Fluoxetine Alters the Biophysics of DPPC and DPPG Bilayers through Phase-Dependent and Electrostatic Interactions.

Lipid membranes can control the permeability of a pharmaceutical drug, whereas the drug can induce changes in the structural and biophysical properties of the membranes. Understanding this interplay of drug-lipid membrane interactions can be of great importance in drug design. Here, we present a molecular dynamics study to provide insights into the interactions between the antidepressant fluoxetine and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) or 1,2-dipalmitoyl-sn-glycero-3-phosphoglycerol (DPPG) bilayers. It was found that, due to the electrostatic interaction, the headgroup of the zwitterionic DPPC lipid is more stable than that of the negatively charged DPPG lipid, allowing the gel phase to persist even at the elevated temperature. At 25 °C, fluoxetine cannot penetrate into the gel-phase DPPC bilayer, while the electrostatic interaction between positively charged fluoxetine and negatively charged DPPG bilayer retains the drug within the lipid headgroup domain. When the temperature is increased to 45 °C, both neutral and charged forms of fluoxetine can partition into the DPPC and DPPG bilayers spontaneously. Analysis of the biophysical and structural changes in both DPPC and DPPG bilayers in the presence of fluoxetine revealed a phase-dependent effect. The binding of fluoxetine to the lipid bilayers limits the movement and orientation of the drug. These findings shed light on the interactions between a commonly prescribed antidepressant and lipid membranes, and such information can be beneficial to the development of potential therapeutic agents.