MARTINI Coarse-Grained Model of Triton TX-100 ... - ACS Publications

Article pubs.acs.org/JPCB

MARTINI Coarse-Grained Model of Triton TX-100 in Pure DPPC Monolayer and Bilayer Interfaces Antonio Pizzirusso, Antonio De Nicola,* and Giuseppe Milano Dipartimento di Chimica e Biologia, Università di Salerno, via Giovanni Paolo II, Fisciano, Salerno I-84084, Italy S Supporting Information *

ABSTRACT: The coarse-grained MARTINI model of Triton TX-100 has been validated by direct comparison of the experimental and calculated area increase in pure DPPC lipid bilayers and monolayers at water/air interfaces in the presence of surfactant and by comparison of electron density profiles calculated with more detailed atomistic models based on the CHARMM force field. Bilayer simulations have been performed and compared with monolayers and with atomistic models. The validated CG model has been employed to study the phase separation of TX-100 molecules in lipid bilayers and the effect of the lipid bilayer curvature.

1. INTRODUCTION Triton X-100 (TX-100) is one of the most common nonionic detergents, and it is widely used in biological applications.1−5 TX-100 can be regarded as an “activator” of lipolytic enzymes;6 in fact, it is used to solubilize phospholipid membranes.1,2,7,8 The addition of TX-100 molecules to lipid vesicles causes the formation of mixed aggregates1 that are usually smaller with respect to pure lipid vesicles. Such process is called solubilization.9 The TX-100 is also used to purify and isolate transmembrane proteins.3,4,10−12 As an example, TX-100 has been used to isolate the integrin αIIbβ3 and to study, in a mimetic biomembrane environment, the conformational state of the protein.4,13 Selective isolation of glycosylphosphatidylinositolanchored proteins from cells and sphingolipid liposomes has been conducted, jointly with saponin, by Triton TX-100 surfactant.14 Mixed micelles formed by Triton, phosphatidylserine, and diacylglycerol have been used to study the kinase C protein activation.15 Another interesting application of Triton is related to the biological treatment of water. In fact, TX-100 is selective for the extraction of toxic eosin dye molecules from water solutions.5 The effect of the Triton on the lipid bilayer, in the process of extraction of transmembrane proteins and in the lipolytic process, is mainly related to the perturbation of lateral packing of the lipids.16 With this in mind, the understanding of the response of lipid bilayer to changes in area/molecule induced © XXXX American Chemical Society

by the presence of TX-100 surfactant is an important point. From the experimental point of view, the direct measure of the change of area/molecule in liposomes or lipid vesicles is very difficult.16 An alternative consists in the measure of area/molecule from a lipid monolayer, employing several techniques16−19 that usually give better results. Examples of the most common and comparable techniques include captive bubble,20,21 pendant drop,22 oscillating bubble,23,24 fluorescence microscopy,25 and Langmuir film surface balance.16,26,27 In the absence of quantitative data of area/molecule obtained from direct measurements performed on liposomes, data obtained from monolayer systems can be considered as well. In fact, it is assumed that under specific conditions of surface pressure (π ≈ 30 mN/m) the behavior of a monolayer can be approximated to the one of a lipid bilayer.16,28−31 Molecular dynamics (MD) simulations using coarse-grained (CG) models became very popular to study phospholipid systems because they can yield both molecular-level details and dynamics on a resolution and time scale not easy accessible by full atomistic simulations.32 The CG approach consists in the reduction of degrees of freedom of the atomistic model by grouping several atoms in a single particle (“effective bead”). The degree of the Received: January 20, 2016 Revised: March 31, 2016

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DOI: 10.1021/acs.jpcb.6b00646 J. Phys. Chem. B XXXX, XXX, XXX−XXX

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The Journal of Physical Chemistry B

