Article pubs.acs.org/JPCB
Influence of Alcohols on the Lateral Diffusion in Phospholipid Membranes Simona Rifici,† Giovanna D’Angelo,*,† Cristina Crupi,† Caterina Branca,† Valeria Conti Nibali,‡ Carmelo Corsaro,† and Ulderico Wanderlingh† †
Dipartimento di Fisica e Scienze della Terra, Università degli Studi di Messina, 98166 Messina, Italy Institute for Physical Chemistry II, Ruhr-University Bochum, 44801 Bochum, Germany
‡
ABSTRACT: The effects of hexanol and octanol on the lateral mobility of 1,2-dimyristoyl-sn-glycero-3-phosphatidylcholine (DMPC) bilayer are investigated by means of pulsed-gradient stimulated-echo NMR spectroscopy. Three distinct diffusions are identified for the DMPC/alcohol systems. They are ascribed to the water, the alcohol, and the lipid. We find that the presence of alcohols promotes the lipid diffusion process both in the liquid and in the interdigitated phases. Furthermore, using the Arrhenius approach, the activation energies are calculated. An explanation in terms of a free volume model, that takes into account also the observed increase of the activation energy in both phases, is proposed. The results obtained here are compared with those presented in our previous work on 1,2-palmitoyl-snglycero-3-phosphocholine (DPPC) in order to examine the dependence of the lipid translational diffusion process upon the membrane acyl chain length. A peculiar influence of alcohols on different membranes is found.
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INTRODUCTION
increase of the chain length until it exceeds about 10−12 carbon atoms, where anesthetic action suddenly disappears. Previous studies suggest that alcohol binds just underneath the charged headgroup of surface lipid, displacing some of the surrounding water. Hydrogen bonds are formed between the polar hydroxyl group of alcohols and the polar lipid atoms at the water/lipid interface,11−14 and the hydrophobic tail of alcohols sticks into the hydrophobic core of the bilayer.15 Because of this location and since alcohols are not as long as the phospholipid hydrocarbon chains, lateral space between the headgroups and voids between chains in the bilayer interior are created. In order to minimize the energy of formation of these voids, the lipid chains interpenetrate, extending partially into the opposite leaflet. This peculiar molecular arrangement, together with the possible decrease of the lipid order, gives rise to a variety of changes, such as a decrease in the hydrophobic thickness,9,16 and an increase of lateral pressure,17 polar head area,9,18 and lipid lateral mobility.19 All these changes strongly influence protein distribution and expression,20 and result in an extensive metabolic alteration in the lipid polar headgroup composition.21,22 Besides these changes, a different phase behavior is generally observed in lipid bilayers under the effect of alcohols. In particular, they cause melting-point (Tm) depression from the gel Lβ to the fluid Lα phase of phospholipid membranes.23 The longer the alcohol chain, the more Tm decreases. Moreover, an interdigitated bilayer phase, LβI,
Lipid bilayers are the main molecular constituents of biological membranes. They are composed of lipids of varying acyl chain length. In Escherichia coli, for instance, the cytoplasmic membrane has lipid tails ranging from C12 to C20 with varying degrees of saturation.1 The polar headgroups mainly contain phosphatidylethanolamine, phosphatidylglycerol, phosphatidylcholine, sphingolipids, and steroid-type molecules like cholesterol. Lipid bilayer stability is assured by the interfacial tension due to hydrophobic effects, the steric repulsion between aliphatic chains, electrostatic interactions with the zwitterionic headgroups, dipole−dipole interactions, and the attractive forces due to the van der Waals interactions and the hydrogen bonding in the headgroup region. As a consequence, the physical and structural properties, phase and phasetransition properties, and dynamics of a lipid bilayer can be easily and strongly modified by changing the degree of hydration, by changing the acyl chain lengths of the lipids inside the membrane, or by the introduction of small amphiphilic molecules, such as short-chain alcohols, at the membrane surfaces.2−5 Although alcohols have been extensively studied,6−9 their mechanism of action is a hot topic. In particular, the study of the molecular interaction of short-chain alcohols with biological membranes is getting great value because of its role in drug delivery, alcohol toxicity, and anesthesia. Just to mention an example, the biological efficacy of alcohols of various chain lengths often displays an unexplained cutoff effect.10 For the shorter alcohols, their potency increases according to the © XXXX American Chemical Society
Received: November 23, 2015 Revised: January 25, 2016
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Figure 1. Diffusion decay in fully hydrated (a) DMPC bilayer and (b) DMPC/octanol at the temperatures indicated. DSC-heating curves: (c) pure DMPC, (d) DMPC/hexanol, and (e) DMPC/octanol.
