Permeability of drugs and hormones through a lipid bilayer: insights from dual-resolution molecular dynamics†

The unassisted permeation process of β-blocker drugs (alprenolol, atenolol, pindolol) and steroid hormones (progesterone, testosterone) through a lipid membrane is simulated by a novel dual-resolution molecular dynamics approach. The lipid and water molecules are described by simple and efficient coarse-grain models, whereas the drug and hormone permeants are represented by traditional atomistic models. Our hybrid method is about two orders of magnitude faster than standard atomic-level counterparts. For each permeant, we calculate the transfer free energy as a function of depth inside the bilayer; these data indicate the location across the membrane where the solutes preferentially partition. Using the free energy profiles, we develop a simple expression that proves remarkably accurate in predicting experimental permeability rankings; the proposed permeation model highlights and addresses potentially problematic aspects of the standard solubility-diffusion theory. We also calculate the diffusion coefficients of the permeants, and track their lateral motion to study their diffusive patterns. Furthermore, we show the drugs' perturbing effect on the bilayer structure and quantify the steroids' preferred orientations. The results obtained compare favourably with experimental measurements and traditional atomic-level simulation data reported in the literature. Promising potential applications of our methodology to areas such as drug design and membrane-protein modelling are discussed.