTRACTINTRODUCTIONRESULTS AND DISCUSSIONCONCLUDING REMARKSACKNOWLEDGEMENTSREFERENCES |
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The main cause of the formation of the interdigitated LßI phase is an increase in the lateral area between the lipid headgroups. Due to this increase, voids are created in the hydrophobic core of the lipid bilayer. Since voids in the bilayer core are energetically unfavorable, the Lß' or Lc phases are destabilized. These voids can be filled by molecules of the opposite monolayer. The bilayer will adapt an interdigitated configuration, in which the lipid tails of one monolayer interpenetrate the opposing layer. Increasing the repulsion between the lipid headgroups, increasing the lipid tail length, or decreasing the tail length of the alcohol, leads to an increase of the volume of these voids. The larger this volume, the more stable the interdigitated phase.
At low concentrations of alcohol the noninterdigitated gel phase is formed and at high concentrations the fully interdigitated phase is the stable phase. In between we find a coexistence region between the interdigitated and noninterdigitated phase, in which the alcohol molecules are inhomogeneously distributed between these two phases. We show that the interdigitated phase is formed at a lipid/alcohol ratio of 2:1, which is significantly lower than was proposed in the literature. At this ratio the formation of the interdigitated phase is energetically more favorable than a noninterdigitated structure with (energetically unfavorable) voids in the hydrophobic core, even if some of the lipid tail ends are exposed to the interfacial water.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTINTRODUCTIONRESULTS AND DISCUSSIONCONCLUDING REMARKSACKNOWLEDGEMENTSREFERENCES |
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Submitted on April 27, 2004; accepted for publication June 7, 2004.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONRESULTS AND DISCUSSIONCONCLUDING REMARKSACKNOWLEDGEMENTSREFERENCES |
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