From Micelles to Vesicle and Membrane Structures of Double Strand

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Interface-Rich Materials and Assemblies

From Micelles to Vesicle and Membrane Structures of Double Strand Ionic Liquids in Water: Molecular Dynamics Simulation Tahereh Ghaed-Sharaf, Ding-Shyue Yang, Steven Baldelli, and Mohammad Hadi Ghatee Langmuir, Just Accepted Manuscript • DOI: 10.1021/acs.langmuir.8b03773 • Publication Date (Web): 25 Jan 2019 Downloaded from http://pubs.acs.org on January 26, 2019

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Langmuir

From Micelles to Vesicle and Membrane Structures of Double Strand Ionic Liquids in Water: Molecular Dynamics Simulation Tahereh Ghaed-Sharaf 1, Ding-Shyue Yang 2, Steven Baldelli 2, Mohammad Hadi Ghatee 1,2*

1 2

(Department of Chemistry, Shiraz University, Shiraz 71946 Iran)

(Department of Chemistry, University of Houston, Houston, Texas 77204-5003, USA)

Tel: +98 713 613-7174 Email: [email protected] [email protected]

*Corresponding Author

1 Environment ACS Paragon Plus

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ABSTRACT The structures of novel double strand imidazolium iodide ionic liquids (ILs) based lipid in water phase have been studied in this research. We report the effect of alkyl chain length of 1,3-dimethyl4,5-dialkyl-imidazolium iodide([2(Me)2(Cn)im]I, n=7,11,15) ILs on their structures in the aqueous solution by molecular dynamics (MD) simulation. The structure details of ILs clusters prompt the various aggregation forms by increasing the alkyl chain length of ILs. The ILs with n=7 and 11 construct micelle structures of different sizes and the IL with n=15 is feasible to make lipid-like vesicle. In order to obtain more details about bilayer properties of [2(Me)2(C15)im]I IL, the membrane of IL is investigated by different IL/water ratio in this study exclusively. The [2(Me)2(C15)im]I IL bilayer thickness and order parameters are compared with lipid membrane and reveal a bit difference. The energies, radial distribution functions (RDF), spatial distribution function (SDF), cluster size, number density, and membrane properties all prove that the stable IL vesicle is formed in the dilution solution but the membrane is formed in the concentrated aqueous solution of [2(Me)2(C15)im]I.

TOC GRAPHIC

KEYWORDS: Ionic liquid-based lipid; Interdigitated structure; Micelle; Vesicle; Artificial Membrane.


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INTRODUCTION Recognition of chemical materials for using as a cellular membrane plays a pivotal role in biological processes. Lipid-like materials, which make biphasic system with water, can be applied in medicinal researches such as drug delivery and drug effect on the cellular membrane. Although there are several studies1-10 on chemical materials such as 1-octanol/water, hexane/water and octane/water as cellular membrane models, such biphasic systems dissolve slightly in the water phase and are far from even slight resemblance to the real cellular membrane. Self-assembly of diblock copolymer has been modeled in water by Coarse-Grain method.11 At varying hydrophilic/hydrophobic ratio of the copolymer consistent with experiment, micelles aggregates of different morphologies were spontaneously assembled. Applications of such block-copolymer are motivated with the aim of substituting lipid bilayer with limited stability in drug delivery and sensor development.12-13 Due to the hyperthick structures of block copolymers, they show remarkably different properties from biomembrane. Organized vesicles which are made spontaneously by polymers14-15, are poorly permeable. These limitations and defects are an encouragement to find a more similar substituted to cellular membrane models for pharmaceutical and biological researches. ILs are special class of materials composed of organic cations and inorganic or organic anions. Some of the ILs with intrinsic amphiphilic character can aggregate in water.16-19 Among long alkyl chain ILs, double strand ILs20 show lower critical micelle concentration (cmc) than single tail ILs.21 Therefore, the lower cmc, the lower the ILs needed to make micelles and vesicles. It is more cost-effective to use the double strand ILs in different fields which micelle and vesicle structures are required. The stable vesicle and micelle structures can be applied in various fields such as catalysis,22-23 producing of new materials24, bio pharmaceutics25, drug delivery26, and antimicrobial activity.27 Wang et al. 20 synthesized pure crystalline of a new


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series of ILs based-lipid with different alkyl chain length and investigated their antimicrobial activity. From their experimental 20 and further MD simulation studies20, 28, it was concluded that an IL with long alkyl chain (containing 15 carbon atoms) demonstrates lower toxicity than shorter ones (by 11 and 7 carbons in cation alkyl). The dialkyl imidazolium bromide and iodide ILs with long alkyl chain length make vesicles in buffer aqueous solution similar to the salt content and pH of the cytosol of living cells, and their drug delivery capability has been suggested 29; shorter alkyl chain(by 11 and 7 carbons) make micelles. The ILs with long alkyl chains keep integrity while placed within the lipid bilayer lamella, however, in the shorter chain length, thermodynamic instability does not allow succeeding lamella with vesicle integrity. Then, the question that arises here as to whether such a characterized long dialkyl ILs ([2(Me)2(C15)im]I) can form a stable membrane and how their chemical and structural feature could dictate the formation of the bilayer membrane, an analog of the lipid bilayer in living cell. We simulate the [2(Me)2(C7)im]I, [2(Me)2(C11)im]I and [2(Me)2(C15)im]I IL/water systems (see Scheme 1 for structures and atomic labels) to compare their aggregation structures of these ILs in water, and construct the [2(Me)2(C15)im]I IL membrane under the human body temperature (310K) and ambient pressure in the same procedure and IL/water molecules ratio that phospholipid molecules make cellular membrane.30 This work is the first MD simulation of a novel application of IL as a cellular membrane with formation details, atomic structures and featured interaction morphology, which is impossible to reveal in detail experimentally. The RDF, SDF, MSD, density profile, cluster size, and membrane properties are studied in this research. The number of ILs and water molecules for simulation of possible aggregation structure and morphology of the three ILs are shown in Table 1.


