Structural organization of surfactant aggregates in vacuo: a molecular dynamics and well-tempered metadynamics study.

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Physical Chemistry Chemical Physics View Article Online

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Structural organization of surfactant aggregates in vacuo. A molecular dynamics and welltempered metadynamics study

Giovanna Longhi,1,2 Sandro L. Fornili,3 Vincenzo Turco Liveri4 1

Dipartimento di Medicina Molecolare e Traslazionale, Università di Brescia, Viale Europa 11, 25123

Brescia, Italy 2

CNISM, Consorzio Interuniversitario Scienze Fisiche della Materia, Via della Vasca Navale 84, 00146

Roma, Italy 3

Dipartimento di Informatica, Università di Milano, Via Bramante 65, 26013 Crema (CR), Italy

4

Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche “STEBICEF”,

Università degli Studi di Palermo, Viale delle Scienze I, 90128 Palermo, Italy

Correspondence to:

Vincenzo Turco Liveri [email protected]

Abstract Experimental investigations by mass spectrometry have established that surfactant molecules are able to form aggregates in gas phase. However, there is not a general consensus on the organization of these aggregates and how it depends on the aggregation number and surfactant molecular structure. In the present paper we investigate the structural organization of some surfactants in vacuo by molecular dynamics and well-tempered metadynamics simulations to widely explore the space of their possible conformations in vacuo. To study how the specific molecular features of such compounds affect their organization, we have considered as paradigmatic surfactants the anionic single-chain sodium dodecyl sulfate (SDS), the anionic double-chain sodium bis(2-ethylhexyl) sulfosuccinate (AOT) and the zwitterionic single-chain dodecyl phosphatidyl choline (DPC) within a wide aggregation number range (from 5 to 100). We observe that for low aggregation numbers the aggregates show in vacuo the typical structure of reverse micelles, while for large aggregation numbers a variety of globular aggregates occurs that are characterized by the coexistence of interlaced domains formed by the polar or ionic heads and by the alkyl chains of the surfactants. Well-tempered metadynamics simulations allows to confirm that the structural organizations obtained after 50ns of molecular dynamics simulations are practically the equilibrium ones. Similarities and differences of surfactant aggregates in vacuo and in apolar media are also discussed.

Physical Chemistry Chemical Physics Accepted Manuscript

DOI: 10.1039/C5CP01926E

Physical Chemistry Chemical Physics

Page 2 of 14 View Article Online

DOI: 10.1039/C5CP01926E

Recently, we have investigated the behavior of aqueous nanodroplets containing sodium bis(2-


ethylhexyl)sulfosuccinate (AOTNa) in vacuo by molecular dynamics simulations[1]. Two concurrent processes occurring in a nanosecond time scale were observed in the case of neutral nanodroplets: the evaporation of the water molecules and the diffusion of AOTNa molecules (initially arranged as direct micelles within the water nanodroplets) at the nanodroplet surface, forming a layer of oriented surfactant molecules with the alkyl chains laying at the droplet surface. The combined action of these processes leads to anhydrous reverse micelle-like aggregates characterized by an internal core formed by the surfactant head groups and an external layer constituted by its alkyl chains (aggregation number up to 10 has been examined in Ref. 1). Interestingly, while no significant difference between the structural organization of surfactant aggregates in vacuo and in apolar media was found in the polar micellar core, the external layer of the micelle constituted by the surfactant alkyl chains may differ considerably depending on the nature of the aliphatic tail[2,3]. The transition from aqueous phase to vacuum of surfactant aggregates has been also investigated by van der Spoel et al.[4,5] by studying the cases of cetyl trimethylammonium bromide (CTAB) and dodecyl phosphocholine (DPC). Simulations have shown that direct CTAB micelles (aggregation number 82) dry or coated by a layer of water molecules invert as reverse micelles within 3 ns when posed in vacuo. On the other hand, incomplete inversion in vacuo is claimed for a water-coated aggregate formed by the zwitterionic surfactant DPC (aggregation number 54) even after 100ns. It is worth to note that these investigations emphasize that formation of surfactant clusters in vacuo are mainly controlled by the molecular processes occurring in a very short time scale immediately after the gas-phase spraying of surfactant solutions. Moreover, recent investigations by mass spectrometry have reported experimental evidences suggesting that the structural organization of surfactant aggregates in vacuo is independent on their state in solution (monomeric or in micellar form) as well as on the nature of the solvent (polar or apolar)[6,7]. These findings indicate that the processes occurring during the spraying of surfactant solutions allow the loss of any memory of the surfactant state in solution and that the structural organization of surfactant aggregate in vacuo is determined only by the surfactant-surfactant intermolecular interactions. Taking into account that the structural features of surfactant aggregates in vacuo are of interest to evaluate their potential technological and biotechnological applications (such as atmospheric cleaning agents, exotic nanosolvents and nanoreactors for specialized chemical processes in confined space),


