Atomistic Simulation of Solubilization of Polycyclic Aromatic Hydrocarbons in a Sodium Dodecyl Sulfate Micelle.

Solubilization of two polycyclic aromatic hydrocarbons (PAHs), naphthalene (NAP, 2-benzene-ring PAH) and pyrene (PYR, 4-benzene-ring PAH), into a sodium dodecyl sulfate (SDS) micelle was studied through all-atom molecular dynamics (MD) simulations. We find that NAP as well as PYR could move between the micelle shell and core regions, contributing to their distribution in both regions of the micelle at any PAH concentration. Moreover, both NAP and PYR prefer to stay in the micelle shell region, which may arise from the greater volume of the micelle shell, the formation of hydrogen bonds between NAP and water, and the larger molecular volume of PYR. The PAHs are able to form occasional clusters (from dimer to octamer) inside the micelle during the simulation time depending on the PAH concentration in the solubilization systems. Furthermore, the micelle properties (i.e., size, shape, micelle internal structure, alkyl chain conformation and orientation, and micelle internal dynamics) are found to be nearly unaffected by the solubilized PAHs, which is irrespective of the properties and concentrations of PAHs.

On the Structural and Dynamical Properties of DOPC Reverse Micelles.

The structure and dynamics of phospholipid reverse micelles are studied by molecular dynamics. We report all-atom unconstrained simulations of 1,2-dioleoyl-sn-phosphatidylcholine (DOPC) reverse micelles in benzene of increasing sizes, with water-to-surfactant number ratios ranging from W0 = 1 to 16. The aggregation number, i.e., the number of DOPC molecules per reverse micelle, is determined to fit experimental light-scattering measurements of the reverse micelle diameter. The simulated reverse micelles are found to be approximately spherical. Larger reverse micelles (W0 > 4) exhibit a layered structure with a water core and the hydration structure of DOPC phosphate head groups is similar to that found in phospholipid membranes. In contrast, the structure of smaller reverse micelles (W0 ≤ 4) cannot be described as a series of concentric layers successively containing water, surfactant head groups, and surfactant tails, and the head groups are only partly hydrated and frequently present in the core. The dynamics of water molecules within the phospholipid reverse micelles slow down as the reverse micelle size decreases, in agreement with prior studies on AOT and Igepal reverse micelles. However, the average water reorientation dynamics in DOPC reverse micelles is found to be much slower than in AOT and Igepal reverse micelles with the same W0 ratio. This is explained by the smaller water pool and by the stronger interactions between water and the charged head groups, as confirmed by the red-shift of the computed infrared line shape with decreasing W0.

Bindings of hMRP1 transmembrane peptides with dodecylphosphocholine and dodecyl-ß-d-maltoside micelles: a molecular dynamics simulation study.

In this paper, we describe molecular dynamics simulation results of the interactions between four peptides (mTM10, mTM16, TM17 and KTM17) with micelles of dodecylphosphocholine (DPC) and dodecyl-ß-d-maltoside (DDM). These peptides represent three transmembrane fragments (TM10, 16 and 17) from the MSD1 and MSD2 membrane-spanning domains of an ABC membrane protein (hMRP1), which play roles in the protein functions. The peptide-micelle complex structures, including the tryptophan accessibility and dynamics were compared to circular dichroism and fluorescence studies obtained in water, trifluoroethanol and with micelles. Our work provides additional results not directly accessible by experiments that give further support to the fact that these peptides adopt an interfacial conformation within the micelles. We also show that the peptides are more buried in DDM than in DPC, and consequently, that they have a larger surface exposure to water in DPC than in DDM. As noted previously by simulations and experiments we have also observed formation of cation-π bonds between the phosphocholine DPC headgroup and Trp peptide residue. Concerning the peptide secondary structures (SS), we find that in TFE their initial helical conformations are maintained during the simulation, whereas in water their initial SS are lost after few nanoseconds of simulation. An intermediate situation is observed with micelles, where the peptides remain partially folded and more structured in DDM than in DPC. Finally, our results show no sign of ß-strand structure formation as invoked by far-UV CD experiments even when three identical peptides are simulated either in water or with micelles.

Structural insights into the membrane receptor ShuA in DDM micelles and in a model of gram-negative bacteria outer membrane as seen by SAXS and MD simulations.

