Molecular Dynamics Simulation of Inverse-Phosphocholine Lipids

Article pubs.acs.org/JPCC

Molecular Dynamics Simulation of Inverse-Phosphocholine Lipids Aniket Magarkar,† Tomasz Róg,‡ and Alex Bunker*,† †

Centre for Drug Research, Faculty of Pharmacy, University of Helsinki, Fl-00014 Helsinki, Finland Department of Physics, Tampere University of Technology, FIN-33101 Tampere, Finland

‡

S Supporting Information *

ABSTRACT: We have performed molecular dynamics simulations of lipid bilayers composed of inverse-phosphatidylcholines (CPe), an analog of phosphatidylcholine (PC) with the choline group directly bound to the glycerol backbone and the phosphate group freely protruding into the water phase. Synthetic phospholipids with the CPe headgroup have been proposed for use as drug delivery liposomes. Our simulation results show that the CPe lipids were characterized by a larger area per lipid molecule than the PC lipids. This can partly explain experimental results that show a higher permeability of small solutes through the membranes of liposomes composed of them. Unlike the PC headgroup, the CPe headgroup was found not to bind sodium ions at the water membrane interface. Both lipid types were found to bind calcium ions but do not bind potassium ions. Inversion of the choline group was found to decrease hydration of the membrane in the carbonyl region of the bilayer as well as hydration of the choline group. From analyzing the water ordering in our simulation, we determined that the orientation of the water layer next to the CPe membrane is effectively inverted with respect to the water ordering of the PC membrane, possibly affecting interaction with biomembranes encountered in drug delivery. Due to changes in ion binding, charge group distribution, and water orientation, the electrostatic potential profiles across the lipid bilayer of CPe membranes were found to differ considerably from those of PC membranes. This is a possible explanation of the experimentally observed changes in the charged solute permeability.

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ature,7 while those with the CPe headgroups exhibit the same transition temperature as naturally occurring PC lipids.8 Liposomes composed of lipids with CPe headgroups do, however, possess some intriguing properties.8 While the overall permeability of CPe lipid liposomes is greater than for liposomes composed of PC lipids, the permeability for anionic compounds is significantly enhanced. For example, the rate of release of anionic carboxyflourescein is 20-fold greater, while that for neutral glucose is only doubled. Also, liposomes composed of CPe lipids display reduced binding of calcium ions relative to liposomes composed of PC lipids. Molecular dynamics simulation provides a unique tool to further study these novel synthetic lipid systems, to gain further insight into the mechanisms behind their properties. We have successfully used molecular dynamics simulation to study a variety of liposome based drug delivery systems,9−12 and this study represents a continuation of this line of work. In this study we have performed molecular dynamics simulation of inverse-phosphocholine (CPe) and phosphotidylcholine (PC) lipids with two linoleic tails (DL, 18:2) in the presence of three different salts (NaCl, KCl, and CaCl2).

INTRODUCTION The application of liposome based drug carriers is one of the most promising current avenues in drug delivery.1,2 The drug delivery liposome (DDL) is a versatile carrier, capable of carrying hydrophobic drugs within the lipid membrane, or hydrophilic drugs in the liposome interior. Targeted delivery can also be achieved through the addition of targeting moieties to the liposome exterior. While originally DDLs have been formulated from standard phospholipid/cholesterol mixtures, for example DSPC/cholesterol, it is possible to instead construct DDLs from novel phospholipids, not found in nature, that possess unique properties that assist in drug delivery. For example, the cationic lipid N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium methyl sulfate (DOTAP)3 and derivatives of 1,4-dihydropyridine4 have been used for DNA transport. Also, PEGylated lipids are incorporated into the liposome formulation in order to achieve a stealth shield in the drug DOXIL.5 A variety of such synthetic lipid systems have recently been created that involve alteration of only the headgroup. These include quaternized amine diacyl lipids (AQ)6 and sulphobetaine lipids (SB).7 A particularly intriguing lipid is inversephosphocholine (CPe),8 created by switching the positions of the phosphate and choline groups of naturally occurring lipids with phosphocholine headgroups (Figure 1). Experimental analysis of liposomes composed of these lipids has found that they possess some intriguing properties. The lipids with the SB headgroups exhibit a significantly increased transition temper© 2014 American Chemical Society

Received: June 6, 2014 Revised: August 1, 2014 Published: August 1, 2014 19444

dx.doi.org/10.1021/jp505633y | J. Phys. Chem. C 2014, 118, 19444−19449

The Journal of Physical Chemistry C

Article

Figure 1. Chemical structures of DLCPe (a) and DLPC (b) with atoms numbered.