Introduction

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equilibrium structural organization of surfactant aggregates in vacuo. As starting structures, we


consider micelles equilibrated in water and then deprived of the surrounding water molecules, since they likely represent structures most different as compared with those expected in vacuo. Therefore, this approach enables us to check whether vacuum conditions are compatible with direct-micelle structure and to explore more widely the possible conformations of surfactant aggregates in vacuo. To this purpose we have also used the recently developed well-tempered metadynamics simulation method[8] to study the behavior of the anionic single-chained sodium dodecyl sulfate (SDS), the anionic double-chained sodium bis(2-ethylhexyl) sulfosuccinate (AOT) and the zwitterionic singlechained DPC in a wide range of aggregation numbers. These paradigmatic compounds have been chosen not only to compare the behavior of surfactants with different molecular structures but also because they are widely employed to study surfactant self-assembling in a variety of experimental conditions.

Computational methods The molecular geometries of AOT, SDS e DPC (see Figure 1-SI) were optimized at HF/6-31G* level. The GAFF[9] parameters for DPC were taken from Ref. 10 while those for AOT [3] and SDS were determined following the RESP approach (at HF/6-31G* level) and using the ANTECHAMBER module of AmberTools[11]. All simulations were performed for 50 ns at 300 K with an integration time of 2 fs using the GROMACS-4.6.5 molecular dynamics code [12], patched with the metadynamics plugin PLUMED2.0.2. [13]. The LINCS algorithm [14] was used to constrain all bonds. The long-range electrostatic interactions were handled with the PME scheme [14]. The non-bonded van der Waals cutoff radius was 10 Å. A Langevin thermostat was used to sample the NPT or NVT ensembles for MD or well-tempered metadynamics simulations, respectively[8]. Each micellar system was firstly simulated in water to induce a direct-micelle conformation, then in vacuo using firstly the classical MD approach and then the well-tempered metadynamics method. The initial configuration for the simulations of aqueous systems was obtained using the LEaP [11] or PACKMOL [15] to form approximate micelles and then using GROMACS preprocessing routines to add TIP3P water molecules and to neutralize the system charge with sodium ions. The resulting periodic dodecahedral box was such that the minimum distance among micelle atoms and box boundary was 1.0 nm at least.


here we report findings of a molecular dynamics simulation (MD) study aiming to ascertain the



DOI: 10.1039/C5CP01926E

removing water and ions from the corresponding final configuration in water, neutralizing the micelle metadynamics simulations were initiated with the last configuration of the corresponding MD simulation in vacuo. For the well-tempered metadynamics simulations, bias was applied to the gyration radius Rgh of the pivot atoms of the surfactant head group (S for AOT and SDS, and P for DPC) and to the gyration radius of the terminal aliphatic carbon atoms, Rgt. Statistical analysis of the trajectories was performed with GROMACS routines, 3V program[16] was used to evaluate aggregate volumes and VMD[17] for structural analysis.