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C21

C7 C20

C19

C17

C15

C18

C16

C4

C14

C11

C9

C10

C12

C5

C27 C28

C26

C24

C23

C21 C22

N3

C19

C4

C20

C2

N1

C8

C25

I

C2 H2

C13

C7

C29

N3

C17

C6

C18

C15 C16

C13 C11 C9 C8 C10 C14 C12

C5

H2

I

N1 C6

(b)

(a) C7 C37

C35 C36

C33 C 34

C29

C31 C32

C30

C27 C28

C25 C26

C23 C24

N3 C4 C2

C21 C22

C17 C15 C9 C19 C11 C13 C8 C10 C18 C16 C20 C14 C12

C5

H2

I

N1 C6

(c) Scheme 1. Structure and atomic labels of (a) [2(Me)2(C7)im]I, (b)[2(Me)2(C11)im]I and (c) [2(Me)2(C15)im]I. No H-atoms are shown for clarity.

Computational Details The IL’s structure is optimized using the Gaussian 03 program.31 The DFT calculation is performed at B3LYP method and 6-311++G(d,p) basis set. Using DFT calculation, the partial charges for each IL is determined by CHELPG procedure.32 Classical molecular dynamics is performed using Gromacs(4.5.5)

33

software with the OPLS-AA34 force field and TIP4P35 model

to simulate the IL and water, respectively (The force field parameters for three ILs are the same and for [2(Me)2(C15)im]I IL is presented in Supporting Information). The potential energy is accounted for according to: =

+

=

+

− 4

+

+ −

+

+ +

(1)

(cos( )) + ∑


(2)

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All the parameters have their usual meaning. Initially, IL ion pairs are randomly distributed and the energy minimization using the steepest descent algorithm is done. The simulation is continued under isothermal-isobaric ensemble (NPT) ensemble for 1 ns by time-step 0.001 ps at 310 K and 1 bar. Temperature and pressure are adjusted with Nose-Hoover and Parrinello-Rahman coupling, respectively. Coupling time constant of 0.5 ps and 2 ps are used for thermostat and barostat respectively. Bond lengths in molecules are constrained by the LINCS algorithms. 36 The water molecules are added to the IL box and in order to attain the constant box volume, the simulation continued under the same condition as the previous NPT simulation. The NVT simulation is done under the heating-cooling cycle and the LINCS algorithms36 is used for constraining the bond length. The temperature is adjusted at 310K by Nose-Hoover with coupling constant of 0.2ps and time step of 0.002ps. The cut-off distance of 1.2 nm is used to account for short-range non-bonded interaction and particle-mesh Ewald37 electrostatics together with dispersion energy corrections used to describe long-range interactions. After about 100ns NVT simulation, the acceptable equilibrium state is attained. The total energies of three IL/water systems, at last 20ns of simulation (Figure S1, Supporting Information) assure the equilibrium state of systems attained at last 20ns MD simulation. The snapshots of first and final simulation steps for three ILs are shown in Figure 1. Different aggregations occur for these IL/water systems: [2(Me)2(C7)im]I makes spherical small micelles which disperse in the water phase (Figure 1 (a.2)), [2(Me)2(C11)im]I makes larger micelles (Figure 1 (b.2)) and [2(Me)2(C15)im]I is feasible to construct the stable vesicle in water phase(Figure 1 (c.2)). These simulated structures are in good agreement with the experimental results.29


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Table 1. Number of IL and water molecules used for aggregation simulation. Ionic Liquid

IL molecules

water molecules

%w/w

Micelles and Vesicle [2(Me)2(C7)im]I

300

53524

11.57

[2(Me)2(C11)im]I

300

53637

14.22

[2(Me)2(C15)im]I

300

70979

13.15

3792

54.73

Membrane [2(Me)2(C15)im]I

128


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Figure 1. The snapshots of (a)[2(Me)2(C7)im]I IL/water, (b)[2(Me)2(C11)im]I IL/water and (c) [2(Me)2(C15)im]I IL/water system. (a.1, b.1 and c.1) first configurations, (a.2, b.2 and c.2) final configurations. Cation head group atoms, pink; tail carbons, blue and yellow; alkyl chain, cyan; iodide, purple. No hydrogen atoms and water molecules are shown.


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RESULTS AND DISCUSSION Radial Distribution Function. The RDF of tail carbons with other carbons of alkyl chain of cations are studied, namely: C14 and C21 in [2(Me)2(C7)im]I; C18 and C29 in [2(Me)2(C11)im]I; C22 and C37 in [2(Me)2(C15)im]I. According to the RDF’s plots shown in Figures 2(a)-(c), tail carbons show a stronger correlation with each other than with other carbons in alkyl chains. To obtain the vesicle wall thickness,38 for [2(Me)2(C15)im]I IL the RDF of C2 atom of vesicle versus distance from center of vesicle is plotted (Figure 3) and illustrates the enhancement of the correlation of C2 atoms centered in two position in the simulation box, at 1.6 nm and at 4.22 nm from the center of vesicle. The C2 positions represent the inner and outer radius of IL vesicle and subsequently the thickness of IL bilayer which is about 2.62 nm. Therefore, this thickness value affirms the interdigitated bilayer form for the long alkyl chain ([2(Me)2(C15)im]I) IL.39 The iodide anions are firmly placed near imidazolium head groups close to H2 atoms, having high probability and low dynamics, Figures 4(a)-(c). Considering the RDFs of all atoms of ILs with H2O studied, the iodide anions demonstrate a higher correlation with water and HWs of water molecules are located near the iodide anions (Figures 5(a)-(c)). Also, the polar hydrogens (H2) of imidazolium ring do not have an appropriate correlation with water molecules. According to the high correlation of iodide anions with water and H2 atoms of cations with iodide anions, the head group of cations protrude to the water phase that results in producing micelles and vesicle in water phase.


