Prediction of Passive Membrane Permeability and Translocation Pathways of Biologically Active Molecules

Abstract

Libraries of naturally-sourced compounds that serve as structural scaffolds in the search for new drug leads are constantly growing. A significant number of natural products with relatively high molecular weights have been shown to passively penetrate through membranes. Partitioning and permeability of the molecules depend on their conformation and orientation in membranes and on their interactions with lipids. We have developed a novel thermodynamics-based computational method for fast prediction of passive permeability of structurally diverse molecules across different membranes. The method operates with atomic 3D structures of molecules and represents anisotropic properties of the lipid bilayer by transbilayer profiles of dielectric and hydrogen-bonding capacity parameters. These profiles have been derived for several artificial and natural membranes from distributions of groups in lipids and membrane protein structures along the bilayer normal [1]. The optimal translocation pathway of a solute was defined by calculating the lowest energy rotational orientation and conformer of the molecule in every point of the transmembrane trajectory. The method calculates: (1) the equilibrium spatial arrangement and binding energy of the solute in membrane, including selective accumulation of amphiphilic compounds at the lipid-water interface; (2) free energy profile of the solute along the translocation pathway; and (3) the permeability coefficient. The results of calculations are consistent with published experimental binding affinities, spatial positions in membranes, and permeability data for small molecules and peptides with known three-dimensional structure. Testing on Caco-2 cell permeability data for ∼150 drug-like compounds allows parameterization of the method to reproduce membrane properties of the gut epithelium. [1] Pogozheva ID, Tristram-Nagle S, Mosberg HI, Lomize AL. Structural adaptations of proteins to different biological membranes. Biochim Biophys Acta. 2013; 1828: 2592-2608.