(DPPC) monolayer. In particular, Duncan compared the experimental and simulated pressure−area isotherms using different atomistic and CG models in different ensembles (NVT, NPT, NπT). They reported that the best ensemble to correctly reproduce the area/lipid of a DPPC, monolayer at the water/air interface, is the surface tension coupling NπT (a definition and more details about this ensemble will be given later). Good results are also obtained for the NPT ensemble using a semi-isotropic pressure coupling. Similar results about similar DPPC monolayer systems are reported by Baoukina44 employing the CG MARTINI force field and Knecht35 using a different CG model.45 Differently from the huge amount of CG models for phospholipids, to the best of our knowledge, only a few models of Triton TX-100 are reported in the literature.46−49 In particular, an atomistic study on the conformational behavior of a single TX-100 molecule in vacuum and in water has been reported.46 A modified full atom CHARMM force field for the Triton X-series has been recently reported,47 and only a CG model of TX-100, based on the MARTINI force field, has been used in a study of membrane phase separation, as reported by Muddana.48 In addition, a hybrid CG model characterized by a field-based description of intermolecular interactions,50−52 employing a mapping 4:1 similar to MARTINI, has been recently reported in the study phase behavior of Triton TX-100 in water solution.49 To the best of our knowledge, no validation, in terms of area increase of pure DPPC mono- and bilayers systems in the presence of TX-100, has been reported in the literature. Furthermore, we only found a study of Muddana et al.48 in which the lateral organization of TX-100 in a mixed lipid bilayer of DPPC:DUPC has been investigated. In particular, we reported a systematic study considering a number of bicomponent systems formed by DPPC mono- and bilayers, including TX-100 molecules. The aim of the present work, first, is to validate the CG model of TX-100 on reproduction by direct comparison with experimental measurements of the area increases in mixed DPPC/TX-100 monolayers at the water/air interface and the area/Triton interface. Then the validated model has been applied to study, using MD simulations of large systems on the microsecond scale, the effect of TX-100 on the structure of lipid bilayers. The article sections are organized as follows. In section 2 the models of DPPC and Triton TX-100 used in the present

CG model, and consequently the level of details, can be selected to study different phenomena. As an example, a CG model with low details can be employed to study the selfassembly process involving a large number of molecules when the dynamics and the structure at the atomic level are not relevant for the phenomenon. CG MARTINI33 is a successful and widely used force field developed for many biological molecules, for example, phospholipids,34−38 sterols,33 sugars,39 peptides,40 and proteins.41,42 In the MARTINI CG model the effective beads interact through an intramolecular bond, angle, and eventually dihedral potentials and as for intermolecular interactions through Coulomb and Lennard−Jones (LJ) pair potentials. It is well known that the MARTINI force field is able to reproduce several structural and dynamic properties of phospholipids bilayers.34−38 Using the MARTINI model, Duncan43 and co-workers reported a detailed study on the behavior of area/lipid for the pure dipalmitoylphosphatidylcholine Scheme 1. Mapping Scheme of DPPC and Triton TX-100 Molecules for the MARTINI CG Modela

a

Beside each bead type is reported in black the MARTINI interaction type, while inside the red brackets are reported the used labels.

Figure 1. Initial configuration of pure DPPC monolayer. (A) CG configuration. (B) Atomistic configuration. CG water beads are reported in light blue, while the carbon tails of the DPPC molecule are depicted in gray. Head beads are reported in blue (NC3), red (PO4), and green (GLY). B


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The Journal of Physical Chemistry B Table 1. System Compositions for the Mixed Monolayer of DPPC/TX-100 system

no. of particles

no. of DPPC

no. of W

no. of TX-100

TX-100/DPPC

I II III IV V VI

49 904 50 380 50 884 51 360 17 247 1525

1250 1250 1250 1250 68 68

34 400 34 400 34 400 34 400 2517 639

36 70 106 152 8 8

0.030 0.056 0.085 0.122 0.122 0.122

box (nm) 20 20 20 20 4.56 4.56

× × × × × ×

20 × 28 20 × 28 20 × 28 20 × 28 4.54 × 6.8 4.54 × 6.8

time (ns) 60 60 60 60 20 20

study are described, and in the section 3 the results and discussion are presented for the validation of MARTINI models in the reproduction of percentage area increase of pure DPPC mono- and bilayer systems in the presence of TX-100. Moreover, results about the phase separation in lipid bilayers in the presence of TX-100, obtained from simulations on the time scale of microseconds, are discussed. Finally, in section 4 the conclusions are summarized.