Results and Discussion Molecular dynamics experiments Molecular dynamics simulations show that AOT, SDS and DPC direct micelles devoid of surrounding water molecules are highly unstable when placed in vacuo. In particular, due to the absence of the hydrophobic effect and to the leading role of the surfactant head-head interactions in vacuo, they undergo in a picoseconds time scale a dramatic structural change characterized by a rapid decrease of the potential energy of the aggregate and of the gyration radius Rgh. As representative examples, Figure 1 shows the time dependence of the aggregate potential energy (Ep, left panel) and of the gyration radius of S atoms (Rgh, right panel) for AOT aggregates with aggregation numbers 5 and 100, which hereafter will be indicated as [AOT5] and [AOT100]. 3.0

0 -20000

2.5

-40000 -60000

---- [AOT100]

--- [AOT100]

2.0

-80000

Rgh (nm)

Ep (kJ/mol)


charge with sodium ions using LeaP, and placing it into a periodic cubic box of edge 10.0 nm. The

0

1.5

-1000 -2000

1.0

----[AOT5]

-3000

--- [AOT5]

0.5

-4000 0

10000

20000

30000

time (ps)

40000

50000

0

10000

20000

30000

40000

50000

time (ps)

Figure 1 Potential energy (left panel) and gyration radius of S atoms (Rgh, right panel) for AOT aggregates with aggregation numbers 5 (black line) and 100 (red line) as a function of the simulation time.


The initial system configuration for each subsequent MD simulation in vacuo was obtained by

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further change is observed in a 50 ns time window, apart from thermal fluctuations of Ep and Rgh. On


the other hand, for [AOT100] the initial rapid decrease of Ep and Rgh is followed by additional less marked changes occurring in a time scale of nanoseconds. This behavior emphasizes the presence of conformational multiplicity of aggregates which increases with the aggregation number (Nag) and slows down the attainment of more energetically stable conformations. Similar trends of Ep and Rgh have been observed for SDS and DPC aggregates, as shown in Figure 2-SI. In Figure 2, we show the Ep and Rgh change vs. Nag for the final conformations of 50-ns MD simulations in vacuo with respect to the corresponding initial conformations. 0

AOT SDS DPC

∆ EP -1

(kJmol )

0 ∆ R gh /N ag

-30000 0

∆ Ep/Nag

0

-0.1

-60000

∆ R gh (nm) -900 0

20 40 60

80 100

-1

-90000 0

20

40

60

80

100

N ag

0

20

40

60

80

-0.2 N 100 ag

Figure 2 Change of potential energy (∆Ep, and of ∆Ep/Nag in the inset, left panel) and gyration radius of the head group pivot atoms (∆Rgh and correspondingly ∆Rgh/Nag, right panel) vs. Nag for the final conformations of 50-ns MD simulations in vacuo with respect to the corresponding initial conformations of AOT, SDS and DPC. The negative ∆Ep values indicate that the structural change from direct micelle to aggregates in vacuo is energetically favorable. Besides, it is of interest to point out that at each aggregation number the ∆Ep value for DPC is significantly lower than those of AOT and SDS. This can be attributed to the nature of surfactant molecules involving substantial differences in the electrostatic interactions among surfactant head groups. Indeed, DPC is characterized by a zwitterionic head while AOT and SDS possess an anionic head whose strong interaction with the sodium counterions allows for a more easy rearrangement of head group atomic charges. Moreover, the ∆Rgh values show surfactant-specific


It is worth to note that for [AOT5] the structural change is completed in a few picoseconds, i.e., no



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shape and internal organization of both direct micelles and aggregates in vacuo, but more interestingly


they are always negative. This suggests that from a geometrical point of view the structural change from direct micelle to aggregates in vacuo implies mainly a change of the surfactant head groups position from the aggregate surface towards its core. More insight can be achieved considering ∆Ep/Nag and ∆Rgh/Nag shown in Figure 2. As to the ∆Ep/Nag trends, DPC shows a behavior different from those of AOT and SDS, further emphasizing the role of the surfactant head group. Instead, the ∆Rgh/Nag trends indicate a relative more marked structural change for the smaller aggregates than for the larger ones, implying that the tendency of the aggregate to invert decreases with Nag. To give a direct evidence of the structural features of surfactant aggregates, Figure 3 shows, as representative examples, the [AOT5] and [AOT100] systems at the start (t=0ns) and at the end (t=50ns) of the corresponding MD simulations in vacuo. Similar snapshots of all the investigated systems are collected in Figure 3-SI.