Successful crystallization of membrane proteins in detergent micelles depends on key factors such as conformational stability of the protein in micellar assemblies, the protein-detergent complex (PDC) monodispersity and favorable protein crystal contacts by suitable shielding of the protein hydrophobic surface by the detergent belt. With the aim of studying the influence of amphiphilic environment on membrane protein structure, stability and crystallizability, we combine molecular dynamics (MD) simulations with SEC-MALLS and SEC-SAXS (Size Exclusion Chromatography in line with Multi Angle Laser Light Scattering or Small Angle X-ray Scattering) experiments to describe the protein-detergent interactions that could help to rationalize PDC crystallization. In this context, we compare the protein-detergent interactions of ShuA from Shigella dysenteriae in n-Dodecyl-ß-D-Maltopyranoside (DDM) with ShuA inserted in a realistic model of gram-negative bacteria outer membrane (OM) containing a mixture of bacterial lipopolysaccharide and phospholipids. To evaluate the quality of the PDC models, we compute the corresponding SAXS curves from the MD trajectories and compare with the experimental ones. We show that computed SAXS curves obtained from the MD trajectories reproduce better the SAXS obtained from the SEC-SAXS experiments for ShuA surrounded by 268 DDM molecules. The MD results show that the DDM molecules form around ShuA a closed belt whose the hydrophobic thickness appears slightly smaller (~22 Å) than the hydrophobic transmembrane domain of the protein (24.6 Å) suggested by Orientations of Proteins in Membranes (OPM) database. The simulations also show that ShuA transmembrane domain is remarkably stable in all the systems except for the extracellular and periplasmic loops that exhibit larger movements due to specific molecular interactions with lipopolysaccharides (LPS). We finally point out that this detergent behavior may lead to the occlusion of the periplasmic hydrophilic surface and poor crystal contacts leading to difficulties in crystallization of ShuA in DDM.

Deciphering the Structure of the Gramicidin A Channel in the Presence of AOT Reverse Micelles in Pentane Using Molecular Dynamics Simulations.

Structural studies of proteins and, in particular, integral membrane proteins (IMPs) using solution NMR spectroscopy approaches are challenging due to not only their inherent structural complexities but also the fact that they need to be solubilized in biomimetic environments (such as micelles), which enhances the slow molecular reorientation. To deal with these difficulties and increase the effective rate of molecular reorientation, the encapsulation of IMPs in the aqueous core of the reverse micelle (RM) dissolved in a low-viscosity solvent has been proven to be a viable approach. However, the effect of the reverse micelle (RM) environment on the IMP structure and function is little known. To gain insight into these aspects, this article presents a series of atomistic unconstrained molecular dynamics (MD) of a model ion channel (gramicidin A, gA) with RMs formed with anionic surfactant diacyl chain bis(2-ethylhexyl) sodium succinate (AOT) in pentane at a water-to-surfactant molar ratio (W0) of 6. The simulations were carried out with different protocols and starting conditions for a total of 2.4 µs and were compared with other MDs used with the gA channel inserted in models of the SDS micelle or the DMPC membrane. We show here that in the presence of AOT RMs the gA dimer did not look like the "dumbbell-like" model anticipated by experiments, where the C-terminal parts of the gA are capped with two RMs and the rest of the dimer is protected from the oil solvent by the AOT acyl chains. In contrast, the MD simulations reveal that the AOT, Na+, and water formed two well-defined and elongated RMs attached to the C-terminal ends of the gA dimer, while the rest is in direct contact with the pentane. The initial ß6.3 secondary structure of the gA is well conserved and filled with 6-9 waters, as in SDS micelles or the DMPC membrane. Finally, the water movement inside the gA is strongly affected by the presence of RMs at each extremity, and no passage of water molecules through the gA channel is observed even after a long simulation period, whereas the opposite was found for gA in SDS and DMPC.

Water Librations in the Hydration Shell of Phospholipids.

The hydrophilic phosphate moiety in the headgroup of phospholipids forms strong hydrogen bonds with water molecules in the first hydration layer. Time-domain terahertz spectroscopy in a range from 100 to 1000 cm-1 reveals the influence of such interactions on rotations of water molecules. We determine librational absorption spectra of water nanopools in phospholipid reverse micelles for a range from w0 = 2 to 16 waters per phospholipid molecule. A pronounced absorption feature with maximum at 830 cm-1 is superimposed on a broad absorption band between 300 and 1000 cm-1. Molecular dynamics simulations of water in the reverse micelles suggest that the feature at 830 cm-1 arises from water molecules forming one or two strong hydrogen bonds with phosphate groups, while the broad component comes from bulk-like environments. This behavior is markedly different from water interacting with less polar surfaces.