2. MODELS AND COMPUTATIONAL DETAILS The MARTINI force field parameters have been employed for the CG models of DPPC37 and Triton TX-100.48 For atomistic models the CHARMM force field has been used for the DPPC and TX-100 molecules.47,53 All simulations have been performed using the GROMACS package version 4.5.54 In Scheme 1 the DPPC and Triton TX-100 chemical structures and the corresponding CG interaction sites are reported. 2.1. Coarse-Grained Models. The MARTINI force field has been used for DPPC and Triton TX-100 models.37,48 The nonbonded interactions are modeled by the Lenard−Jones (LJ) pair potential and electrostatic Coulombic potential. For both a cutoff rcut = 1.2 nm has been used; moreover, the LJ potential has been smoothly shifted to zero from the distance rshift = 0.9 nm to the cutoff. For electrostatic interactions a dielectric constant ε = 15 has been used. The neighbor list has been updated every 10 steps, and a time step of 0.03 ps has been employed for all CG simulations. The temperature has been kept constant by a Berendsen thermostat using a temperature coupling τT = 1.0 ps for the monolayer and τT = 1.5 ps for the bilayer systems. 2.2. Atomistic Models. Atomistic simulations have been performed employing the CHARMM force field.55,56 In particular, for the DPPC molecule we used the optimized CHARMM37 for the phospholipid bilayers,53 and for the atomistic Triton TX-100 molecule we used the model of Yordanova.47 In addition, the TIP3P57 water model has been used in all atomistic simulations. The LJ interactions have been evaluated considering a cutoff rcut = 1.2 nm and switched from 1.0 nm. For the Coulomb interactions a cutoff of rcut = 1.2 nm has been employed; instead, the long-ranged electrostatic interactions have been treated using the Particle Mesh Ewald method.58,59 All bonds involving hydrogen atoms have been constrained using the LINCS algorithm.60 A time step of 2 fs has been used for all atomistic simulations. The temperature has been kept constant using Nose−Hoover thermostat with a time coupling of 1 ps. The pressure has been controlled by a Parrinello−Rhaman barostat with a pressure coupling of τP = 1.0 ps for all atomistic systems. 2.3. Molecular Dynamic Simulations. MD simulations have been performed in two different ensembles, NPT and NπT. To this purpose a semi-isotropic and surface tension pressure coupling have been used. For the NPT ensemble a lateral pressure (on XY plane) of −30 bar has been used for the

Figure 2. Electron density profiles calculated for the monolayer systems (V and VI of Table 1) at 295 K for (A) MARTINI CG model and (B) all atom CHARMM models.53,55,56 Distributions of Cend correspond to the last C bead type of each tail of the two present in a molecule of DPPC, while the Ctot‑end distribution is calculated by the difference between the distribution of all C type minus the Cend distribution. For both profiles, atomistic and CG, an average over the last 5 ns and between each layer of the system (see Figure 1) has been computed.

monolayer systems; instead, for the bilayer system a lateral pressure of 1 bar has been used for all simulated systems. The normal pressure component with respect to the lipid bilayer (Z direction) has been kept constant at 1 bar for all simulations. All other extra-diagonal terms of the pressure tensor have been set to 0 bar. For the NπP simulations of monolayer systems, the surface pressure π = 30 mN/m has been kept constant. The surface pressure π is defined as π = γ0 − γ (1) where γ0 is the surface tension of the pure water at a given temperature61 and γ is the surface tension of the DPPC monolayer. The average surface tension γ(t) is calculated from the difference between the normal and the lateral pressure of the bilayer. The coupling constant for the Berendsen barostat has been set to τP = 1.0 ps for the monolayer and τP = 1.5 ps for C


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Figure 3. Percentage area increase calculated at different TX-100/DPPC ratios and temperatures. On top of the plot are reported, for a temperature of 298 K, the snapshots of DPPC monolayer systems in the presence of TX-100 along the normal and in-plane directions. TX-100 molecules are reported in blue, while the head of DPPC is reported in light green and the hydrophobic tails of DPPC molecule in dark green. The water along the normal of the bilayer is reported in light cyan. Experimental data16 (open black triangle) are referred to a temperature of 295 K. The black line represents the linear fit of experimental data, while the purple open diamond is referred to the area increment calculated from atomistic simulation.

the bilayer systems. The compressibility of the system has been set at 5 × 10−6 bar−1 for the monolayer43 and 3 × 10−5 bar−1 for the bilayer systems.37 The pure DPPC/water monolayer has been prepared packing two monolayers (625 lipids for layer) placed so that their head groups were initially separated by 10 nm of CG water molecules (34 400 CG beads) and their tail groups were separated by 12 nm of empty space. The final system was contained in a box of size 20.0 × 20.0 × 28.0 nm, corresponding to an initial area/molecule of 0.64 nm2. In Figure 1 is reported a snapshot of the initial configuration of the DPPC monolayer. Smaller systems have been prepared to perform atomistic simulations. In particular, a pure DPPC monolayer for the atomistic simulation has been prepared by packing two monolayers (34 DPPC molecules/layer), in a similar way described for the CG model, placed so that their head groups were separated by a layer of water molecules of 4 nm (2517 water molecules) and their tails were separated by 12 nm of empty space. The final

Figure 4. Calculated area/TX-100 in DPPC monolayer as a function of TX-100 content. The black diamond represents the experimental value.65 The last 10 ns of simulations have been considered for the calculation of the area/Triton.