Langmuir

20

30

(a)

(b) 25

C₁₈ - C₂₉

C₁₄ - C₂₁

15

C₁₈ - C₁₈

C₁₄ - C₁₄

20

C₂₉ - C₂₉

g(r)

C₂₁ - C₂₁

g(r)

10

15

10 5 5

0

0 0.2

0.4

0.6

0.8

1

1.2

0.2

1.4

0.4

0.6

0.8

1

1.2

1.4

r/nm

r/nm 45

(c)

40

g(r)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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35

C₂₂ - C₃₇

30

C₂₂ - C₂₂ C₃₇ - C₃₇

25 20 15 10 5 0 0.2

0.4

0.6

0.8

1

1.2

1.4

r/nm

Figure

2.

RDF

for

tail

carbons

of

(a)[2(Me)2(C7)im]I,

(c)[2(Me)2(C15)im] ILs at equilibrium for the last 20ns simulation.


(b)[2(Me)2(C11)im]I

and

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12 rinner ≈ 1.6 10

RDF of C2

8 router ≈ 4.22

2.62 nm bilayer thickness

6 4 2 0 0

1

2

3

4

5

Distance from center of vesicle/nm

Figure 3. The RDF for C2 versus distance from center of vesicle of [2(Me)2(C15)im]I at equilibrium for the last 20ns simulation. 9 4

(a)

C₄ - I C₅ - I C₂ - I N₁ - I N₃ - I H₂ - I

C₄ - I C₅ - I C₂ - I N₁ - I N₃ - I H₂ - I

7 6

g(r)

3

(b)

8

g(r)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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2

5 4 3 2

1

1 0

0 0.2

0.4

0.6

0.8

1

1.2

0.2

0.4

r/nm

0.6

0.8

r/nm


1

1.2

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18

C₄ - I C₅ - I C₂ - I N₁ - I N₃ - I H₂ - I

(c)

16 14

g(r)

12 10 8 6 4 2 0 0.2

0.4

0.6

0.8

1

1.2

r/nm

Figure 4. The RDF for Iodide anion with head group atoms of (a)[2(Me)2(C7)im]I, (b)[2(Me)2(C11)im]I and (c)[2(Me)2(C15)im] ILs at equilibrium for the last 20 ns simulation.

3.5

3.5 OW - H₂

(a)

OW - H₂

(b)

HW - I

3

HW - I

3

OW - I

OW - I 2.5

2.5

2

2

g(r)

g(r)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1.5

1.5

1

1

0.5

0.5

0

0 0.1

0.3

0.5

0.7

0.9

0.1

r/nm

0.3

0.5

r/nm


0.7

0.9

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3

(c) 2.5 OW - H₂ HW - I

2

OW - I

g(r)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1.5

1

0.5

0 0.1

0.3

0.5

0.7

0.9

r/nm

Figure 5. The RDF for OW of water with H2 atom of cation and HW and OW of water molecules with Iodide anion of (a)[2(Me)2(C7)im]I, (b)[2(Me)2(C11)im]I and (c)[2(Me)2(C15)im]I ILs at equilibrium for the last 20 ns simulation. Spatial Distribution Function. The SDF analysis is good evidence to indicate the probability distributions of the anion and water around the cation of ILs. The SDF for anion and water molecules around cation is visualized via the VMD package40 and shown in Figures 6(a)-(c). In [2(Me)2(C7)im]I, [2(Me)2(C11)im]I and [2(Me)2(C15)im]I both anions and water molecules are placed around the cation head groups, however anions are located closer to the cation head groups. The SDFs results reveal the micelle structures of ILs in water phase that head groups and anions of ILs molecules protrude toward the water and alkyl chains buries themselves inside the micelle to the degree that is determined and balanced by the alkyl chain length.


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Figure

6.

SDF

of

cations

of

(a)

[2(Me)2(C7)im]I,

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(b)[2(Me)2(C11)im]I

and

(c)

[2(Me)2(C15)im]I ILs. Nitrogens of imidazolium ring, yellow; carbons, cyan; hydrogens, white; iodide, purple; water, blue. Cluster Size. The cluster size, number of atoms in clusters, and number of atoms in cluster with maximum size for cation of ILs are obtained (Figures 7(a)-(c)). The number of clusters is shown in Figure 7(a), and simulation reveals that in [2(Me)2(C7)im]I, [2(Me)2(C11)im]I, and [2(Me)2(C15)im]I ILs, the cations make about 37, 4 and 1 clusters in aqueous phase, respectively. The [2(Me)2(C7)im]I IL is the smallest one and makes smaller and more micelles than [2(Me)2(C11)im]I and [2(Me)2(C15)im]I ILs. The smaller size of the IL contributes to the more dynamics of molecules and leads to more fluctuations in the number of [2(Me)2(C7)im]I cation clusters. The average cluster (Figure 7(b)) size and maximum cluster size (Figure 7(c)) of ILs demonstrate that more clusters with fewer number of cations are formed in [2(Me)2(C7)im]I/water system. As shown in Figure 7(c), the maximum cluster size of [2(Me)2(C11)im]I IL holds 18286, 13202, 11398 and 10250 cation atoms (corresponding to about 223, 161, 139 and 125 IL cation molecules respectively). The maximum cluster size in [2(Me)2(C11)im]I changes by simulation