Derivation of original RESP atomic partial charges for MD simulations of the LDAO surfactant with AMBER: applications to a model of micelle and a fragment of the lipid kinase PI4KA.

In this paper, we describe the derivation and the validation of original RESP atomic partial charges for the N, N-dimethyl-dodecylamine oxide (LDAO) surfactant. These charges, designed to be fully compatible with all the AMBER force fields, are at first tested against molecular dynamics simulations of pure LDAO micelles and with a fragment of the lipid kinase PIK4A (DI) modeled with the QUARK molecular modeling server. To model the micelle, we used two distinct AMBER force fields (i.e. Amber99SB and Lipid14) and a variety of starting conditions. We find that the micelle structural properties (such as the shape, size, the LDAO headgroup hydration, and alkyl chain conformation) slightly depend on the force field but not on the starting conditions and more importantly are in good agreement with experiments and previous simulations. We also show that the Lipid14 force field should be used instead of the Amber99SB one to better reproduce the C(sp3)C(sp3)C(sp3)C(sp3) conformation in the surfactant alkyl chain. Concerning the simulations with LDAO-DI protein, we carried out different runs at two NaCl concentrations (i.e. 0 and 300 mM) to mimic, in the latter case, the experimental conditions. We notice a small dependence of the simulation results with the LDAO parameters and the salt concentration. However, we find that in the simulations, three out of four tryptophans of the DI protein are not accessible to water in agreement with our fluorescence spectroscopy experiments reported in the paper.

Modeling the Self-Aggregation of Small AOT Reverse Micelles from First-Principles.

This Letter is the first attempt at studying the self-aggregation of AOT reverse micelles from first-principles. It focuses on predicting the aggregation number, the radius of gyration, and the hydrodynamic radius of a low water content reverse micelle by theoretical means. We show that molecular dynamics simulation in the µs time range combined with atomistic potentials is capable of reproducing and explaining, to a convenient degree, experimental results on the size and dimensions of reverse micelles of AOT of low water content, [H2O]/[AOT] ≈ 5.

Structure of Bolaamphiphile Sophorolipid Micelles Characterized with SAXS, SANS, and MD Simulations.

The micellar structure of sophorolipids, a glycolipid bolaamphiphile, is analyzed using a combination of small-angle X-ray scattering (SAXS), small-angle neutron scattering (SANS), and molecular dynamics (MD) simulations. Numerical modeling of SAXS curves shows that micellar morphology in the noncharged system (pH< 5) is made of prolate ellipsoids of revolution with core-shell morphology. Opposed to most surfactant systems, the hydrophilic shell has a nonhomogeneous distribution of matter: the shell thickness in the axial direction of the ellipsoid is found to be practically zero, while it measures about 12 Å at its cross-section, thus forming a "coffee bean"-like shape. The use of a contrast-matching SANS experiment shows that the hydrophobic component of sophorolipids is actually distributed in a narrow spheroidal region in the micellar core. These data seem to indicate a complex distribution of sophorolipids within the micelle, divided into at least three domains: a pure hydrophobic core, a hydrophilic shell, and a region of less defined composition in the axial direction of the ellipsoid. To account for these results, we make the hypothesis that sophorolipid molecules acquire various configurations within the micelle including bent and linear, crossing the micellar core. These results are confirmed by MD simulations which do show the presence of multiple sophorolipid configurations when passing from spherical to ellipsoidal aggregates. Finally, we also used Rb(+) and Sr(2+) counterions in combination with anomalous SAXS experiments to probe the distribution of the COO(-) group of sophorolipids upon small pH increase (5 < pH < 7), where repulsive intermicellar interactions become important. The poor ASAXS signal shows that the COO(-) groups are rather diffused in the broad hydrophilic shell rather than at the outer micellar/water interface.

Molecular Dynamics Simulations of a Characteristic DPC Micelle in Water.