Table 2. Compositions for the Bilayer Systems systema

no. of particles

no. of DPPC

no. of W

no. of TX-100

TX-100/DPPC

VII VIII IX X XI XII XIII XIV

66 600 67 104 67 580 68 084 68 560 274 912 1566 17 247

1250 1250 1250 1250 1250 5000 68 68

51 600 51 600 51 600 51 600 51 600 206 400 630 2517

0 36 70 106 152 608 8 8

0.000 0.029 0.056 0.085 0.122 0.122 0.122 0.122

box (nm) 20 20 20 20 20 40 4.56 4.56

× × × × × × × ×

20 × 20 20 × 20 20 × 20 20 × 20 20 × 20 40 × 20 4.54 × 6.8 4.54 × 6.8

time (ns) 1000 1000 1000 1000 1000 1000 20 20

a

The systems from VI to XI have been simulated at three temperatures (295, 298, and 323 K). Systems XII and XIII have been simulated at a temperature of 295 K. D


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Figure 5. Electron density profile calculated for the pure DPPC bilayer in the presence of TX-100 (χ = 0.122) at 295 K for (A) CG model and (B) full atomistic CHARMM models. (C) Snapshots of atomistic and CG bilayer systems. In cyan are reported the water molecules. In dark blue have been reported the TX-100 molecules. An average over the last 5 ns of simulation for CG and atomistic simulations has been considered.

Figure 7. Time evolution of the system at χ = 0.122 at a temperature of 323 K. In blue are reported the TX-100 molecules, while in red are reported the DPPC molecules.

system was contained in a box of 4.56 × 4.54 × 18.0 nm. According to the composition of systems reported in Table 1, a number of TX-100 molecules have been randomly inserted in both DPPC pure monolayers (CG and atomistic). In a similar way we prepared the bilayer systems. In particular, a bilayer composed by 625 DPPC molecules for the layer has been solvated by 51 600 CG water in a cubic box with a side length of 20 nm. To the initial DPPC bilayer, in which the area/ molecule is 0.64 nm2, a number of Triton molecules have been randomly inserted. The composition and setup of the systems are reported in Table 1. The initial configurations of both monolayer and bilayer have been prepared using the Packmol code.62

3. RESULTS AND DISCUSSION It is known from the literature that the MARTINI force field is able to reproduce, with reasonable agreement with the respect to experimental data, the correct area/lipid of phospholipids. In particular, pure DPPC bilayers37 and monolayers43,44 models have been tested and validated. As reported by Duncan,43 MARTINI CG lipid model gives predictions that are very close to those of atomistic simulations, and much more variation, due to the different experimental techniques employed,20 among experimental isotherms is found than between isotherms obtained from CG and atomistic simulations. In fact, the experimental range of area/lipid in monolayer, at a surface pressure of

Figure 6. Comparison of percentage area increment calculated for both mono- and bilayer at (A) 295, (B) 298, and (C) 323 K. For the bilayer systems an NPT ensemble with a semi-isotropic pressure coupling in which along the normal and lateral directions of bilayer the pressure has been kept constant at a value of 1.0 bar. E


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Figure 8. (A) View along the normal of the bilayer for the pure DPPC and those in the presence of TX-100 at a temperature of 323 K. In red are reported the polar heads of phospholipids. In light green are reported the hydrophobic chains of the lipid bilayer, while in blue are represented the TX-100 molecules. In order to show the distribution of Triton chains in the bilayer, the water bulk phase has been illustrated as a continuous transparent region. (B) Snapshot of the normal view of the bilayer illustrating the two curvatures (positive and negative) induced by the Triton molecule. In the snapshot the whole lipid bilayer is reported in gray, while the TX-100 molecules are reported in light gray.

