Solubilization in mixed micelles studied by molecular dynamics simulations and COSMOmic.

Up to now, micelles composed of different surfactants (mixed micelles) are rarely studied with molecular methods. This is in contrast to their importance for pharmaceutical or industrial applications, where it is of great interest to predict the partition behavior for a large set of solutes (screening) within mixed micelles. This work is focused on molecular simulations of phase equilibria in mixed surfactant systems, because mixtures of different types of surfactants (nonionic or ionic) in aqueous solution can change the partition behavior of solutes tremendously. The extension of COSMO-RS for anisotropic phases, named COSMOmic, is computationally efficient and can be used as a screening tool for finding adequate surfactant systems for a specific extraction task. However, it needs micellar structures as an input. Therefore, molecular dynamics (MD) simulations of the self-assembly of pure Brij35 (polyethylene glycol dodecyl ether) and mixtures either with CTAB (cetyltrimethyl ammonium bromide) or SDS (sodium dodecyl sulfate) at different concentrations are performed. The micelles from the self-assembly MD simulations are used to predict the partition behavior of various solutes between micelle and bulk water with COSMOmic. In this way, various micelles of different size and composition are investigated and structural influences on partition equilibria of solute molecules like ephedrine, acetone, toluene, coumarin, isovanillin, ferulic acid, vanillic acid, syringic acid, and phenol are analyzed. For the first time, the self-assembly of pure Brij35 and the mixtures of Brij35/CTAB and Brij35/SDS is studied on an atomistic scale. Significant influences of atomic structure and composition of mixed micelles on partition equilibria are elucidated. The findings of this detailed analysis are in good agreement with experimental data and likely to improve the knowledge and understanding of mixed micellar extraction processes and can pave the way for more practical applications in the future.

Molecular dynamics simulation of SDS and CTAB micellization and prediction of partition equilibria with COSMOmic.

Molecular dynamics (MD) simulations of the self-assembly of different ionic surfactants have been performed in order to obtain representative micellar structures. Subsequently, these structures were used to predict the partition behavior of various solutes in these micelles with COSMOmic, an extension of COSMO-RS. This paper includes multiple self-assembled micelles of SDS (sodium dodecyl sulfate, anionic surfactant) and CTAB (cetyltrimethylammoniumbromide, cationic surfactant) at different concentrations. Micellar size, density profiles, and shape (eccentricity) have been investigated. However, the size strongly depends on the functional definition of a micelle. For this reason, we present a method based on the free monomer concentration in aqueous solution as an optimization criterion for the micelle definition. The combination of MD with COSMOmic has the benefit of combining detailed atomistic information from MD with fast calculations of COSMOmic. For the first time the influence of micelle structure on pratition equilibria, predicted with COSMOmic, were investigated. In case of SDS more than 4600 and for CTAB more than 800 single micelles have been studied. The predictions of the partition coefficients with COSMOmic are in good agreement with experimental data. Additionally, the most favorable locations of selected molecules in the micelles as well as probable energy barriers are determined even for complex solutes such as toluene, propanolol, ephedrine, acetone, phenol, lidocaine, syringic acid, coumarin, isovanillin, ferulic acid, and vanillic acid. This method can therefore be applied as a potential screening tool for solutes (e.g., drugs) to find the optimal solute-surfactant combination.

Prediction of micelle/water and liposome/water partition coefficients based on molecular dynamics simulations, COSMO-RS, and COSMOmic.

Liposomes and micelles find various applications as potential solubilizers in extraction processes or in drug delivery systems. Thermodynamic and transport processes governing the interactions of different kinds of solutes in liposomes or micelles can be analyzed regarding the free energy profiles of the solutes in the system. However, free energy profiles in heterogeneous systems such as micelles are experimentally almost not accessible. Therefore, the development of predictive methods is desirable. Molecular dynamics (MD) simulations reliably simulate the structure and dynamics of lipid membranes and micelles, whereas COSMO-RS accurately reproduces solvation free energies in different solvents. For the first time, free energy profiles in micellar systems, as well as mixed lipid bilayers, are investigated, taking advantage of both methods: MD simulations and COSMO-RS, referred to as COSMOmic (Klamt, A.; Huniar, U.; Spycher, S.; Keldenich, J. COSMOmic: A Mechanistic Approach to the Calculation of Membrane-Water Partition Coefficients and Internal Distributions within Membranes and Micelles. J. Phys. Chem. B 2008, 112, 12148-12157). All-atom molecular dynamics simulations of the system SDS/water and CTAB/water have been applied in order to retrieve representative micelle structures for further analysis with COSMOmic. For the system CTAB/water, different surfactant concentrations were considered, which results in different micelle sizes. Free energy profiles of more than 200 solutes were predicted and validated by means of experimental partition coefficients. To our knowledge, these are the first quantitative predictions of micelle/water partition coefficients, which are based on whole free energy profiles from molecular methods. Further, the partitioning in lipid bilayer systems containing different hydrophobic tail groups (DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine), SOPC (stearoyl-oleoylphosphatidylcholine), DMPC (1,2-dimyristoyl-sn-glycero-3-phosphocholine), and POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine)) as well as mixed bilayers was calculated. Experimental partition coefficients (log P) were reproduced with a root-mean-square error (RMSE) of 0.62. To determine the influence of cholesterol as an important component of cellular membranes, free energy profiles in the presence of cholesterol were calculated and shown to be in good agreement with experimental data.