appears below the main transition temperature24 and this phase is favored for longer alcohol chains.25 The threshold alcohol concentration at which the interdigitated state becomes the more energetically favorable is equal to 2:1 alcohol/lipid ratio, as it has been observed for the DPPC/n-butanol system.26 A detailed analysis of the lateral diffusion of phospholipid bilayers can lead to insight into understanding the role of alcohols in permeation and in some main activities of the membrane. Actually, different membrane parameters can be controlled by the lateral motion of lipids, such as the microviscosity of both the headgroup region and the upper hydrophobic part of the phospholipids.27 Although it is clear that many factors such as pressure, temperature, hydration, amount of cholesterol, proteins, or alcohols may have strong influences on lipid dynamics, an exact knowledge of the basic principles of lipid lateral diffusion is still far from being complete. Various methods can be used to study membrane diffusion and each of them is sensitive to different time scales; as a consequence, diffusion coefficients can vary over a wide range. Typical values of 4 × 10−8 cm2/s for the diffusion coefficient, D, are obtained in fluid lipid membranes from fluorescence correlation spectroscopy on the millisecond time scale, whereas neutron scattering experiments, operating in the picosecond range, produce significantly higher values from about 1 × 10−7−2 × 10−4 cm2/s.28−30 The difference in these values originates from different modes of diffusion. On short time scales the diffusion is generally assumed to be dominated by confined motion in a local free volume defined by nearest-
neighbor lipids, whereas diffusion on the millisecond time scale rather resembles Brownian motion in a viscous fluid.31 Pulsed field gradient magic-angle spinning (PFG-MAS) NMR spectroscopy and pulsed gradient stimulated-echo (PGSTE) NMR spectroscopy are also extremely useful and very attractive techniques to study the lateral diffusion process of different molecules included in a lipid membrane, providing information up to some millimeter distances. PFG-MAS NMR spectroscopy presents a lot of advantages in the study of the diffusion constants, such as the high resolution of the resonances obtained using a small amount of sample and the homogeneity of the magnetic field. Nevertheless, because of the fast MAS, the sample is pressed against the spherical walls of the rotor and it tends to dehydrate with an undesirable influence on the diffusion process.32 This situation can be avoided performing a (PGSTE) NMR measurement on supported multibilayers. In the present work (PGSTE) NMR spectroscopy revealed to be particularly suited to study the effects of two medium chain alcohols, hexanol and octanol, on the lateral mobility of 1,2-dimyristoyl-sn-glycero-3-phosphatidylcholine (DMPC). DMPC consists of a phosphatidylcholine headgroup and two saturated 14-membered hydrocarbon chains. The numbers “1”, “2”, and “3” refer to the positions of the fatty acids and the phosphatidylcholine group on the glycerol. In this case the two identical fatty acids are placed next to each other and the phosphatidylcholine group is placed at the end of the glycerol. The nitrogen is positively charged, whereas one of the oxygens of the phosphate is negatively charged. The results here obtained are compared with those presented in our previous work on 1,2-palmitoyl-sn-glycero-3-phosphoB
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∼10−11−10−10 m2/s. A similar behavior is found also in the DMPC/hexanol system (not shown). In Figure 2 the diffusion
choline (DPPC)8 in an alcoholic environment. DPPC consists of a phosphatidylcholine headgroup, like DMPC, and differs from it just in the acyl chain length (two saturated 16membered hydrocarbon chains). This comparison allowed us to study the dependence of the lipid translational diffusion upon the acyl chain length of the lipid membrane and to reveal the peculiar influence of alcohols on membranes with different acyl chain lengths. Furthermore, the phase behavior of DMPC/alcohol systems was analyzed by means of differential scanning calorimetry (DSC) measurements.
