The importance of membrane-water partition coefficients led to the recent extension of the conductor-like screening model for realistic solvation (COSMO-RS) to micelles and biomembranes termed COSMOmic. Compared to COSMO-RS, this new approach needs structural information to account for the anisotropy of colloidal systems. This information can be obtained from molecular dynamics (MD) simulations. In this work, we show that this combination of molecular methods can efficiently be used to predict partition coefficients with good agreement to experimental data and enables screening studies. However, there is a discrepancy between the amount of data generated by MD simulations and the structural information needed for COSMOmic. Therefore, a new scheme is presented to extract data from MD trajectories for COSMOmic calculations. In particular, we show how to calculate the system structure from MD, the influence of lipid conformers, the relation to the COSMOmic layer size, and the water/lipid ratio impact. For a 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) bilayer, 66 partition coefficients for various solutes were calculated. Further, 52 partition coefficients for a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayer system were calculated. All these calculations were compared to experimental data.

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Quantitative predictions of biomembrane/water partition coefficients are important, as they are a key property in pharmaceutical applications and toxicological studies. Molecular dynamics (MD) simulations are used to calculate free energy profiles for different solutes in lipid bilayers. How to calculate partition coefficients from these profiles is discussed in detail and different definitions of partition coefficients are compared. Importantly, it is shown that the calculated coefficients are in quantitative agreement with experimental results. Furthermore, we compare free energy profiles from MD simulations to profiles obtained by the recent method COSMOmic, which is an extension of the conductor-like screening model for realistic solvation to micelles and biomembranes. The free energy profiles from these molecular methods are in good agreement. Additionally, solute orientations calculated with MD and COSMOmic are compared and again a good agreement is found. Four different solutes are investigated in detail: 4-ethylphenol, propanol, 5-phenylvaleric acid, and dibenz[a,h]anthracene, whereby the latter belongs to the class of polycyclic aromatic hydrocarbons. The convergence of the free energy profiles from biased MD simulations is discussed and the results are shown to be comparable to equilibrium MD simulations. For 5-phenylvaleric acid the influence of the carboxyl group dihedral angle on free energy profiles is analyzed with MD simulations.

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.

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