We present the first comparative molecular dynamics investigation for a dodecylphosphocholine (DPC) micelle performed in condensed phase using the CHARMM36, GROMOS53A6, GROMOS54A7, and GROMOS53A6/Berger force fields and a set of parameters developed anew. Our potential consists of newly derived RESP atomic charges, which are associated with the Amber99SB force field developed for proteins. This new potential is expressly designed for simulations of peptides and transmembrane proteins in a micellar environment. To validate this new ensemble, molecular dynamics simulations of a DPC micelle composed of 54 monomers were carried out in explicit water using a "self-assembling" approach. Characteristic micellar properties such as aggregation kinetic, volume, size, shape, surface area, internal structure, surfactant conformation, and hydration were thoroughly examined and compared with experiments. Derived RESP charge values combined with parameters taken from Amber99SB reproduce reasonably well important structural properties and experimental data compared to the other tested force fields. However, the headgroup and alkyl chain conformations or the micelle hydration simulated with the Amber99SB force field display some differences. In particular, we show that Amber99SB slightly overestimates the trans population of the alkyl Csp(3)-Csp(3)-Csp(3)-Csp(3) dihedral angle (i.e., CCCC) and reduces the flexibility of the DPC alkyl chain. In agreement with experiments and previously published studies, the DPC micelle shows a slightly ellipsoidal shape with a radius of gyration of ∼17 Šfor the different potentials evaluated. The surface of contact between the DPC headgroup and water molecules represents between 70% and 80% of the total micelle surface independently of the force field considered. Finally, molecular dynamics simulations show that water molecules form various hydrogen-bond patterns with the surfactant headgroup, as noted previously for phospholipids with a phosphatidylcholine headgroup.

Molecular simulations of dodecyl-ß-maltoside micelles in water: influence of the headgroup conformation and force field parameters.

This paper deals with the development and validation of new potential parameter sets, based on the CHARMM36 and GLYCAM06 force fields, to simulate micelles of the two anomeric forms (α and ß) of N-dodecyl-ß-maltoside (C(12)G(2)), a surfactant widely used in the extraction and purification of membrane proteins. In this context, properties such as size, shape, internal structure, and hydration of the C(12)G(2) anomer micelles were thoroughly investigated by molecular dynamics simulations and the results compared with experiments. Additional simulations were also performed with the older CHARMM22 force field for carbohydrates (Kuttel, M.; et al. J. Comput. Chem. 2002, 23, 1236-1243). We find that our CHARMM and GLYCAM parameter sets yield similar results in the case of properties related to the micelle structure but differ for other properties such as the headgroup conformation or the micelle hydration. In agreement with experiments, our results show that for all model potentials the ß-C(12)G(2) micelles have a more pronounced ellipsoidal shape than those containing α anomers. The computed radius of gyration is 20.2 and 25.4 Å for the α- and ß-anomer micelles, respectively. Finally, we show that depending on the potential the water translational diffusion of the interfacial water is 7-11.5 times slower than that of bulk water due to the entrapment of the water in the micelle crevices. This retardation is independent of the headgroup in α- or ß-anomers.

Structure, stability, and hydration of a polypeptide in AOT reverse micelles.

In this communication, we provide theoretical evidence that the folded structure of a simple peptide, alanine zwitterionic octapeptide, or A8, unstable in solution, becomes stable in a reverse micelle (RM) of appropriate size. Our molecular dynamics simulations were carried out for realistic models of sodium 2-ethylhexylsulfosuccinate RM in isooctane, simulated for an extended period of time. For the RM of the smaller size, we find that a helical structure is stable for the whole length of the simulation. On the contrary, the peptide very quickly takes an extended structure in larger micelles.

Effect of surfactant conformation on the structures of small size nonionic reverse micelles: a molecular dynamics simulation study.

We used constant pressure (P=0.1 MPa) and temperature (T=298 K) molecular dynamics simulations to study the structures and dynamics of small size reverse micelles (RMs) with poly(ethylene glycol) alkyl ether (CmEn) surfactants. The water-to-surfactant molar ratio was 3, with decane as the apolar solvent. We focused on the effect of the two possible imposed conformations (trans vs gauche) for the surfactant headgroups on RMs structures and water dynamics. For this purpose, we built up two RMs, which only differ by their surfactant headgroup conformations. The results obtained for the two RMs were compared to what is known in the literature. Here, we show that the surfactant headgroup conformation affects mainly the water-related properties such as the water core size, the area per surfactant headgroup, the headgroup hydration, and the water core translational diffusion. The properties computed for the RM with the surfactant in trans conformation fit better with the experimental data than the gauche conformation. We further show that the surfactant hydrophilic headgroup plays a crucial role in the micellar structures, favors the entrapment of the micellar water, and reduces strongly their diffusion compared to the bulk water.