π = 30 mN/m, goes from 0.40 to 0.54 nm2, while the range including the atomistic and CG simulations is restricted to 0.52−0.58 nm2. In Figure S1 of the Supporting Information the experimental and simulated isotherms at three different temperatures are reported. It is important to underline that at the surface pressure π = 30 mN/m the behavior of the monolayer can be approximated to that of bilayer, as reported in the literature.16,28,63 Furthermore, as evidenced by Duncan43 for pure DPPC, CG and atomistic models give closer results with respect to experimental measurements at surface pressure around π = 30 mN/m. Considering the computational advantages of CG models and their capability to have access to larger time and length scales, they are a reasonable choice, once they have been validated, to study more complex systems. According to the setup described by Duncan,43 we performed MD simulations using CG MARTINI models to study pure DPPC mono- and bilayers in the presence of TX-100. The composition of each system is reported in Table 1. 3.1. Pure DPPC Monolayer in the Presence of TX-100. In order to compare the properties of the pure DPPC monolayer in the presence of TX-100 with respect to experiments, we fixed for our systems the temperature, TX-100/ DPPC molecular ratio (indicated in the following as χ = NTX‑100/NDPPC), and surface pressure π = 30 mN/m as in the experimental measurements reported by Slotte.64 The setup of the CG simulations is summarized in Table 1. As a first validation we compared the electron density profiles obtained from atomistic and CG simulations. In Figure 2 the calculated profiles for the pure DPPC monolayer in the presence of TX-100 (χ = 0.122) have been reported. From the electron density profiles it can be seen that the CG model gives a structure of the pure DPPC monolayer in the presence of TX-100 very close to that obtained from the atomistic model. Moreover, the CG profile (Figure 2A) is smoother for polar head groups (NC3 and PO4), and the position of such peaks is almost comparable to the atomistic profile (Figure 2B). This behavior is similar, as expected, to that reported by Marrink for the pure DPPC system.37 The thickness of the monolayer,

calculated as the peak−peak distance between the PO4 and the Cend types, for the CG and atomistic models is comparable. Only a slightly difference of +0.2 nm has been found for the atomistic model with the respect to CG model. Slotte et al.,16 reported the area increase of pure DPPC monolayer in the presence of TX-100, experimentally measured by keeping an external surface of π = 30 mN/m. To compare the area increment obtained from CG model, we chose setup systems having a box size 5 times larger (systems I−IV, Table 1) than the smaller one used for the comparison of density profile. The percentage increment of the area is calculated considering the area difference between DPPC in the presence of TX-100 monolayer and that of pure DPPC monolayer. In Figure 3 the percentage area increment calculated for the CG systems, at different temperature and TX-100 content, is reported. In addition, for a temperature of 295 K, the CG and atomistic area increments are compared with the experimental one. As can be seen from Figure 3, similarly to the experimental behavior,16 the percentage area increase obtained from CG simulations is linearly dependent on the TX-100 content. In particular, for low TX-100 concentration, the CG model shows a slight positive deviation with respect to the experiments.16 On the contrary, in the region at high TX-100 content there is a slight negative deviation of percentage area increase. Moreover, the CG simulations at different temperatures give comparable area increases. It is worth nothing that although GC and atomistic models give close results in terms of structures, the latter overestimate the area increment. In particular, at χ = 0.122 the area increment of the atomistic model (see purple open diamond in Figure 3) is about 1.3 times the experimental value, while the CG model, at the same TX-100 content, gives closer agreement with experiments (area increment is 0.9 times the experimental value). This difference depends on two concomitant effects. First, the length scale of TX-100 domains we found in the large CG systems is larger than the atomistic system size. According to this the TX-100 aggregation in the atomistic simulations is F


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Figure 9. 2D plot of the height deviation from the lipid bilayer center of mass calculated separately for the upper and lower layer for the whole bilayer for DPPC and TX-100 molecules. Only for 2D plots of TX-100, white field regions have the meaning of the absence of TX-100 molecules. (A) DPPC bilayer in the presence of TX-100 having a composition of χ = 0.122. In the last right column are reported snapshots of the bilayer plane corresponding to each layer. In blue are reported the TX-100 molecules, while in red and green are reported the polar head and hydrophobic chains of the DPPC molecule. (B) DPPC bilayer in the presence of TX-100 bilayer with a ratio χ = 0.03. (C) Pure DPPC bilayer. In the right side of C is schematized a bilayer illustrating the upper and lower layer and the height (h = 0) of the bilayer center of mass. The temperature for all systems has been kept constant at 323 K.