trends as a function of Nag, reflecting the overlap of multiple effects caused by the changes of size,

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Figure 3 Snapshots of [AOT5] and [AOT100] aggregates at the start (t=0ns), and at the end (t=50ns) of MD simulations in vacuo. Sodium ions (blue), and sulfur and oxygen atoms (yellow and red, respectively) of the SO3- polar heads are displayed in a space-filling mode to evidence their location, whereas alkyl chains are displayed as black lines and hydrogen atoms are not shown, to avoid crowding. Figure 3 shows that the initial configuration of [AOT100] is characterized by the typical structure of direct micelles, i.e., head groups at the surface of the aggregate and alkyl chains crowded to form an internal apolar core, while the surfactant tails are largely outwardly exposed in the case of [AOT5]. On the other hand, while at low aggregation number AOT forms in vacuo reverse micelle-like aggregates (head groups in the core and alkyl chains protruding towards the assembly exterior), surprisingly, at high aggregation number the formation of globular aggregates characterized by the coexistence of interlaced polar and apolar domains is observed. Such aggregation pattern is markedly different from that found in condensed apolar media, where elongated cylindrical or ellipsoidal aggregates are present[7]. Since in the center of nearly spherical aggregates there is not enough room to accommodate all the head groups, the peculiar structure shown in vacuo by the surfactant aggregates at sufficiently high aggregation number suggests that in vacuo the formation of globular assemblies is strongly preferred. This is in agreement with the findings by Robinson et al., who observe by linear field ion mobility mass spectrometry that surfactant aggregates (in particular, a series of n-alkyl trimethyl ammonium bromides) show a spheroidal shape even at very high aggregation number (up to 180)[7].



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present findings is that in vacuo surfactant head groups and alkyl chains self-assemble forming globular


aggregates characterized by spatially separated polar and apolar nanodomains. It can be envisaged that such peculiar structure results from a compromise between the tendency to maximize the electrostatic head-head interactions and minimize the alkyl chains/vacuum interface. The latter feature is obviously absent when surfactant aggregates are dispersed in apolar media leading to a different structural arrangement for large aggregates. In the case of SDS, this feature leads to the existence of aggregates in vacuo but not in apolar media[18]. To gain a deeper insight into the coexistence of polar and apolar nanodomains inside surfactant aggregates in vacuo, we used the Voss Volume Voxelator program “3V” [16], based on the rolling probe method [19,20], with a 25Å probe radius applied to the whole aggregate to evaluate the total volume (Vtot), and with 1Å and 25Å probe radii applied to the surfactant head groups (SO3+Na for AOT, SO4+Na for SDS and PO4+N for DPC) to estimate the volume of the polar domain and that of the inner apolar regions (see Fig.3, t=50ns). Indeed, with the 1Å radius we evaluate the volume of the polar domain only (V1Å-heads), while with the 25Å radius we evaluate the volume of the region that includes also the apolar domain surrounded by the polar one (V25Å-heads). Thus, the quantity Vint =V25Åheads-V1Å-heads

is an estimate of the volume of the apolar domain secluded in the interior of the

aggregate. On the other hand, the quantity Vext =Vtot-V25Å-heads estimates the volume of the apolar domain totally exposed to the aggregate exterior. A vivid picture of Vext and Vint of the [AOT100], [SDS100] and [DPC100] aggregates is shown in Figure 4. Qualitatively, it can be noted that all of them show a more or less extended external hydrophobic layer (gray domain) as well as an internal hydrophobic region (cyan domain) surrounded by the surfactant polar heads (red domain).