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time and it is due to the cation molecules transferred among 4 clusters made by [2(Me)2(C11)im]I IL. From the maximum cluster size results, it can be observed that the most probable cluster with maximum size in simulation time occurs with 125 cation molecules in [2(Me)2(C11)im]I/water system. The average of maximum cluster size in [2(Me)2(C7)im]I contains 1373 cation atoms (corresponding to about 24 cation molecules ). The average cluster size atoms of [2(Me)2(C15)im]I is 31800 that indeed holds all 300 IL cations involved. So, the simulations reveal that [2(Me)2(C15)im]I IL can make only one highly stable cluster, which is, on the other hand, more stable quantitatively than [2(Me)2(C7)im]I and [2(Me)2(C11)im]I ILs. The ILs with long alkyl chain show larger domains and more ordered structure than small alkyl chain ones. The biggest IL ([2(Me)2(C15)im]I) is feasible to build a vesicle with a bilayer wall that cation alkyl chains located in an interdigitated forms, which is similar to the earlier reports for single chain imidazolium ILs.39

50

35000

(a)

45

(b)

30000

40

[2(Me)2(C₇)im]I - Cation [2(Me)2(C₁₁)im]I - Cation [2(Me)2(C₁₅)im]I - Cation

25000

35

Number of atoms

Number of clusters

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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30 25

[2(Me)2(C₇)im]I - Cation

20

[2(Me)2(C₁₁)im]I - Cation

15

[2(Me)2(C₁₅)im]I - Cation

20000 15000 10000

10 5000

5 0

0 0

5000

10000

15000

20000

0

Time/ps

5000

10000

Time/ps


15000

20000

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35000

(c)

30000 [2(Me)2(C₇)im]I - Cation

Number of atoms

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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25000

[2(Me)2(C₁₁)im]I - Cation [2(Me)2(C₁₅)im]I - Cation

20000 15000 10000 5000 0 0

5000

10000

15000

20000

Time/ps

Figure 7. Cluster size plots (a) Number of clusters made by cation of ILs in IL/water systems, (b) Number of cation atoms in average cluster size, (c) Number of cation atoms in cluster with maximum size. Mean Square Displacement. Transport properties are the important symbol of the particle dynamics within the ILs/water systems during the simulation. The MSDs for cations and anions of ILs for the last 10 ns of simulation are shown in Figure 8. It can be observed that the MSD of cations are lower than anions, and the MSD of cations and anions decreases by increasing the cation chain length. The anion dynamics substantially decreases on going from [2(Me)2(C7)im]I to [2(Me)2(C11)im]I and [2(Me)2(C15)im]I; the cations dynamics decreases steadily among cation. Therefore, under roughly the same weight% of IL/water solution, the larger IL the lower the dynamics of both cation and anion.


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160 [2(Me)2(C₇)im]I - Cation [2(Me)2(C₇)im]I - Anion [2(Me)2(C₁₁)im]I - Cation [2(Me)2(C₁₁)im]I - Anion [2(Me)2(C₁₅)im]I - Cation [2(Me)2(C₁₅)im]I - Anion

120 MSD/ nm2

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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80

40

0 0

2000

4000

6000

8000

10000

Time/ps

Figure 8. MSD of cation and anion of ILs for the last 10 ns of simulation.

Membrane Formation. Hence, like the phospholipid molecules, the [2(Me)2(C15)im]I IL can form the stable vesicle and crucially the concept of bilayer membrane can be studied by IL membrane structure in the water phase. According to Marrink et al.30 that performed the MD simulation of lipid membrane by phospholipid molecules, we applied the same ratio of IL/water molecules (Table 1) for attaining the large scale simulation of [2(Me)2(C15)im]I IL bilayer membrane, as detailed in Supporting Information. The snapshot of first and final simulation steps are shown in Figure 9(a) and Figure 9(b), respectively. The stable IL membrane in water can be constructed after 100ns simulation which imidazolium molecules distributed in the middle of the box and water molecules at both side of IL leaflets in bilayer. The following analyses affirm the bilayer membrane structure and its properties in details.


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Figure 9. The snapshots of simulation step of [2(Me)2(C15)im]I IL/water system. (a) 0 ns, (b) 100 ns at 310K. Head group atoms, pink; cation alkyl atoms, cyan; iodide, purple; oxygen of water molecules, blue; No H atoms are shown. Energy variations of IL/water system at different stages demonstrate the necessity of a heatingcooling process on the rate of bilayer formation in a reasonable simulation time scale. Potential energy of IL/water system evolves smoothly in the initial simulation stage at 310 K (Figure S2(a), Supporting Information) and indicates no appreciable tendency towards an ordered bilayer formation within 50 ns. The potential energy after heating (to 350 K) increases appreciably (by about 9.15%), which qualifies the system passing through barrier for bilayer formation process. The trend of van der Waals (vdW) intermolecular interaction potential (decreasing by 694%) reveals an aggregation behavior transforming cation alkyl chains into completion of an organized bilayer construction (Figure S2(b), Supporting Information), while vdW interactions between alkyl chain increase substantially. The total and kinetic energies (Figures S2(c) and S2(d), Supporting Information) also affirms the passing this barrier and bilayer construction under a heating-cooling cycle. Variation of potential energy in heating-cooling cycle suggest the pattern of free energy profile for deriving and shaping an organized bilayer. Number Density of Membrane. Density profile of iodide anion, head group, tail carbons (C22 and C37) of ILs and water demonstrate (Figures 10(a)-(e)) the framework of IL bilayer formation


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consistent with the experiment.29 Imidazolium cation head groups protrude to the water phase having iodides at the vicinity, which is susceptible to penetrate deep into water. The maximum of number density for alkyl tail carbons (C22, C37) show maxima symmetrically at the middle of head group maxima, which indicates tail carbons of each leaflet of ILs are taking distance from water molecules phase. The water density under maxima neighborhood is the lowest. The final density profile at 310 K (improved further by continuing the simulation for last 10 ns with rcut-off=2.0 nm) is very similar to the lipid membrane.30 So, these evidences highly update our impression to conclude a new IL artificial membrane.