Analyzing the lateral organization of TX-100 in the pure DPPC monolayer, a behavior depending on TX-100 content has been found. In particular, at high TX-100/DPPC ratio, starting from χ = 0.056, the formation of small domains reach of TX-100 has been found, while at low concentration the TX-100 molecules are arranged randomly and do not show relevant aggregation (snapshots in Figure 3). In addition to percentage area increase, we can also compare the area/TX-100 with respect to experiments. The comparison between simulations and experimental data65 is reported in Figure 4. As can be seen from the figure, the area/TX-100 of both atomistic (0.55 nm2) and experiment65 (0.54 nm2) is well reproduced within an error of about 3%, by CG model.

different. Second, the undulations of the layer observed in the large CG systems have wavelengths on the same order of the small atomistic system. This effect will be more clear and evident in the following when the behavior of the bilayer will be considered. To evaluate how the finite size effect contributes to the overestimation of area, a CG simulation of a system having the same size of the atomistic one (see Table 1, systems V and VI) has been performed. For this simulation the area overestimation, with ,respect to the experiments, of about 1.1 times is observed. Also in the case of the CG model, the small system gives an overestimation of the area increment, while the larger system, at same conditions, gives a result closer to the experimental one. G


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The Journal of Physical Chemistry B 3.2. Pure DPPC Bilayer in the Presence of TX-100. Adopting the same scheme used for the validation of DPPC monolayer in the presence of TX-100, also for the DPPC bilayer we compared, first, the electron density profiles calculated from CG and atomistic simulations (systems XIII and XIV, Table 2). In Figure 5 the density profiles, calculated from both models, are reported. As can be seen from the profiles, the TX-100 is equally distributed on each layer. Moreover, the peaks corresponding to the PO4 group, used to calculate the bilayer thickness, are separated by about 4.1 nm for the CG, while 3.8 nm is obtained for the atomistic, whereas the distributions of alkyl carbon tails are quite similar for both systems. However, the electron density profile calculated from the CG model shows fair agreement with respect to the more detailed atomistic one. To the best of our knowledge, in the absence of experimental data of the area increase in the DPPC bilayer in the presence of TX-100 we can use the results obtained from the monolayer as good reference to be compared with those of the bilayer. This assumption is justified by the fact that in specific experimental condition of external surface pressure (π = 30 mN/m) the behavior of the monolayer can be approximated to that of the bilayer.16,28,63 To this aim we prepared four different systems for the DPPC bilayer with the same setup adopted for the monolayer (systems VIII and XII, Table 2). In Figure 6 the comparison of percentage area increment between mono- and DPPC bilayer with the presence of TX-100 is reported. The area increment of systems with the presence of TX-100 has been calculated with the respect to the equilibrium area of the pure mono- or bilayer, respectively. As can be seen from the Figure 6, for all compositions and temperatures simulated, the percentage area increment for mono- and bilayer is almost comparable. A deviation of about 2%, observed at 295 K with a χ = 0.122, appears to be the biggest one. Similarly to the behavior found for the monolayer, also for the bilayer systems the atomistic model overestimates the percentage area increase. The main reason arises from the small size of atomistic simulations. In addition, for the bilayer systems, the dimension of TX-100 aggregates and the amplitude of bilayer undulation in the presence of TX-100 is much more evident (snapshots of Figures 7 and 8A). Moreover, from simulations of pure DPPC bilayer in the presence of TX-100 we found a value of area/TX-100 of 0.58 ± 0.04 nm2, similar to the experimental value of 0.54 nm2 reported by Schott for pure DPPC monolayer in the presence of TX-100.65 Once the TX-100 CG model has been validated with respect to both experiments and atomistic simulations, attention can be focused on the perturbation of lipid bilayer structure due the presence of TX-100. Similarly to the behavior observed for pure DPPC monolayer in the presence of TX-100, also the bilayer simulations show a lateral phase separation of TX-100 inside the bilayer. In particular, starting from χ = 0.056, clusters formation of TX-100 molecules are observed in the lipid bilayer (snapshots corresponding to equilibrium configurations of phase separated systems at χ going from 0.03 to 0.08 are shown in the Supporting Information). In Figure 7 snapshots showing the plane of pure DPPC bilayer in which the phase separation of TX-100 molecules takes place are reported. Starting from 100 ns, the domains formation reach of TX-100 is observed and the size of these domains is not changing from 300 ns to 1 μs. Going from a TX-100 content of χ = 0.030−0.122, pronounced curved bilayer structures are obtained. Moreover, we observed that the TX-100 molecules