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METHODS Two lipid bilayer types were used in this computer simulation study, one made of dilinoleoylphosphatidylcholine (2-18:2c9 PC) (DLPC) and a second of the CPe equivalent, DLCPe. The chemical structure of both lipids is shown in Figure 1. MD simulations were performed at the physiological temperature of 310 K; thus, both systems are in the liquid phase. The initial structure of the DLPC bilayer was taken from the final configuration of a previous simulation study13 and consists of 288 DLPC molecules, ∼19800 water molecules, and either NaCl, KCl, or CaCl2 salt. The DLCPe lipid membrane was constructed from a DLPC system, modifying the headgroup structure of the lipids. Three different salts were examined in these studies: NaCl, KCl, and CaCl2. For the NaCl system, concentration was set to the physiologically relevant level of 140 mM, and for comparison, the concentration for the other two salt solutions was set to the same ionic strength (140 mM for KCl and 70 mM for CaCl2). For both lipid types and ions, the all-atom optimized parameters for liquid simulations (OPLS-AA) force field was used14 with additional parameters derived specifically for lipids.15 Partial charges for both lipid types are shown in Supporting Information Table S1. For water the TIP3P model was used. This model is compatible with OPLS-AA parametrization.16 For all systems, the time taken for the system to equilibrate was determined and then a further 100 ns were simulated, and this part of the trajectory was the data used in our analysis. The equilibration time was determined based on the surface area of

the bilayers and numbers of ions adsorbed to the membrane surface (see Supporting Information, Figures S1 and S2), and for all systems this time was between 40 and 80 ns. In order to further verify that we obtained a complete equilibrated sample, we continued one of the simulations, the DLCPe system with NaCl, to 500 ns and found no variation in the area per lipid result (Supporting Information Figure S3). Simulations were performed using the GROMACS 4.5 software package.17 Periodic boundary conditions with the usual minimum image convention were used in all three directions. The linear constraint solver (LINCS) algorithm was used to preserve the lengths of the covalent bonds.18 The time step was set to 2 fs. The temperature (310 K) and pressure (1 bar) were controlled using the Nosé−Hoover19,20 and Parrinello−Rahman21 methods, respectively. The temperatures of the solute and solvent were controlled independently. For pressure, a semi-isotropic control was used. The Lennard-Jones interactions were cut off at 1.0 nm, and the electrostatic interactions were evaluated using the particle mesh Ewald method.22 In the analysis of our data we calculated ion binding using the same methodology and definition of a bound ion, used in previous work, described by Stepniewski et al.9

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RESULTS The surface area per lipid molecule can be seen as the most representative structural parameter describing the lipid bilayer. Surface area determines the order of the hydrocarbon phase23 as well as numerous properties of the water membrane interface.24 As shown in Table 1 the area of the CPe lipids is 19445



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adsorb to the water membrane interface and the depth of penetration of Na+ and Cl− into the membrane was found to be the same. For the case of K+ we also did not observe adsorption to the interface; however, Cl− penetrated deeper into the membrane than K+, the reverse situation in comparison to the case of the PC bilayer. Contrary to the case for Na+ and K+, Ca2+ binds to CPe lipid headgroups, although the mass density profiles indicate a difference in the binding behavior. For the case of the PC lipids, Ca2+ locates a bit below the maximum of the phosphate atoms in a position where they both (1) interact with phosphate and (2) are able to form links with carbonyl oxygen atoms. For the case of the CPe lipids, however, the Ca2+ peak is located a bit above the maximum of the phosphate atoms; thus, interaction with the carbonyl groups is not possible. A possible reason for this is electrostatic repulsion of the choline group blocking access to the carbonyl group. In terms of overall binding, the number of bound Ca2+ ions is reduced in comparison to the PC system; however, our result does not show as marked an effect as that indicated by experimental results.8 This may result from the absence of polarization effects in the OPLS-AA model, possibly resulting in an overestimation of the strength of the interaction between phosphate and calcium atoms.28 The mass density profiles with the phosphate and choline groups included are shown in Supporting Information Figure S5. Water binds with phosphatidylcholines via two types of interactions: (1) H-bonds with all polar oxygen and (2) interactions with the choline groups. Water forms clathrates around the choline group, a water shell of six to ten molecules.24 In Tables 2 and 3 the number of H-bonds between lipid oxygen atoms and water and the number of water molecules neighboring choline methyl and ethyl groups (for