Number Density/nm-3

Number Density/nm-3

20

50 ns, 310 K 20 ns, 350 K 10 ns, 330 K 10 ns, 310 K 10 ns, 310 Kᵃ

(a)

1.2

0.8

0.4


(b)

15

10

5

0.0 -3

-2

-1

0

1

2

0

3

-3

-2

-1

Z/nm


(c )

1.5

1.0

0.5

0.0 -3

-2

-1

0

0

1

2

3

Z/nm

1

2

3

2.0

Number Density/ nm-3

2.0

Number Density/nm-3

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Langmuir


(d )

1.5

1.0

0.5

0.0 -3

-2

Z/nm

-1

0

Z/nm


1

2

3

Langmuir

(e )

50 ns, 310 K 20 ns, 350 K 10 ns, 330 K 10 ns, 310 K

120.0

Number Density/nm-3

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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10 ns, 310 Kᵃ

80.0

40.0

0.0 -3

-2

-1

0

1

2

3

Z/nme

Figure 10. Number density profile of (a) iodide anion, (b) head group, (c) C22 (tail carbon), (d) C37 (tail carbon) of [2(Me)2(C15)im]I IL and (e) water molecules during simulation steps. (aThe final stage of simulation is performed at rcut-off=2 nm) Radial distribution Function of Membrane. The RDFs in Figure 11(a) indicates that C12 and C27 (the middle alkyl chain) carbon atoms are maximally correlated with tail carbons C37 and C22, respectively. This strong correlation presents at short-range importantly extends with appreciable probability at long-range too. Such strong organization is consistent with dialkyl chains of one cation IL embedded inside that of another one, which is located and extend in reverse direction relative to each other across the bilayer arrangement. The evenly appreciable correlations is shown with the second, third and etc. The nearest alkyl neighbors confirm long-range order between dialkyl chains. The sharp peak, at about 1.26 nm, appeared in C12-C22 and C27-C37 in RDF diagrams indicate the intramolecular interaction between middle (C12, C27) and tail (C22, C37) carbons in each alkyl chain. The RDF of tail carbons of IL bilayer in membrane form (Figure 11(a)) is a bit different from the vesicle form (Figure 2(c)). In the vesicle form the tail-tail carbons show the higher correlation than tail-middle carbon and it is due to the asymmetric distribution of ILs molecules in top and bottom leaflets of bilayer. More IL’s head groups are located in the outer


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surface of vesicle which protrudes toward the water and fewer ILs’ head group are placed on the reverse side in the inner surface where the water molecules fill in the vesicle hole. Therefore the more ILs in the top leaflet, the more correlation between their tail-tail carbons of that leaflet. This leads to a less correlation between the tail-middle carbons of top and bottom (reverse) ones. In the bilayer membrane, the molecules are distributed symmetrically in both top and bottom leaflets and the atomic correlations can be discussed better than vesicle form. The thickness of IL bilayer in vesicle (2.62nm, Figure 3) is near to the bilayer thickness (at 2.66 nm, presented in Table 2) in membrane structure and it confirms the same structures of bilayers in vesicle and membrane forms. As shown in Figure 11(b), the iodide anions are near the head group of imidazolium cations. This is also shown in Figure 4(c), for vesicle structure. C₁₂ - C₁₂ C₁₂ - C₂₂ C ₁₂ - C₃₇ C₂₇ - C₂₂ C₂₇ - C₂₇ C₂₇ - C₃₇

(a)

4.0

3.0

g(r)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Langmuir

2.0

1.0

0.0 0.0

0.4

0.8

1.2

1.6

r/nm


2.0

Langmuir

5.0

(b)

H₂-I C₂ - I

4.0

N₁ - I N₃ - I C₄ - I

3.0

C₅ - I

g(r)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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2.0

1.0

0.0 0.0

0.4

0.8

1.2

1.6

2.0

r/nm

Figure 11. (a) RDF for C12 and C27 carbons of each alkyl chain of [2(Me)2(C15)im]I IL with middle carbons (C12, C27), C12 and C27 and tail carbons(C22, C37) at equilibrium for the last 10 ns simulation. (b) RDF for iodide anion with head group atoms of [2(Me)2(C15)im]I IL at equilibrium for the last 10 ns simulation. The heat effect on both RDF diagram and potential energy at different simulation time scales for C12-C12 can be seen in Figure 12. (Also, the time-dependent RDF diagrams of C12-C12 are offset in one plot as shown in Figure S3(a), Supporting Information). The RDF (Figure 12) illustrate that by heating (to 350 K), the potential energy of the system increases and the long-range correlations enhance and gradually appear with well-defined sharper peaks (compare with 50 ns at 310 K). These long-range, as well as short-range correlations, are enhanced upon cooling to lower temperatures at the final stage of the simulation. Continuing simulation at an extended cut-off distance (up to 2 nm) for last 10 ns refined the correlation peaks. The effect of heating treatment cycle displays the same time-dependent RDF diagram for other carbons of cation alkyl chain (as shown in Figures S3(b)-(h), Supporting Information). Hence, a strong short- and long-range correlations between the middle and tail carbon atom of the dialkyl group is established and qualifies the well-organized IL head groups and the alkyl chains as lipid-like bilayer membrane.


