Do adsorbed drugs to P-glycoprotein influence its efflux capability?
The membrane biophysical aspects by which multidrug resistance (MDR) relates with ABC transporters function still remain largely unknown. Notwithstanding the central role that efflux pumps like P-glycoprotein have in MDR onset, experimental studies classified additionally the lipid micro-environment where P-gp is inserted as determinant for the increased efflux capability demonstrated in MDR cell lines. Recently, a nonlinear model for drug-membrane interactions showed that, upon drug adsorption, long-range mechanical alterations are predicted to affect the P-gp ATPase function at drug external concentrations of ~10-100 µM. However, our results also show that drug adsorption may also occur at P-gp nucleotide-binding domains where conformational changes driving efflux takes place. Thus, we assessed the effect of drug adsorption to both protein-water and lipid-water interfaces, by means of molecular dynamics simulations. The results show that free energies of adsorption are lower for modulators in both lipid/water and protein/water interfaces. Important differences in drug-protein interactions, protein dynamics and membrane biophysical characteristics were observed between the different classes. Therefore, we hypothesize that drug adsorption to the protein or lipid-water interface account for a complex network of events that affect the transporters' ability to efflux drugs.