It is, however, worth noting that the point of main theoretical and applicative interest coming from the

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[AOT100]

[SDS100]

[DPC100]

Figure 4 Representation of the polar and apolar domains within [AOT100], [SDS100] and [DPC100] aggregates in vacuo (gray, external hydrophobic domain; red, polar heads domain; cyan, internal hydrophobic domain). The external tails are also shown.

It is interesting to compare the opposite behavior of surfactant aggregates as direct-micelles and in vacuo by considering the Vext /Vtot and Vint/Vtot data shown in Figure 5, where these quantities are reported as a function of Nag for the final conformations obtained after 50-ns MD simulations in water (left panel) and in vacuo (rigth panel). Indeed Vext /Vtot decreases for direct-micelles and increases in vacuo, while Vint/Vtot increases in direct-micelles and decreases in vacuo. Moreover, while for the direct-micelles these trends show initially a rapid change followed by a plateau, in vacuo there is a slow and continuous change. One can also note that the behavior of surfactant aggregates in vacuo indicates that an increasing portion of surfactant alkyl chains tends to be secluded in the interior of the aggregates and this tendency is in the order DPC>>SDS>AOT.



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1.0

Vint/Vtot


0.8

0.8

0.6

0.6

0.4

0.4

Vint/Vtot

Vext/Vtot

0.2

Vext/Vtot

0.2

0.0

0.0 0

20

40

60

Nagg

80

100

0

20

40

60

80

100

Nagg

Figure 5 Vext /Vtot and Vint/Vtot quantities for the final aggregate conformations of 50-ns MD simulations in water (left panel) and in vacuo (right panel) for AOT, SDS and DPC as a function of the aggregation number (black lines, AOT; red lines, SDS; blue lines, DPC)

Metadynamics simulations Taking into account that surfactant aggregates in vacuo are obtained by 50-ns MD simulations starting from their typical conformations in water, it could be reasonably suspected that the attained structures are not the thermodynamically stable ones, which instead would be possibly obtained after a much longer simulation time. This because the initial dramatic structural changes could drive the aggregates towards conformations that are separated by high energy barriers from the equilibrium ones in vacuo. To establish if the conformations attained at the end of the 50ns molecular MD simulations correspond to the global free energy minimum or to kinetically trapped aggregates, we have used well-tempered metadynamics[8]. This simulation approach allows to accelerate the occurrence of rare events and at the same time provides an estimate of the free energy surface (FES) of the system as a function of some selected system collective variable(s). The system evolution is driven by a biasing potential built up as a sum of Gaussians which allows to explore the collective variable(s) space. As appropriate collective variables we have chosen the gyration radius of the surfactant head group pivot atom (S for AOT and SDS, and P for DPC) and the gyration radius of the terminal carbon atom of the alkyl chain. Welltempered metadynamics simulations is controlled by the height (h) of the Gaussians, their width (σ), the bias factor

b which regulates the progressive rescaling of the Gaussian height during the

simulation, and the frequency (φ=1/τ) at which they are added to the bias potential. We have assumed τ=4 ps for all simulations and we carried out preliminary calculations to select the most suitable h, b values, taking into account that higher h and b values lead to a larger range of the


1.0

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we have observed that the ensemble of the aggregate conformations does not include the direct micelle-


like structure. We have also found that high h and b values generally lead to aggregate fragmentation. A good compromise to gain a large range of collective variables and a fine description of the free energy landscape without fragmentation has been found using for all the investigated systems h=20, and b=20. The σ values, which have been determined as suggested in Ref. [21], are reported in Table 1SI. Figure 6 shows the free energy vs Rgh at various aggregation number for AOT, SDS and DPC.