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-150000 60-70 ns

Potential Energy/kJ.mol-1

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Langmuir

-160000

70-80 ns 40-50 ns 90-100 ns

-170000


-180000

-190000 0

20

40

60

80

100

Time/ns

Figure 12. The variations of potential energy and RDF of C12-C12 of [2(Me)2(C15)im]I IL at different simulation time scales. (a The final stage of simulation is performed at rcut-off= 2 nm) The head group arrangement of IL in water phase (Figure 10(a)) can be influenced by its electrostatic charge. The net charge of head group atoms (N1, N3, C4, C5, C2, C6(CH3), C7(CH3) and H2) is about +0.616e, which is the most positive charge environment in this IL. This results in appreciable head-head repulsion interaction and pushes the whole ILs assembly away from each other. Hence, various relative structures and positioning are made possible. For instance, ILs heads stay optimally far from each other and provide the possibility of stress-free inter-diffusion of dialkyl chain as demonstrated in Figure 13(a). This interdigitated structure41 is owing to the repulsion between the IL’s head groups, which is absent in zwitterion phospholipid and exist in cationic lipid membrane.41-43 The free space seen in this case of IL is absent in the phospholipid bilayer. The zwitterionic form of phospholipid molecules originates an electrostatic interaction due to the positive and negative parts in the head group region44, and the non-interdigitated bilayer formation is made possible by the specific zwitterionic arrangement of lipid membrane, so the free space seen in this case of IL is absent in the phospholipid bilayer. This accounts why the structure of present IL bilayer and zwitterionic phospholipid membrane is different, hence a different expectation arises. Accordingly, some IL alkyl chains interlay in between two chains of another


Langmuir 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

dialkyl chain (Figure 13(b) and Figure 13(c)) to accommodate maximum vdW interactions in alkyl chains, leading to construction of packed alkyl zone in between two arrays of imidazolium head groups. This special packaging is also due to the organization by the virtue of C 4=C5 from which the dialkyl are branched as dangling double strands. Such an extra packing is absence in phospholipid double strand, which involves only one single chiral C atom from which the double strand is branched. Therefore, the dialkyl strands of upper IL array penetrate and interlay into the dialkyl assembly of the lower one across the bilayer. This featured structure of two alkyl chains, each being attached to different imidazolium ring carbon (C4 and C5) atoms, is relevant to the divers pattern of parallel and perpendicular interdigitated arrangement observed (Figure 13(d)).

Figure 13. The snapshots of positioning of the imidazolium cations relative to each other (For clarity some molecules are selected from 128 molecules of ILs at the end of simulation time; no H atoms are shown). Head group atoms, pink; alkyl chains, cyan and green; C12 and C27 atoms, red; C22 and C37, blue. Membrane Properties. From 128 IL ion-pairs initially distributed randomly (within 3792 water molecules), the final bilayer formed consists of 62 ion-pairs arranged in the top leaflet and 66 ionpair in the bottom leaflet, which demonstrate the tendency of IL aggregation into bilayer with accurate symmetry. The surface area/IL (AIL) is about 0.754nm2 (calculated via GridMAT-MD


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Page 25 of 32

analysis tool45), which is more than area per lipid in realistic cellular membrane lipid46 and this is somehow accordance with the cationic lipid membrane.44, 47 This excess surface is not only due to imidazolium ring size but also due to the special packing of interdigitated dialkyl. The Bilayer Thickness (h). h is determined for IL system, based on C2 atom of the IL head group as a reference atom, using the GridMAT-MD analysis tool 45(Figure 14). The thickness of bilayer involving this IL is smaller than different lipid bilayer

46, 48

because of shorter chain length and

more effective vdW interaction with inverted interlaid alkyl chain. The values of surface area/IL, bilayer thickness and average order parameters are reported in Table 2.

2.4 2.6 2.8 3.0 3.2 3.4

6

5

4

y/nm

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Langmuir

3

2

1

0 0

1

2

3

x/nm

4

5

6

Figure 14. The thickness of IL bilayer. The time average is over the last 10 ns of the simulation. The legend shows the IL bilayer thickness (nm). Deuterium Order Parameters of [2(Me)2(C15)im]I IL in Membrane. Deuteron Magnetic Resonance (DMR) is used to determine the deuterium order parameter experimentally. The deuterium atom can be attached to any position in a molecule through suitable chemical synthesis and the differences between the different positions of the molecule can be observed and no structural changes can be seen by replacing the hydrogen by deuterium. In these spectra, only the deuterium signal of the labeled molecule can be detected and assigned unambiguously.49 Deuterium order parameters are useful in the determination of liquid-ordered or liquid disordered


Langmuir 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 26 of 32

phase of the lipid bilayer. The acyl chains behavior in lipid bilayers can be investigated via the orientational order parameter, SCD, which can be obtained experimentally by the spectroscopic method of quadrupolar splitting, ∆vQ: ∆vQ = 3/4(e2qQ/h)SCD

(3)

where e2qQ/h is the quadrupolar coupling constant.50 In MD simulation, deuterium order parameters are obtained for each carbon atoms along the sn-1 and sn-2 tails using the second order Legendre polynomial −

where

is

( ) = (3〈cos

〉 − 1)

(4)

the angle between the carbon–deuterium bond (hydrogen for the simulations) of the

n-th carbon atom of the alkyl chain and the membrane normal. Here, the brackets show the averages over time. Due to fact that -SCD(n) which is obtained experimentally for acyl chain in phospholipid molecules51 are in good agreement with MD simulation results, the deuterium order parameter (Figure 15) for C atoms along the sn-1 and sn-2 chains of [2(Me)2(C15)im]I IL is obtained to conclude the behavior and structural arrangement as compared with phospholipid molecules in lipid bilayer. The -SCD(n) of [2(Me)2(C15)im]I is a bit more than the phospholipid molecules46, 52 which is due to the stronger vdW interactions between more orderly packed alkyl chains in IL than in lipid bilayer.