Table 1. Results for Area per Lipid and Percentage of Bound Cations to Headgroup in All Six Systemsa lipid system

cation

area per lipid (nm2)

% ions bound to headgroup

DLCPE DLCPE DLCPE DLPC DLPC DLPC

Ca K Na Ca K Na

0.711(7) 0.705(7) 0.707(6) 0.679(9) 0.688(7) 0.670(8)

37(3) 5(2) 14(3) 43(3) 8(2) 55(2)

a

Number in parentheses is standard deviation, in units of the last significant figure shown.

larger than that of the natural PC lipids. The geometrically related quantity of bilayer membrane thickness, as expected, also decreases (Supporting Information Figure S4). This result is in agreement with an observed higher permeability of the inverse lipid membrane, as it has been shown that the area per lipid or membrane surface density correlates with permeability for a large number of small molecules.25,26 Observing the percentage of bound ions, also shown in Table 1, we see that both the CPe and PC lipids bind Ca2+ ions, but do not bind K+ ions. Regarding Na+ ions, there is, however, a difference in binding behavior: the PC lipid membrane binds a significantly greater portion of Na+ ions than the CPe lipid membrane. Our results for the mass density profiles, shown in Figure 2, are in agreement with this. In agreement with previous studies,13,27 for the case of the PC lipids, Na+ and Ca2+ adsorb to the water membrane interface, as demonstrated by a clear peak in the mass density profile colocalized with phosphate atoms in the lipid headgroups. Also, in agreement with previous studies, we do not observe K+ to adsorb to the membrane interface. For the case of the CPe lipids, Na+ did not

Figure 2. Mass density profiles for all systems. Again we see the most marked effect for the Na+: in the CPE systems the Na+ ions have the same profile as Cl− ions indicating no binding. 19446



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Table 2. Number of Hydrogen Bonds, between Lipid Oxygen Atoms and Water, per Lipid Moleculea DLCPe O12 O13 O14 O11 O21 O22 O31 O32

DLPC

Na

K

Ca

Na

K

Ca

0.51 1.87 1.88 0.18 0.00 0.16 0.00 0.17

0.50 1.89 1.89 0.18 0.00 0.15 0.00 0.17

0.53 1.80 1.77 0.17 0.00 0.15 0.00 0.17

0.41 1.78 1.78 0.07 0.75 0.84 0.39 0.88

0.40 1.89 1.91 0.08 0.78 0.83 0.35 0.92

0.41 1.72 1.81 0.08 0.78 0.88 0.34 0.93

a

Figure 3. Water ordering as a function of distance. This is expressed as the average cosine of the angle between the water molecule and the membrane normal. A positive value corresponds to the water oxygen oriented toward the membrane, and a negative value, away from the membrane. We see that the ordered water layer for the CPE systems is inverted from that present in the PC systems.

Standard error is less than 0.01. Atom identities are as shown in Figure 1.

Table 3. Number of Water Oxygen Atoms Neighboring Choline Methyl and Ethyl Groupsa DLCPe C2 C3 C4 C5

DLPC

Na

K

Ca

Na

K

Ca

2.07 3.34 3.31 1.51

2.05 3.34 3.09 1.53

2.08 3.30 3.13 1.53

4.20 4.17 4.17 2.76

4.03 4.02 4.02 2.63

4.07 4.07 4.07 2.70

can be observed. The peak of the potential in the headgroup region is shifted toward the bilayer center and is roughly 0.15 mV higher for the case of the CPe lipids than for the PC lipids. In total, the barrier for cations is 0.25 mV higher for the case of CPe vs PC lipids. We measured the reorientational autocorrelation function (RAF) of the P−N vector for the first Legendre polynomial,30 shown in Figure 5. We see a decreased decay rate for all DLCPe systems, in comparison to the DLPC systems, indicating a decreased rotation rate of the headgroups and, thus, slower mobility. Thus, the CPe headgroup is more restricted in comparison to the PC headgroup. The rotation of CPe shows negligible dependence on the variety of salt present, while for the case of the PC bilayer, the type of salt affects the rotational motion of the headgroup.

a

Standard error is less than 0.02. Atom group identities are as shown in Figure 1.