are mainly localized in spatial regions of the DPPC bilayer corresponding to higher curvature, with respect to a flatter surface in the absence of TX-100, as reported in Figure 8A. It is worth noting that we observe no undulation in smaller bilayer systems, atomistic or CG, because their size is too small with respect to the wavelength of the undulation (about 9 nm), while for the larger CG systems undulations are observed. We computed the distribution of the height deviation, calculated as the difference between the bilayer center of mass and that of each single molecule, for DPPC and TX-100 in both layers, upper and lower. In Figure 9A and 9B 2D plots of such distributions and snapshots of each layer, including the TX-100 positions (in blue), have been reported. As can be seen from the Figure 9, the higher the content of TX-100, the larger is the height deviation of molecules from the center of mass of bilayer. In Figure 9C the 2D plots of pure DPPC bilayer, having a natural undulation, have been reported for the sake of comparison with respect to a bilayer with TX-100. Furthermore, comparing the upper and lower layers of Figure 9A, it is clear that when in the upper layer a TX-100 domain is present; the corresponding region of the lower layer is poor of TX-100 and vice versa. This behavior, as schematized in Figure 10, is related to the curvature induced by TX-100 molecules when they are present

Figure 10. Scheme representing the packing of Triton TX-100 molecules in both cases in a positive curved bilayer and in a negative curved bilayer. Each molecule type, TX-100 in the equilibrium conformation, DPPC molecule, and TX-100 in a stretched conformation, are reported on the right of the scheme.

at high concentration. In particular, in order to keep the conformational freedom of hydrophilic chains, as depicted in Figure 10, TX-100 molecules induce a positive curvature in the bilayer. Correspondingly, the region below the water bilayer interface has a negative curvature not compatible with the presence of TX-100 molecules, because they would have H


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Figure 11. ⟨P2⟩ order parameter calculated for consecutive bonds are reported for pure DPPC and those in the presence of TX-100 at a temperature of (A) 295, (B) 298, and (C) 323 K. Data are averaged over both tails and over time. (D) ⟨P2⟩ order parameter calculated on the whole DPPC molecule with respect to the bilayer normal direction at different temperatures.

The brackets denote an average, for each configuration, over all DPPC lipids forming the bilayer and over time. We compared for the pure DPPC bilayer and that of DPPC in the presence of TX-100 the ⟨P2⟩ calculated on the whole DPPC molecule and that calculated over consecutive bonds of alkyl chains (Figure 11). As can be seen from the figure, a decrease of ⟨P2⟩ as the TX-100 content increases has been observed for all considered temperatures (Figure 11D). This result is in agreement with the experimental observations.71,72 In fact, Goni,72 using 2H NMR spectroscopy, reported a decrease of the order parameter for a monocomponent lipid bilayer of phosphatidylcholine (PC) when the TX-100 is inserted. Other experimental evidence of the effect of Triton on the lipid order has been reported by Lasch,71 in which in a pure egg-PC and mixed egg-PC/Octylgl ß-D-Glucopyranoside (OG) lipid bilayer a lower packing in the lipid fatty acid chains, caused by Triton TX-100 presence, is observed. Furthermore, on analyzing the order parameter of consecutive bonds we can understand, with more detail, which part of the bilayer is mainly perturbed by TX-100 presence (Figures 11A−C). As results from Figure 11, the portion of alkyl tails of the DPPC bilayer is mainly perturbed, while only a small perturbation is observed for the polar head groups. In the Supporting Information tables of the ⟨P2⟩ parameter calculated at three different temperatures plus the radial distribution functions calculated for polar and aliphatic chains of DPPC lipid are reported. As additional analysis, in order to correlate the reduction of the order parameter as a function of TX-100 domains, we compared the 2D contour plot of ⟨P2⟩ calculated over a grid (12 × 12) according to the position in the xy plane as a function of TX-100 content. We observe, also in this case,

stretched to avoid chains superpositions. It is known that the Triton forms, in water solution, micelles having high curvature.49,66,67 Cylindrical-shaped molecules, like phospholipids, are defined as curvophobic because they tend to selfassemble along flatter surfaces having a small curvature.68 The bilayer system under investigation can be considered a mixture of curvophobic (lipids) and curvophilic (TX-100) molecules. Regions of bilayer rich of TX-100 spontaneously assume a positive curvature (Figure 10). The curvature effects we found on the bilayer are consistent with previous hypotheses reported by Andelman69 and Lichtenberg68 about the solubilization process of biomembranes by TX-100. In particular, the positive curvature of the surfactant in lipid bilayer was supposed to be an important step in the first of the three-stage model,70 one of the most accepted models describing the solubilization process of biomembranes.68 As described by Lichtenberg,68 in the initial step the bilayer curvature is supposed to be altered by the presence of surfactants. Then, by increasing the surfactant concentration, the curved bilayer with surfactant inserted in starts to be disrupted by the formation of mixed lipid/surfactant micelles until the whole lipid bilayer is completely dissolved. In addition to analysis of bilayer distortions, we analyzed how the orientation order parameter ⟨P2⟩ is perturbed by the TX-100 molecules. The definition of the ⟨P2⟩ based on the average of the second Legendre polynomial is ⟨P2(cos θ )⟩ =