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EXPERIMENTAL DETAILS 1,2-Dimyristoyl-sn-glycero-3-phosphatidylcholine (DMPC) (C36H72NO8P, molecular weight 677.933 g, C 63.78%, H 10.70%, N 2.07%, O 18.88%, P 4.57%, transition temperature 296 K) was bought from Avanti Lipids (Alabaster, AL, USA); hexanol and octanol were bought from Sigma. All chemicals were used without further purification. Mechanically aligned bilayers for PGSTE-NMR experiments were prepared following the procedure described elsewhere.8 The molar concentration of lipid:alcohol studied was 1:2. Unoriented large multilamellar vesicles (MLVs) for the DSC measurements were prepared by adding alcohols and water to lipid in the desired proportions (molar ratio of lipid:alcohol:water of 1:2:10). 1 H NMR spectra of the fully hydrated alcohol−DMPC systems in the temperature range 263−325 K were recorded on a 700 MHz Bruker Avance NMR spectrometer. All measurements were carried out in fully hydrated condition.19 DSC scans were carried out with a PerkinElmer-Pyris 1 DSC instrument at a 1 K/min heating rate from 270 to 300 K. Further details on the sample preparation and measurement techniques can be found elsewhere.8
Figure 2. Self-diffusion coefficients as a function of T: (a) DW (filled squares) and DL (empty squares) in pure DMPC; (b) DW (filled diamonds), DA (crossed diamonds), and DL (empty diamonds) in DMPC/hexanol; and (c) DW (filled triangles), DA (crossed triangles), and DL (empty triangles) in DMPC/octanol. Arrows indicate the corresponding Tm temperatures.
coefficients DW, DA, and DL for pure DMPC, DMPC/hexanol, and DMPC/octanol systems are shown in a semilog plot as a function of T. Arrows indicate the corresponding T m temperatures. The DW and DA values of the DMPC/octanol system appear not to depend on the transition temperature, Tm, while a dependence is observed in the DMPC/hexanol system that is even more evident in pure DMPC. Conversely, for all the systems, DL values show a definite change near Tm. It is worth nothing that, concerning the lipid diffusion of pure DMPC in the liquid phase, we found good agreement with the literature data.35,36 In order to compare the lipid diffusion coefficients of the three investigated systems in the gel and in the liquid phase, in Figure 3 the DL values are plotted as a function of temperature normalized to the corresponding Tm. In both the liquid and the interdigitated phase, the presence of hexanol or octanol promotes the lipid diffusion process. Concerning the liquid phase, the DL values of all systems decrease slowly with decreasing temperature. Furthermore, for both systems with alcohol, they have similar values, showing that hexanol and octanol have the same influence on the diffusion process. At temperatures near Tm, a sudden slope is observed in all systems, and this is especially evident in the pure DMPC sample. In the gel phase the DL values of pure DMPC are almost constant, suggesting a slight temperature dependence; moreover, the presence of alcohol promotes the diffusion and this effect is even more evident in the system with the longer alcohol chain length. Unfortunately, for the systems with alcohols, it was not possible to obtain the DL values over a lower temperature range due to instrument limitations. In agreement with our previous work,8 the free volume theory37 and its further development38−40 can give a feasible explanation for the increasing of DL with increasing temperature. According to this model, lateral diffusion is ruled by the free volume distribution within the bilayer and by the activation energy associated with diffusion.
