COSMO Mechanistic Prediction of Passive Membrane Permeability for Neutral Compounds and Ions and Its pH Dependence.

We present a new and entirely mechanistic COSMO method to predict passive membrane permeabilities for neutral compounds, as well as anions and cations. The COSMO approach is based on compound-specific free energy profiles within a membrane of interest from COSMO-RS (conductor-like screening model for realistic solvation) calculations. These are combined with membrane layer-specific diffusion coefficients, for example, in the water phase, the polar head groups, and the alkyl tails of biochemical phospholipid bilayers. COSMO-RS utilizes first-principle quantum chemical structures and physically sound intermolecular interactions (electrostatic, hydrogen bond, and van der Waals). For this reason, it is unbiased toward different application scenarios, such as in cosmetics and industrial chemical or pharmaceutical industries. A fully predictive calculation of passive permeation through phospholipid bilayer membranes results in a performance of = 0.92; rmsd = 0.90 log units for neutral compounds and anions, as compared to gold standard black lipid membrane experiments. It will be demonstrated that new membrane types can be generated by the related COSMO method and directly used for permeability studies by COSMO.