3 cos2 θ − 1 2

(2)

where θ is the angle between the molecular vector (considered from NC3 and the last C1 beads of lipid chain, see Scheme 1) with the respect to the normal direction of the lipid layer. I


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derive a scaling factor for the time.73 One possible way to quantify the effective time sampled, and hence the different dynamics in simulations, is to calculate the ratio of the diffusion coefficients between CG and atomistic models. In our specific case it would be useful to estimate the scaling factor relative to lateral diffusion. For the pure DPPC bilayer in the presence of TX-100 (χ = 0.122), the ratio between lateral diffusion coefficients of CG/atomistic has been found to be 10 for the DPPC and 5 for TX-100 molecules (a table containing lateral diffusion coefficients calculated by atomistic and CG models at different composition is reported in the Supporting Information). These values are slightly larger than that reported by Marrink33,37 (a factor of 4 for lateral diffusion of pure DPPC bilayers).

4. CONCLUSIONS We provided a direct validation of the MARTINI force field for pure DPPC monolayer in the presence of TX-100 at the water/ air interface. In particular, the experimental behavior of the percentage area increase is reproduced in good agreement by the CG model. Moreover, we confirm, as emerges from the literature, that the behaviors of pure DPPC mono- and bilayers in the presence of TX-100 are similar, and we found for both a good agreement in the reproduction of the area/Triton with respect to experiments. Furthermore, the structure of a monoand bilayer of DPPC containing TX-100, at vacuum and water interfaces, has been validated by comparison of the electron density profile between CG and more detailed atomistic simulations. Application of the validated CG model revealed a phase separation of TX-100 in the DPPC bilayer. In phase-separated TX-100 domains an increase of the natural curvature of the lipid bilayer has been observed, in agreement with mechanisms proposed in the literature for biomembranes solubilization process. On the basis of our results and considering the versatility and the time and length scales accessible to the MARTINI CG models, we can conclude that e MARTINI TX-100 model can be extended to study complex biological mechanisms such as integral transmembrane proteins extraction and isolation, protein activation, and liposomes solubilization.

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Figure 12. 2D contour plot of the ⟨P2⟩ order parameter calculated including both DPPC and TX-100 molecules. (A) System with χ = 0.122. (B) System with χ = 0.03. For each contour plot a snapshot of the corresponding plane, upper of lower, has been reported. In blue are reported the TX-100 molecules, while in red and green are reported the polar head and hydrophobic chains of the DPPC molecule.

ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jpcb.6b00646. Experimental and simulated isotherms; pressure conditions for all simulated monolayer systems; additional behavior of percentage increase of area in mixed monolayer systems; additional density profiles of mono- and bilayers; values of diffusion coefficient computed for all bilayer systems; numerical values of the order parameter corresponding to Figure 11; additional snapshots of the equilibrium configuration of mixed Triton/DPPC bilayer; radial distribution functions calculated for pure DPPC bilayer and in the presence of TX-100 (PDF)

that regions reach of TX-100 have lower order parameter. In particular, lower values of ⟨P2⟩, from 0.35 to 0.55, are observed in TX-100 domains, while in the TX-100-poor regions the ⟨P2⟩ is systematically higher, from 0.63 to 0.88, as can be seen in Figure 12. Instead, the system having a lower TX-100 content (χ = 0.03) shows a more homogeneous distribution of the order parameter, and only small portions of the bilayer are perturbed by the TX-100 presence. It is known that the dynamics of coarse-grained models is faster than the corresponding atomistic ones. This is mainly due to the smoother energy landscapes as a result of the larger particle size. In order to connect the dynamic properties calculated from CG with atomistic models, it is essential to

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest. J


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ACKNOWLEDGMENTS A.D.N. thanks the HPC team of CINECA (http://hpc.cineca. it) for using GALILEO and FERMI HPC facilities (Project Is36_TLPM).

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