our definition of “neighboring” see Murzyn et al.24) are given, respectively. This data indicates that the CPe lipids in general are less hydrated. The largest decrease of H-bonds is observed for the case of carbonyl and ether oxygen atoms, with the polar groups located deepest within the bilayer. This can be seen also in the mass density profiles, which indicate that water does not penetrate as deeply for the case of the CPe as for the PC membrane. Also, the choline group is substantially less hydrated, and only a small increase in the hydration of phosphate oxygen atoms is observed. Due to the above-described interactions, water next to the lipid bilayer surface is specifically ordered.29 The ordering of water molecules in the vicinity of the water−membrane interface can be characterized by a time averaged projection of the water dipole unit vector onto the interfacial normal. The orientation of the water dipoles as a function of the distance from the bilayer center in both bilayers is presented in Figure 3. As can be seen, the profiles of water ordering of the CPe and PC lipid systems differ significantly. For the case of the PC membrane, we observe a strong negative peak located between the carbonyl and phosphate groups. This peak is greatly reduced for the case of the CPe membrane. The second positive peak, which is relatively weak for the PC system, is very strong for the CPe system and dominates the behavior of water above the membrane. This peak can be interpreted as the result of H-bonds between water and phosphate groups, without significant involvement of the choline group. Because the distribution of charge groups (position of phosphate and choline group), ion distribution, and water ordering at the water membrane interface can affect the electrostatic potential, we calculated the electrostatic potential across the lipid bilayers by computing the charge density and then integrating twice over the Z coordinate across the membrane, as shown in Figure 4. Although the shape of the electrostatic potential is similar in both cases, clear differences

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DISCUSSION The results of our simulations show that inversion of the phosphatidylcholine headgroup dramatically affects the properties of the lipid bilayer and, in particular, the properties of the water membrane interface. From the perspective of drug delivery liposomes composed of these lipids, bilayer permeability is an important property. Our simulations show larger surface area per lipid molecule, which can be indicative of higher permeability,25 which was indeed experimentally observed for CPe liposomes.8 The increase of surface area can be simply explained by the fact that, the choline group, as a result of its water clathrate, is larger than the phosphate group. The insertion of this bulky group deeper into the bilayer requires more space at the interface. Permeability can also be affected by the changes of the electrostatic properties of the bilayer; however, this effect should be specific for the charge of the molecule in question. Cationic molecules should be less permeable while anionic molecules more permeable, possibly supporting the experimental results. In addition, our results show that the DLCPe membrane has lower headgroup mobility. This can also be linked to the larger choline group with its water clathrate being located deeper in the membrane, in this case constricting the headgroup motion. We also observed that the CPe synthetic lipids do not bind Na+ ions. While we were not able to determine a precise mechanism that causes this, it is possible to speculate that this results from (1) the existence of a partially enclosed cavity 19447



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Figure 4. Electrostatic potential as a function of distance from the membrane center. In all cases the potential barrier is higher and the peak closer to the membrane center, for the DLCPE systems.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: alex.bunker@helsinki.fi. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We wish to thank the Academy of Finland (T. R. Center of Excellence in Biomembrane Research), the European Research Council (Advanced Grant Project CROWDED-PRO-LIPIDS), and the Finnish Cultural foundation (A.M.) for financial support. We wish to thank the CSC-IT Centre for Science Ltd. (CSC) (Espoo, Finland) for computational resources.

Figure 5. Rotational autocorrelation function for the headgroups; we see that for all cases the results for CPE systems have a slower rotation rate than the PC systems.

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between the phosphate and carbonyl groups in the PC lipid membrane that is not present in the CPe membrane and (2) the phosphate groups in the CPe membrane being more mobile than in the PC membrane, thus binding in a less stable fashion. Another important observation which can have potential importance for drug delivery is the effect of the headgroup structure on water behavior; the CPe headgroup is less hydrated and water ordering can be seen as effectively inverted. Both effects might be important for the fusion of liposomes composed of CPe lipids with biological membranes. Dehydration is part of the fusion process, thus lowering the number of bound water molecules that might be seen as a factor promoting fusion. Ordered water at two opposite surfaces leads to the repulsive interaction between them, known as the hydration force.31 For the case of a CPe membrane interacting with a membrane composed of classical lipids, such as biomembranes, this water might effectively be an attractive factor. This phenomenon has been previously discussed by Eun and Berkowitz.32

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ASSOCIATED CONTENT

S Supporting Information *

Supplementary figures: equilibration of area per lipid and number of bound ions, area per lipid, bilayer membrane thickness, and mass density profiles with phosphate and choline groups. Supplementary table of partial charges used in parametrization. This material is available free of charge via the Internet at http://pubs.acs.org. 19448



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Molecular Dynamics Simulation of Inverse-Phosphocholine Lipids

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