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H C

0.45

C

C

C C

sn-1

C

C

C

C

C

C

C

C

C

C

C

C

C

C 14 C

C14 C

0.2 0

2

4

6

8

10

12

14

C C

C

C

0.25

C2 C

C

C

0.3

C

C

C

sn-2

C

N

C2

0.35

I

N

0.4

-SCD

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Langmuir

sn-2

sn-1

Cn

Figure 15. Deuterium order parameters of individual carbon atoms of sn-1 and sn-2 (two- alkyl chain of IL) in [2(Me)2(C15)im]I IL.

Table 2. Structural properties determined for IL/water system for membrane formation over the course for the last 10 ns at 310 K including surface area (AIL) per IL, bilayer thickness (h), and average order parameters ( −〈

〉 )for the sn-1 and sn-2 tails.

System

AIL /nm2

h/nm

IL/water(membrane)

0.754

2.660

−〈

〉 0.397

−〈

〉 0.402

CONCLUSION In summary, this MD simulation of double-strand ILs based lipid represents different structure in the water phase. As the chain length of ILs increases, the aggregation number increases consistent with experimental observations.29 In water phase, the [2(Me)2(C7)im]I ILs construct domains with high dynamics and [2(Me)2(C11)im]I form the large size micelles. The formation of stable IL vesicle and membrane in molecular details with the structure comparable with realistic cellular membrane is made by [2(Me)2(C15)im]I spontaneously. By comparing the


Langmuir 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

[2(Me)2(C15)im]I IL bilayer thickness and order parameter with cellular membrane it can be seen that the bilayer thickness of [2(Me)2(C15)im]I IL is less and -SCD(n) is more than cellular membrane. So, [2(Me)2(C15)im]I IL make an interdigitated bilayer that is more packed than cellular membrane and the RDF plots of IL membrane confirm these conclusions. Despite a bit different in [2(Me)2(C15)im]I IL and lipid structures, this IL bilayer is very similar to lipid construction. Therefore, the results open a new insight on using the lipid-like materials in the different processes. Due to the renewability and stability of [2(Me)2(C15)im]I IL in water phase, it is affordable to be used in biological and pharmaceutical fields. As a part of sustainability, it is invaluable to apply this IL in drug delivery that has been commenced in our group.

CONFLICTS OF INTEREST The authors declare no competing financial interests.

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected], [email protected]

ACKNOWLEDGMENT Authors are indebted to the research council of Shiraz University for the financial support. Computer time is partly provided by High-Performance Computing research laboratory of Institute for Research in Fundamental Sciences (IPM). Also, computer time provided in part by the University of Houston uHPC founded by NSF (Award No. ACI: 1531814).


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Supporting Information Provided in two files involving details of simulation methods for Membrane formation, energy, RDF graphs and force field parameters are presented in Supporting Information. The following files are available free of charge. REFERENCES 1. Young, R. C.; Mitchell, R. C.; Brown, T. H.; Ganellin, C. R.; Griffiths, R.; Jones, M.; Rana, K. K.; Saunders, D.; Smith, I. R. Development of a new physicochemical model for brain penetration and its application to the design of centrally acting H2 receptor histamine antagonists. J. Med. Chem. 1988, 31 (3), 656-671. 2. Perlovich, G. L.; Kazachenko, V. P.; Strakhova, N. N.; Schaper, K.-J.; Raevsky, O. A. Solubility and transfer processes of some hydrazones in biologically relevant solvents. Journal of Chemical & Engineering Data 2013, 58 (9), 2659-2667. 3. Perlovich, G. L.; Kazachenko, V. P.; Strakhova, N. N.; Raevsky, O. A. Impact of sulfonamide structure on solubility and transfer processes in biologically relevant solvents. Journal of Chemical & Engineering Data 2014, 59 (12), 4217-4226. 4. Józan, M.; Takács-Novák, K. Determination of solubilities in water and 1-octanol of nitrogen-bridgehead heterocyclic compounds. Int. J. Pharm. 1997, 159 (2), 233-242. 5. Alantary, D.; Yalkowsky, S. Calculating the Solubilities of Drugs and Drug-Like Compounds in Octanol. J. Pharm. Sci. 2016, 105 (9), 2770-2773. 6. Perlovich, G.; Volkova, T.; Sharapova, A.; Kazachenko, V.; Strakhova, N.; Proshin, A. Adamantane derivatives of sulfonamides: sublimation, solubility, solvation and transfer processes in biologically relevant solvents. Phys. Chem. Chem. Phys. 2016, 18 (13), 9281-9294. 7. Hall, L. M.; Hall, L. H.; Kier, L. B. Methods for predicting the affinity of drugs and druglike compounds for human plasma proteins: a review. Curr. Comput. Aided Drug Des. 2009, 5 (2), 90-105. 8. Blokhina, S. V.; Ol’khovich, M. V.; Sharapova, A. V.; Proshin, A. N.; Perlovich, G. L. Partition coefficients and thermodynamics of transfer of novel drug-like spiro-derivatives in model biological solutions. The Journal of Chemical Thermodynamics 2013, 61, 11-17. 9. Carpenter, T. S.; Kirshner, D. A.; Lau, E. Y.; Wong, S. E.; Nilmeier, J. P.; Lightstone, F. C. A method to predict blood-brain barrier permeability of drug-like compounds using molecular dynamics simulations. Biophys. J. 2014, 107 (3), 630-641. 10. Tew, G. N.; Liu, D.; Chen, B.; Doerksen, R. J.; Kaplan, J.; Carroll, P. J.; Klein, M. L.; DeGrado, W. F. De novo design of biomimetic antimicrobial polymers. Proceedings of the National Academy of Sciences 2002, 99 (8), 5110-5114. 11. Srinivas, G.; Discher, D. E.; Klein, M. L. Self-assembly and properties of diblock copolymers by coarse-grain molecular dynamics. Nature materials 2004, 3 (9), 638-644. 12. Chakraborty, A. K.; Golumbfskie, A. J. Polymer Adsorption–Driven Self-Assembly of Nanostructures. Annu. Rev. Phys. Chem. 2001, 52 (1), 537-573. 13. Förster, S.; Zisenis, M.; Wenz, E.; Antonietti, M. Micellization of strongly segregated block copolymers. The Journal of chemical physics 1996, 104 (24), 9956-9970.