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RESULTS AND DISCUSSION As an example, in parts a and b, respectively, of Figure 1 the diffusion decay of Ψ for pure DMPC and DMPC/octanol systems, as a function of Q2Δ (where Q = γgδ/2π), is shown. The curves, normalized to the maximum intensity of Ψ, are reported at three different temperatures chosen near the corresponding main transition temperature. These transition temperatures were checked by means of DSC experiments. In parts c, d, and e, respectively, of Figure 1 the DSC heating curves for pure DMPC, DMPC/hexanol, and DMPC/octanol systems are shown. The pure lipid membrane undergoes a typical pretransition (Tpre) at 284.3 K and the main transition (Tm) at 296.4 K. The presence of both hexanol and octanol lowers the melting point of the phospholipid bilayers as evidenced by the shift of the main transition to a lower temperature: the longer the alcohol chains, the more Tm decreases. This downshift is indicative of a disorder of lipid chains induced by hydrocarbon chains of alcohol molecules.23 The decay of Ψ for pure DMPC (Figure 1a) can be described as the sum of two components. The faster component, characterized by a diffusion coefficient, DW, of ∼10−10 m2/s, is ascribed to water diffusion between bilayers, while the slower component, characterized by a diffusion coefficient, DL, of ∼10−12−10−11 m2/s, is due to lipid diffusion.8,33,34 In the DMPC/octanol system (Figure 1b), a further component has to be considered. It is ascribed to alcohol molecule diffusion, with a diffusion coefficient, DA, of C
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Figure 3. DL values for the three investigated systems as a function of T normalized to the corresponding main transition temperature Tm. The solid lines are guides to the eyes and indicate the change of diffusion coefficient across the liquid/solid transition.
More specifically, in our case, the lateral diffusion coefficient DL is assumed to depend on the free area, the packing properties, and the energy factor as follows:41 ⎛ a E ⎞ D ∼ exp⎜ − 0 − a ⎟ kBT ⎠ ⎝ af
(1)
where a0 corresponds to the average cross-sectional molecular area for a DMPC molecule, af is a measure for the average amount of free area per molecule in the bilayer, and Ea is the activation energy associated with diffusion. In lipid bilayer, the activation energy takes into account the following: (a) the interactions of a lipid molecule with its neighbors and with the bounding fluid in the bilayer and (b) the energy required to create a hole next to the diffusing molecule, whenever this event is locally associated with an energy change.38 In order to infer detailed information about the molecular diffusion processes, the activation energies were calculated from the slope of the Arrhenius plot using a linear regression model. For the liquid and gel phases of DMPC we find Ea ∼ 25 and 10 kJ/mol, whereas for the liquid and the interdigitated phases the values Ea ∼ 26 and 15 kJ/mol for DMPC/hexanol and Ea ∼ 28 and 19 kJ/mol for DMPC/octanol are determined, respectively. Note that the energy value of DMPC is in good agreement with experimental estimates for similar bilayers.35 In Figure 4 the Arrhenius plots of the temperature dependence of the DL coefficients for DMPC, DMPC/hexanol, and DMPC/octanol are shown along with the fit based on eq 1. Dashed regions refer to the liquid phase. The apparent activation energies, Ea, and the corresponding error values are also indicated. As can be observed, the presence of alcohol increases the value of Ea both in the liquid and in the interdigitated phase. The longer the alcohol chains, the higher the apparent activation energies are. Despite the increase of Ea, DL is higher in the DMPC/alcohol systems over all the temperature range investigated. This apparent contradiction can be solved considering that the area factor is predominant over the energy factor in controlling the lateral diffusion of lipid. In effect, the increasing of the polar head area of lipids caused by the addition of alcohol in the bilayers9 gives rise to a
Figure 4. From top to bottom: Arrhenius plots of the temperature dependence of the obtained lateral diffusion coefficients (DL) for DMPC, DMPC/hexanol, and DMPC/octanol. The solid lines are fits to the data. Dashed regions refer to the liquid phase. The apparent activation energies, Ea, and the corresponding error values are also indicated.