AOT

[5]

[10]

[20]

[35]

[50]

[100]

SDS

[5]

[10]

[20]

[35]

[50]

[100]

DPC

0

0

0

FES

FES

FES

-100

-100

[5]

[10]

[20]

[35]

[50]

[100]

-100 -200

-200

-300

-300 0

0.5

1

1.5

Rgh2

-200 0

0.5

1

1.5

Rgh

2

0

0.5

1

1.5

Rgh 2

Figure 6 Free energy (FES) vs Rgh at various aggregation number for AOT, SDS and DPC The most important result is that the Rgh values at the global minimum are practically the same as those obtained at the end of 50ns of MD simulations in vacuo. This can be more clearly appreciated by comparing in Table 1 the latter Rgh values with those at the minimum of the free energy surface. Table 1. Rgh values at the end of 50ns MD simulations, Rgh (MD) and at the minimum of the free energy surface Rgh min (FES) AOT Nag

5 10 20 35 50 100

Rgh (MD) 0.37 0.47 0.89 1.32 1.43 1.87

Rgh min (FES) 0.32 0.49 0.85 1.31 1.47 1.88

SDS

Rgh (MD) 0.34 0.43 0.62 0.84 1.03 1.48

Rgh min (FES) 0.34 0.43 0.61 0.78 0.93 1.36

DPC

Rgh (MD) 0.45 0.66 1.05 1.16 1.44 1.93

Rgh min (FES) 0.45 0.60 1.03 1.10 1.32 1.89


explored collective variables but to a poorer quality of the free energy surface. In all cases, however,



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observed agreement indicates that there is no significant structural difference between the


conformations attained after 50 ns of MD simulation in vacuo and those at the global free energy minima obtained analyzing the metadynamics trajectories. Then it can be concluded that 50ns of MD simulations are long enough to reach the equilibrium conformation of the hereby examined surfactant aggregates. The same conclusion can be achieved considering the data of Vext/Vtot and Vint/Vtot shown in Table 2-SI. Thus, the interlaced-domain assemblies shown in Figure 3 and Figure 3-SI should be considered the most probable conformations of surfactant aggregates at high aggregation number.

Conclusions Using MD simulations and well-tempered metadynamics, simulations, we have investigated the structural organization of AOT, SDS and DPC aggregates in vacuo. In all examined cases, considering as initial conformations of the MD simulations in vacuo the typical direct-micelle structures obtained with MD simulations in water, it was found that these aggregates invert to form globular assemblies characterized by an internalization of the head groups. The major changes of the inversion process occur in a very short time scale (of the order of tens of ps) and is mainly controlled by the anisotropic surfactant-surfactant intermolecular interactions. For low aggregation numbers, reverse micelle-like aggregates are formed with an internal polar core surrounded by the surfactant alkyl chains, while at high aggregation numbers, a variety of aggregates are obtained, that are characterized by interlaced polar and apolar domains. Metadynamics simulations allow to assure that the conformations found after 50ns of MD simulations are practically the equilibrium ones. In conclusion, this investigation allows to emphasize that the structural organization of surfactant clusters in vacuo are determined by the molecular reshuffles driven by the surfactant-surfactant interactions. Moreover, the peculiar structure of surfactant aggregates in vacuo suggests that they can be used as effective atmospheric cleaning agents, nanosolvents and nanoreactors for specialized chemical processes in confined space. Further experimental and computational studies could shed more light on the role of intermolecular interactions (attractive, repulsive and steric) as driving forces of the supramolecular aggregation of surfactant molecules in absence of surrounding medium. This is particularly required since surfactant aggregates show in vacuo quite unique structural features distinct from those observed in apolar media.


Considering that the Rgh value is an effective probe of the structural organization of the aggregates, the

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Josephin Domain Structural Conformations Explored by Metadynamics in Essential Coordinates.

MM Molecular Dynamics with Advances in Metadynamics.

Molecular modeling study on the dynamical structural features of human smoothened receptor and binding mechanism of antagonist LY2940680 by metadynamics simulation and free energy calculation.

Structure, stability, and fragmentation of sodium bis(2-ethylhexyl)sulfosuccinate negatively charged aggregates in vacuo by MD simulations.

Temperature dependent dynamics of DegP-trimer: A molecular dynamics study.