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14. Antonietti, M.; Förster, S. Vesicles and liposomes: a self‐assembly principle beyond lipids. Advanced Materials 2003, 15 (16), 1323-1333. 15. Hamley, I. Nanoshells and nanotubes from block copolymers. Soft Matter 2005, 1 (1), 3643. 16. Wang, H.; Wang, J.; Zhang, S.; Xuan, X. Structural effects of anions and cations on the aggregation behavior of ionic liquids in aqueous solutions. The Journal of Physical Chemistry B 2008, 112 (51), 16682-16689. 17. Zhao, Y.; Gao, S.; Wang, J.; Tang, J. Aggregation of Ionic Liquids [C n mim] Br (n= 4, 6, 8, 10, 12) in D2O: A NMR Study. The Journal of Physical Chemistry B 2008, 112 (7), 2031-2039. 18. Blesic, M.; Lopes, A.; Melo, E.; Petrovski, Z.; Plechkova, N. V.; Canongia Lopes, J. N.; Seddon, K. R.; Rebelo, L. s. P. N. On the self-aggregation and fluorescence quenching aptitude of surfactant ionic liquids. The Journal of Physical Chemistry B 2008, 112 (29), 8645-8650. 19. Wang, J.; Wang, H.; Zhang, S.; Zhang, H.; Zhao, Y. Conductivities, volumes, fluorescence, and aggregation behavior of ionic liquids [C4mim][BF4] and [C n mim] Br (n= 4, 6, 8, 10, 12) in aqueous solutions. The Journal of Physical Chemistry B 2007, 111 (22), 6181-6188. 20. Wang, D.; Richter, C.; Rühling, A.; Drücker, P.; Siegmund, D.; Metzler‐Nolte, N.; Glorius, F.; Galla, H. J. A Remarkably Simple Class of Imidazolium‐Based Lipids and Their Biological Properties. Chemistry–A European Journal 2015, 21 (43), 15123-15126. 21. Jungnickel, C.; Łuczak, J.; Ranke, J.; Fernández, J. F.; Müller, A.; Thöming, J. Micelle formation of imidazolium ionic liquids in aqueous solution. Colloids and Surfaces A: Physicochemical and Engineering Aspects 2008, 316 (1-3), 278-284. 22. Voets, I. K.; de Keizer, A.; Stuart, M. A. C. Complex coacervate core micelles. Adv. Colloid Interface Sci. 2009, 147, 300-318. 23. Langevin, D. Complexation of oppositely charged polyelectrolytes and surfactants in aqueous solutions. A review. Adv. Colloid Interface Sci. 2009, 147, 170-177. 24. Gröschel, A. H.; Walther, A.; Löbling, T. I.; Schmelz, J.; Hanisch, A.; Schmalz, H.; Müller, A. H. Facile, solution-based synthesis of soft, nanoscale Janus particles with tunable Janus balance. J. Am. Chem. Soc. 2012, 134 (33), 13850-13860. 25. De las Heras Alarcón, C.; Pennadam, S.; Alexander, C. Stimuli responsive polymers for biomedical applications. Chemical Society Reviews 2005, 34 (3), 276-285. 26. Mahajan, S.; Sharma, R.; Mahajan, R. K. An investigation of drug binding ability of a surface active ionic liquid: micellization, electrochemical, and spectroscopic studies. Langmuir 2012, 28 (50), 17238-17246. 27. Garcia, M. T.; Ribosa, I.; Perez, L.; Manresa, A.; Comelles, F. Aggregation behavior and antimicrobial activity of ester-functionalized imidazolium-and pyridinium-based ionic liquids in aqueous solution. Langmuir 2013, 29 (8), 2536-2545. 28. Wang, D.; de Jong, D. H.; Rühling, A.; Lesch, V.; Shimizu, K.; Wulff, S.; Heuer, A.; Glorius, F.; Galla, H.-J. Imidazolium-Based Lipid Analogues and Their Interaction with Phosphatidylcholine Membranes. Langmuir 2016, 32 (48), 12579-12592. 29. Drücker, P.; Rühling, A.; Grill, D.; Wang, D.; Draeger, A.; Gerke, V.; Glorius, F.; Galla, H.-J. Imidazolium salts mimicking the structure of natural lipids exploit remarkable properties forming lamellar phases and giant vesicles. Langmuir 2016, 33 (6), 1333-1342. 30. Marrink, S. J.; Lindahl, E.; Edholm, O.; Mark, A. E. Simulation of the spontaneous aggregation of phospholipids into bilayers. J. Am. Chem. Soc. 2001, 123 (35), 8638-8639.


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From Micelles to Vesicle and Membrane Structures of Double Strand

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