smaller molecular packing; as a consequence, higher DL values are expected with respect to the pure membrane. Finally, in order to study the dependence of the translational diffusion upon the acyl chains length of lipids and to underline the influence of alcohols on the lateral diffusion of membranes, we compare the lipid diffusion process of pure DMPC and DMPC/alcohol systems with that presented in our previous work on 1,2-palmitoyl-sn-glycero-3-phosphocholine (DPPC).8 In Figure 5 the DL values for DMPC and DPPC (Figure 5a) and for DMPC/octanol and DPPC/octanol (Figure 5b) are plotted as a function of temperature normalized to the corresponding Tm. As argued in Figure 5a, despite its higher molecular weight, DPPC exhibits a faster diffusion with respect to DMPC, especially in the gel phase. This result is in agreement with previous studies reporting that DL increases with increasing acyl chain length.42,43 These results can be explained taking into account the free volume theory. The volume per lipid acyl chain increases with increasing chain length. DPPC bilayers are consequently more expanded than DMPC bilayers, and as a result, more free area per molecule is available for diffusion. As a matter of fact, paying particular attention to temperatures below Tm, alcohols seem to have an opposite effect on DPPC and DMPC membranes. Diffusion in DPPC is hindered by alcohols, and this effect is increasing with alcohol chain length. By contrast, diffusion in DMPC is promoted by the D
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Figure 5. DL as a function of T normalized to the corresponding main transition temperature Tm: (a) comparison between pure DPPC8 (circles) and pure DMPC (squares); (b) comparison between DPPC/octanol8 (filled circles) and DMPC/octanol (empty triangles). (c and d) DL for DPPC (circles) and DMPC (squares) at a temperature ∼10 K below Tm as a function of the acyl chain length of the alcohol included in the bilayer.
phospholipid membranes. The longer the alcohol chains, the more the temperature Tm decreases. Both liquid and interdigitated phases have been investigated. An accurate analysis of the interdigitated phase shows that the presence of hexanol and octanol promotes the lipid diffusion process and this effect is even more evident in the system with the longer alcohol chain. These findings are explained using a twodimensional diffusion model that takes into account for both the free area available for diffusion and the activation energy of the diffusion process. Furthermore, we compare the lipid diffusion process of DMPC and DMPC/alcohol systems with that presented in our previous work on DPPC and DPPC/alcohol systems. At temperatures below Tm, alcohols appear to have an opposite effect on DPPC and DMPC membranes. Diffusion in DPPC is hindered by alcohols, and this effect is increasing with alcohol chain length. Conversely, diffusion in DMPC is promoted by the presence of alcohol. This unexpected behavior is ascribed to the limited acyl chain length of DMPC that prevents occurrence of interdigitation.
presence of alcohol: the longer the alcohol acyl chain, the more diffusion is favored. This effect leads to a peculiar situation in which, as can be inferred from Figure 5b, diffusion in DMPC/ octanol and DPPC/octanol systems has a similar behavior. We show in Figure 5c,d the DL values of DPPC and DMPC as a function of the acyl chain length of the alcohol included in the bilayer. Note that, in order to compare all samples at about the same distance from the main transition temperature, the data shown in Figure 5c,d correspond to a temperature ∼10 K below Tm. Concerning DPPC systems, we explained this behavior taking into account the higher Ea with respect to the pure sample and considering that in the interdigitated phase the energy of formation of voids inside the bilayer is minimized. This results in a more packed structure and in a less free area per molecule, af, available for diffusion.8 This is more evident for the DPPC/octanol system with respect to the DPPC/ butanol system, since interdigitation is more energetically favorable for alcohols with longer chains.25 Concerning DMPC systems, the observed opposite behavior can be tentatively attributed to a loss of interdigitation. It was actually reported that a high concentration of DMPC, over 60%, may block the formation of interdigitated structure in DPPG/DMPC binary systems.44 As a consequence, if in DMPC systems interdigitated phase is not entirely obtained, the presence of alcohol has the only effect to disorder the system, increasing polar head area, thus leading to a less packed structure. In this case the increasing of the diffusion process is justified by more free area available for diffusion.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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REFERENCES
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CONCLUSIONS The effects of structural changes, caused by the addition of a high hexanol or octanol concentration, on the phase behavior and on the lateral mobility of DMPC have been studied by performing DSC and PGSTE-NMR spectroscopy measurements. We find that the addition of alcohols causes melting point (Tm) depression from the gel Lβ to the fluid Lα phase of E
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