Passive Transport across Cell Membranes beyond the Overton Rule: Insights from Solute Exchange in Vesicles and Molecular Dynamics of Atropisomers

• DOI: 10.1021/acsami.4c22459
• Publication Date: 2025-04-10T23:34:36Z
• Authors: Margarida M. Cord...; Alexandre C. Oliv...; Paulo E. Abreu; Luis G. Arnaut; Maria João Moreno; Luís M. S. Loura
• Keywords: Atropisomer

Bioavailability of a drug is critically dependent on its cell membrane permeability. Empirical rules guiding design consolidated the dogma that large molecules cannot cross membranes by passive diffusion. However, more amphiphilic atropisomers redaporfin, an 1135 Da bacteriochlorin photosensitizer used in photodynamic therapy, exhibited fast uptake and high activity vitro. This motivated detailed studies redaporfin their interactions with models. Experimental affinity, permeation rates, exchange dynamics were complemented molecular simulations, to reveal nature between lipid bilayers, orientation location membrane-bound atropisomers, free energy profiles, mechanisms governing permeation. Our results indicate asymmetric distribution meso-phenyl sulfonamide groups (atropisomer α4) generates moment. enhances affinity positions ring deeper membrane. these strong result slow α4 membranes, restricting complex, membrane-rich environments. In contrast, symmetrical atropisomer αβαβ exhibits approximately 10-fold lower localizes closer membrane-water interface. weaker interaction facilitates rapid occurring within minutes at 37 °C. Molecular simulations relatively low barriers for translocation, consistent experimentally estimated translocation. Distinct observed two providing insights into differential behavior transport. particular, properly described bind-flip mechanism, where first approach bilayer "binding" mode, then molecule "flips" place macrocycle internal position. show how amphiphilicity conformation flexibility are critical determinants cellular internalization molecules.